- Email: [email protected]
Is additional neurohormonal antagonism useful in patients with severe chronic heart failure already receiving a combination of neurohormonal antagonists? Results of the Copernicus study
A.52
Selected abstracts Cardiology, May
from the XIVth 5-9,2002
World
Congress
Heart,
of
ultrasonograph. Statistical analyses between groups of mice were performed using ANOVA and the unpaired Student t-test after normalisation for differences in body weight. Results LM+/mice had significantly larger left ventricular enddiastolic (LVDD) and end-systolic (LVSD) diameters, reduced fractional shortening (LVFS) and larger left atria1 diameter (LA) when compared with LM+/mice and wildtype mice. LV wall thickness was similar between the three groups. Heart rates were lower in LM+/mice than in than LM+/mice and wildtype mice. There were no significant differences in echocardiographic parameters between LM+/mice and wildtype mice. Parameter Body weight LVDD (mm) LVSD (mm) LVFS (%) LA (mm)
LM+
Wildtype (g)
HR(bpm)
*Significant difference LM t mice.
17.38 2.93 1.11 62 1.51 681k
+ zi + ? *
2.76
0.24 0.14 3 0.05 84
(I’ < 0.001) compared
18.49 2.97 1.22 59 1.53
LM-/-
e 2.65
t 0.23 f 0.18 zk 5 f 0.03
68bk38
with wildtype
8.66 3.58 3.17 11 1.51 552
+ r + + + r
1.57*
0.23* 0.21’ 3* 0.06’ 83*
and with
Conclusion These data demonstrate that the absence of lamins A and C results in the development of severe DCM and suggest that congestive cardiac failure may be the cause of premature death in LM -/- mice. LMNA knockout mice will provide a useful model for studies of the pathogenesis of DCM. Key zuords: Cardiomyopathies, dilated, Genetics, Heart failure, Molecular biology Is additional neurohormonal antagonism useful in patients with severe chronic heart failure already receiving a combination of neurohormonal antagonists? Results of the Copernicus study Henrv Krumi, AJS Coats*, MB Fowler3, HA Katus4, I’ Mohasci5, J L Romeat@, M Tendera ‘Monash University, Australia; *Royal Brompton Hospital, London, United Kingdom; 3Stanford University Medical Center, Stanford, CA, United States; 4Universitaets-Klinkum Luebeck, Luebeck, Germany; 5University Hospital Bern, Bern, Switzerland; 6University Health Network and Mount Sinai Hospital, Toronto, Canada; 7Silesian School of Medicine, Kutowice, Poland Background The results of the Val-HeFT study suggested that broad based neurohormonal blockade may have deleterious effects in patients with heart failure (CHF), but this hypothesis has not been evaluated in other trials. Methods The 2289 patients with severe CHF in the COPERNICUS trial were randomized to placebo (PBO) or carvedilol (CRV), which were added to diuretics and an ACE inhibitor (? digitalis) for up to 29 months. Of these patients, 445 were also on spironolactone at baseline and thus received 3 neurohormonal antagonists if they were randomized to CRV. Compared with those not on spironolactone, patients on spironolactone had more advanced CHF at baseline, as reflected by a lower blood pressure and serum Na (both P < 0.001) but were similar in other baseline characteristics. Results Shown are l-year Kaplan-Meier rates and hazard ratios (CRVPBO) [Cox model]. CRV reduced the risk of a major clinical event in patients on spironolactone to an extent similar to that seen in patients not on spironolactone.
PBO (n = 225) All-cause mortality Death or hositalization for worsening CHF Death or cardiovascular hospitalization Death o’ any hospitalization
Spironolactone RCV (n = 220)
Hazard ratio
19.1%
11.4%
39.3%
26.3%
0.65 0.63
41.6%
29.1%
0.61
47.2%
38.4%
0.76
PBO (n = 908) All-cause mortality Death or hositalization for worsening CHF Death or cardiovascular hospitalization Death or any hospitalization
Lung
and Circulation
No Spironolactone CRV (n = 936)
2003; 12
Hazard ratio
18.4% 37.5%
11.3% 25.4%
0.70
41.6%
30.4%
0.75
53.3%
42.1%
0.76
0.65
Conclusion These data indicate that the morbidity and mortality of patients with severe CHF receiving drugs that interfere with more than one neurohormonal target can be reduced substantially with further neurohormonal antagonism (with CRV). Key words: Aldosterone, Beta-Adrenergic receptor blockers, Heart failure, treatment Platelet nitric oxide resistance in patients with congestive heart failure is ameliorated with ACE inhibition WY, Andrew S Holmes’, Jackie M Stepien’, Richard A Anderso$, Michael I’ Frenneatu?, Michael I’ Frenneaux*, John D Horowitz’ ‘Cardiology Unit, Queen Elizabeth Hospital, Australia; *Wales Heart Research Institute, United Kingdom Background ACE inhibitor (ACEi) therapy in patients with congestive heart failure (CHF) reduces incidence of acute myocardial infarction. Platelets from patients with stable and unstable angina pectoris are hypo-responsive to the antiaggregatory effects of nitric oxide (NO) donors, such as nitroglycerine and sodium nitroprusside (SNP), but no analogous data are available for CHF patients. We now investigated whether (1) platelets from CHF patients display ‘NO resistance’ and (2) platelet responsiveness to NO is affected by ACEi therapy with perindopril (Per). Methods ADP (1 umol/L)-induced platelet aggregation (impedance aggregometry in whole blood) and its inhibition by SNP (10 pmol/L) were compared in 18 CHF patients receiving ACEi, 35 normal subjects and 29 nonischaemic patients (NIP). Impact of 3 days’ treatment with Per on antiaggregatory and cGMP-elevating effects of SNP, and on whole blood O,- levels were examined in 10 CHF patients. Results Patients with CHF not treated with ACEi exhibited diminished platelet responsiveness to the antiaggregatory effect of SNP (36 f 6% inhibition of aggregation vs. 60 + 3% and 65 f 4% in normal subjects and NIP, respectively; P < 0.001) and increased 0, levels (20 + 4 mV vs. 8.5 f 1.0 mV in normals; P < 0.02). After short-term treatment with Per platelet response to SNP increased to 58 f 6% (P < 0.01); this was paralleled by an increase in the extent of intraplatelet cGMP elevation by SNP. O,- levels decreased to 16 * 2 mV (n.s.). Chronic ACEi therapy was associated with 63 f 6% inhibition of aggregation by SNP and O,levels of 10.8 f 1.5 mV (both n.s. vs. normal subjects and NIP). Conclusion Untreated CHF is associated with platelet resistance to NO which is ameliorated by acute and chronic ACEi therapy. These changes may contribute to the anti-ischaemic effects of ACEi therapy in CHE Key words: ACE inhibitor, Heart failure, treatment, Nitric oxide, Platelets Angiotensin Receptor Blockade is More Effective at Attenuating Remodeling than Endothelin Converting Enzyme Inhibition or Endothelin Receptor Antagonism Paul MartinI, Henry Krum’, Alicia Stein-Oakley* ‘Clinical Pharmacology, Departments Medicine, Epidemiology and Preventative Medicine, Monash University, Australia; =Alfred Hospital, Melbourne, Australia Background Blockade of the endothelin system using endothelin receptor antagonists (ETRA) attenuates pathological post myocardial infarction (MI) cardiac remodeling, however, endothelin converting enzyme inhibitors (ECEi) have only been studied short-term and no direct comparison has been made with angiotensin receptor blockade (ARB).
Selected abstracts Cardiology, May
from the XIVth 5-9,2002
World
Congress
Heart,
of
ultrasonograph. Statistical analyses between groups of mice were performed using ANOVA and the unpaired Student t-test after normalisation for differences in body weight. Results LM+/mice had significantly larger left ventricular enddiastolic (LVDD) and end-systolic (LVSD) diameters, reduced fractional shortening (LVFS) and larger left atria1 diameter (LA) when compared with LM+/mice and wildtype mice. LV wall thickness was similar between the three groups. Heart rates were lower in LM+/mice than in than LM+/mice and wildtype mice. There were no significant differences in echocardiographic parameters between LM+/mice and wildtype mice. Parameter Body weight LVDD (mm) LVSD (mm) LVFS (%) LA (mm)
LM+
Wildtype (g)
HR(bpm)
*Significant difference LM t mice.
17.38 2.93 1.11 62 1.51 681k
+ zi + ? *
2.76
0.24 0.14 3 0.05 84
(I’ < 0.001) compared
18.49 2.97 1.22 59 1.53
LM-/-
e 2.65
t 0.23 f 0.18 zk 5 f 0.03
68bk38
with wildtype
8.66 3.58 3.17 11 1.51 552
+ r + + + r
1.57*
0.23* 0.21’ 3* 0.06’ 83*
and with
Conclusion These data demonstrate that the absence of lamins A and C results in the development of severe DCM and suggest that congestive cardiac failure may be the cause of premature death in LM -/- mice. LMNA knockout mice will provide a useful model for studies of the pathogenesis of DCM. Key zuords: Cardiomyopathies, dilated, Genetics, Heart failure, Molecular biology Is additional neurohormonal antagonism useful in patients with severe chronic heart failure already receiving a combination of neurohormonal antagonists? Results of the Copernicus study Henrv Krumi, AJS Coats*, MB Fowler3, HA Katus4, I’ Mohasci5, J L Romeat@, M Tendera ‘Monash University, Australia; *Royal Brompton Hospital, London, United Kingdom; 3Stanford University Medical Center, Stanford, CA, United States; 4Universitaets-Klinkum Luebeck, Luebeck, Germany; 5University Hospital Bern, Bern, Switzerland; 6University Health Network and Mount Sinai Hospital, Toronto, Canada; 7Silesian School of Medicine, Kutowice, Poland Background The results of the Val-HeFT study suggested that broad based neurohormonal blockade may have deleterious effects in patients with heart failure (CHF), but this hypothesis has not been evaluated in other trials. Methods The 2289 patients with severe CHF in the COPERNICUS trial were randomized to placebo (PBO) or carvedilol (CRV), which were added to diuretics and an ACE inhibitor (? digitalis) for up to 29 months. Of these patients, 445 were also on spironolactone at baseline and thus received 3 neurohormonal antagonists if they were randomized to CRV. Compared with those not on spironolactone, patients on spironolactone had more advanced CHF at baseline, as reflected by a lower blood pressure and serum Na (both P < 0.001) but were similar in other baseline characteristics. Results Shown are l-year Kaplan-Meier rates and hazard ratios (CRVPBO) [Cox model]. CRV reduced the risk of a major clinical event in patients on spironolactone to an extent similar to that seen in patients not on spironolactone.
PBO (n = 225) All-cause mortality Death or hositalization for worsening CHF Death or cardiovascular hospitalization Death o’ any hospitalization
Spironolactone RCV (n = 220)
Hazard ratio
19.1%
11.4%
39.3%
26.3%
0.65 0.63
41.6%
29.1%
0.61
47.2%
38.4%
0.76
PBO (n = 908) All-cause mortality Death or hositalization for worsening CHF Death or cardiovascular hospitalization Death or any hospitalization
Lung
and Circulation
No Spironolactone CRV (n = 936)
2003; 12
Hazard ratio
18.4% 37.5%
11.3% 25.4%
0.70
41.6%
30.4%
0.75
53.3%
42.1%
0.76
0.65
Conclusion These data indicate that the morbidity and mortality of patients with severe CHF receiving drugs that interfere with more than one neurohormonal target can be reduced substantially with further neurohormonal antagonism (with CRV). Key words: Aldosterone, Beta-Adrenergic receptor blockers, Heart failure, treatment Platelet nitric oxide resistance in patients with congestive heart failure is ameliorated with ACE inhibition WY, Andrew S Holmes’, Jackie M Stepien’, Richard A Anderso$, Michael I’ Frenneatu?, Michael I’ Frenneaux*, John D Horowitz’ ‘Cardiology Unit, Queen Elizabeth Hospital, Australia; *Wales Heart Research Institute, United Kingdom Background ACE inhibitor (ACEi) therapy in patients with congestive heart failure (CHF) reduces incidence of acute myocardial infarction. Platelets from patients with stable and unstable angina pectoris are hypo-responsive to the antiaggregatory effects of nitric oxide (NO) donors, such as nitroglycerine and sodium nitroprusside (SNP), but no analogous data are available for CHF patients. We now investigated whether (1) platelets from CHF patients display ‘NO resistance’ and (2) platelet responsiveness to NO is affected by ACEi therapy with perindopril (Per). Methods ADP (1 umol/L)-induced platelet aggregation (impedance aggregometry in whole blood) and its inhibition by SNP (10 pmol/L) were compared in 18 CHF patients receiving ACEi, 35 normal subjects and 29 nonischaemic patients (NIP). Impact of 3 days’ treatment with Per on antiaggregatory and cGMP-elevating effects of SNP, and on whole blood O,- levels were examined in 10 CHF patients. Results Patients with CHF not treated with ACEi exhibited diminished platelet responsiveness to the antiaggregatory effect of SNP (36 f 6% inhibition of aggregation vs. 60 + 3% and 65 f 4% in normal subjects and NIP, respectively; P < 0.001) and increased 0, levels (20 + 4 mV vs. 8.5 f 1.0 mV in normals; P < 0.02). After short-term treatment with Per platelet response to SNP increased to 58 f 6% (P < 0.01); this was paralleled by an increase in the extent of intraplatelet cGMP elevation by SNP. O,- levels decreased to 16 * 2 mV (n.s.). Chronic ACEi therapy was associated with 63 f 6% inhibition of aggregation by SNP and O,levels of 10.8 f 1.5 mV (both n.s. vs. normal subjects and NIP). Conclusion Untreated CHF is associated with platelet resistance to NO which is ameliorated by acute and chronic ACEi therapy. These changes may contribute to the anti-ischaemic effects of ACEi therapy in CHE Key words: ACE inhibitor, Heart failure, treatment, Nitric oxide, Platelets Angiotensin Receptor Blockade is More Effective at Attenuating Remodeling than Endothelin Converting Enzyme Inhibition or Endothelin Receptor Antagonism Paul MartinI, Henry Krum’, Alicia Stein-Oakley* ‘Clinical Pharmacology, Departments Medicine, Epidemiology and Preventative Medicine, Monash University, Australia; =Alfred Hospital, Melbourne, Australia Background Blockade of the endothelin system using endothelin receptor antagonists (ETRA) attenuates pathological post myocardial infarction (MI) cardiac remodeling, however, endothelin converting enzyme inhibitors (ECEi) have only been studied short-term and no direct comparison has been made with angiotensin receptor blockade (ARB).