Kasama et al. JACC. 2007 Feb 13; 49(6):667-74 .

Clinical Trial Results . orgClinical Trial Results . org

Effects of Intravenous Atrial Natriuretic Peptide on Cardiac Sympathetic Nerve Activity and Left

Ventricular Remodeling in Patients with First Anterior Acute Myocardial Infarction

Effects of Intravenous Atrial Natriuretic Peptide on Cardiac Sympathetic Nerve Activity and Left

Ventricular Remodeling in Patients with First Anterior Acute Myocardial Infarction

Shu Kasama, MD; Takuji Toyama, MD; Takashi Hatori, MD; Shu Kasama, MD; Takuji Toyama, MD; Takashi Hatori, MD; Hiroyuki Sumino, MD; Hisao Kumakura, MD; Yoshiaki Takayama, MD; Hiroyuki Sumino, MD; Hisao Kumakura, MD; Yoshiaki Takayama, MD;

Shuichi Ichikawa, MD; Tadashi Suzuki, MD; Masahiko Kurabayashi, MDShuichi Ichikawa, MD; Tadashi Suzuki, MD; Masahiko Kurabayashi, MD

Published in JACCPublished in JACC

February 13, 2007February 13, 2007

Effects of Intravenous Atrial Natriuretic Peptide on Cardiac Sympathetic Nerve Activity and Left Ventricular Remodeling in

Patients with First Anterior Acute Myocardial Infarction

Effects of Intravenous Atrial Natriuretic Peptide on Cardiac Sympathetic Nerve Activity and Left Ventricular Remodeling in

Patients with First Anterior Acute Myocardial Infarction


IV Atrial Natriuretic Peptide and Cardiac Sympathetic Nerve Activity and LV Remodeling in Anterior Acute MI: Background

IV Atrial Natriuretic Peptide and Cardiac Sympathetic Nerve Activity and LV Remodeling in Anterior Acute MI: Background

• Event-free survival after acute myocardial Event-free survival after acute myocardial infarction (AMI) is influenced by the extent of infarction (AMI) is influenced by the extent of residual myocardial ischemia and the global residual myocardial ischemia and the global left ventricular (LV) ejection fraction.left ventricular (LV) ejection fraction.

• In addition, because activation of the In addition, because activation of the sympathetic nervous system is a chief sympathetic nervous system is a chief indicator of a failing human heart, plasma indicator of a failing human heart, plasma norepinephrine concentrations also affect the norepinephrine concentrations also affect the morbidity and mortality in patients with AMI.morbidity and mortality in patients with AMI.

• Event-free survival after acute myocardial Event-free survival after acute myocardial infarction (AMI) is influenced by the extent of infarction (AMI) is influenced by the extent of residual myocardial ischemia and the global residual myocardial ischemia and the global left ventricular (LV) ejection fraction.left ventricular (LV) ejection fraction.

• In addition, because activation of the In addition, because activation of the sympathetic nervous system is a chief sympathetic nervous system is a chief indicator of a failing human heart, plasma indicator of a failing human heart, plasma norepinephrine concentrations also affect the norepinephrine concentrations also affect the morbidity and mortality in patients with AMI.morbidity and mortality in patients with AMI.

Kasama et al. JACC. 2007 Feb 13; 49(6):667-74.Kasama et al. JACC. 2007 Feb 13; 49(6):667-74.


Effects of Intravenous Atrial Natriuretic Peptide on Cardiac Sympathetic Nerve Activity and Left Ventricular Remodeling in Patients

with First Anterior Acute Myocardial Infarction: Background (cont.)


with First Anterior Acute Myocardial Infarction: Background (cont.)

• Atrial natriuretic peptide (ANP) has a wide range of Atrial natriuretic peptide (ANP) has a wide range of potent biologic effects, including natriuretic, diuretic, potent biologic effects, including natriuretic, diuretic, and vasodilatory properties and inhibition of the and vasodilatory properties and inhibition of the RAAS.RAAS.

• Intravenous administration of ANP has been shown to Intravenous administration of ANP has been shown to prevent LV dilation and remodeling after primary prevent LV dilation and remodeling after primary coronary angioplasty in patients with AMI.coronary angioplasty in patients with AMI.

• This study sought to evaluate the effects of ANP on This study sought to evaluate the effects of ANP on CSNA and LV remodeling in patients with first CSNA and LV remodeling in patients with first anterior AMI after primary coronary angioplasty.anterior AMI after primary coronary angioplasty.

• Atrial natriuretic peptide (ANP) has a wide range of Atrial natriuretic peptide (ANP) has a wide range of potent biologic effects, including natriuretic, diuretic, potent biologic effects, including natriuretic, diuretic, and vasodilatory properties and inhibition of the and vasodilatory properties and inhibition of the RAAS.RAAS.

• Intravenous administration of ANP has been shown to Intravenous administration of ANP has been shown to prevent LV dilation and remodeling after primary prevent LV dilation and remodeling after primary coronary angioplasty in patients with AMI.coronary angioplasty in patients with AMI.

• This study sought to evaluate the effects of ANP on This study sought to evaluate the effects of ANP on CSNA and LV remodeling in patients with first CSNA and LV remodeling in patients with first anterior AMI after primary coronary angioplasty.anterior AMI after primary coronary angioplasty.




with First Anterior Acute Myocardial Infarction: Study Design


with First Anterior Acute Myocardial Infarction: Study Design

Primary Endpoint: Extent Score (ES) determined from Primary Endpoint: Extent Score (ES) determined from 99m99mTc-pyrophosphate Tc-pyrophosphate scintigraphy to evaluate the area of initial myocardial damage 3 to 5 days scintigraphy to evaluate the area of initial myocardial damage 3 to 5 days after initial angioplasty. after initial angioplasty.

Secondary Endpoint: LV end-diastolic volume and LV ejection fraction Secondary Endpoint: LV end-diastolic volume and LV ejection fraction determined by left ventriculography after 2 weeks.determined by left ventriculography after 2 weeks.

Tertiary Endpoint: Delayed heart/mediastinum count (H/M) ratio, delayed Tertiary Endpoint: Delayed heart/mediastinum count (H/M) ratio, delayed total defect score (TDS), and washout rate (WR) determined from total defect score (TDS), and washout rate (WR) determined from 123123I-MIBG I-MIBG scintigraphy after 3 weeks. scintigraphy after 3 weeks.

Primary Endpoint: Extent Score (ES) determined from Primary Endpoint: Extent Score (ES) determined from 99m99mTc-pyrophosphate Tc-pyrophosphate scintigraphy to evaluate the area of initial myocardial damage 3 to 5 days scintigraphy to evaluate the area of initial myocardial damage 3 to 5 days after initial angioplasty. after initial angioplasty.

Secondary Endpoint: LV end-diastolic volume and LV ejection fraction Secondary Endpoint: LV end-diastolic volume and LV ejection fraction determined by left ventriculography after 2 weeks.determined by left ventriculography after 2 weeks.

Tertiary Endpoint: Delayed heart/mediastinum count (H/M) ratio, delayed Tertiary Endpoint: Delayed heart/mediastinum count (H/M) ratio, delayed total defect score (TDS), and washout rate (WR) determined from total defect score (TDS), and washout rate (WR) determined from 123123I-MIBG I-MIBG scintigraphy after 3 weeks. scintigraphy after 3 weeks.

Atrial Natriuretic Peptide (ANP)> 48 h of 0.025 μg/kg/min

n=25

Atrial Natriuretic Peptide (ANP)> 48 h of 0.025 μg/kg/min

n=25

Isosorbide Dinitrate (ISDN)> 48 h of 0.67 μg/kg/min

n=25

Isosorbide Dinitrate (ISDN)> 48 h of 0.67 μg/kg/min

n=25

50 patients with AMI (chest pain > 30 min, ST-segment elevation of >2 mm in 2 contiguous ECG leads and more than threefold increase in serum creatine phosphokinase activities

Prospective. Randomized. Double-blind. Exclusion Criteria: cardiogenic shock or hypotension (SBP<80 mm Hg), prior MI, multivessel disease, and need

for mechanical support (intra-aortic balloon pumping, mechanical ventilation, or both).

50 patients with AMI (chest pain > 30 min, ST-segment elevation of >2 mm in 2 contiguous ECG leads and more than threefold increase in serum creatine phosphokinase activities

Prospective. Randomized. Double-blind. Exclusion Criteria: cardiogenic shock or hypotension (SBP<80 mm Hg), prior MI, multivessel disease, and need

for mechanical support (intra-aortic balloon pumping, mechanical ventilation, or both).

RR



CharacteristicCharacteristic ANP ANP (n=25)(n=25)

ISDNISDN(n=25)(n=25) p valuep value

Age Age (yrs(yrsSD)SD) 61 61 12 12 62 62 13 13 0.780.78

Male Male (%)(%) 20 (80.0)20 (80.0) 19 (76.0)19 (76.0) 0.730.73

History of Stroke History of Stroke (%)(%) 2 (8.0)2 (8.0) 1 (4.0)1 (4.0) 0.550.55

Diabetes Diabetes (%)(%) 7 (28.0)7 (28.0) 6 (24.0)6 (24.0) 0.740.74

Hypertension Hypertension (%)(%) 14 (56.0)14 (56.0) 13 (52.0)13 (52.0) 0.770.77

Hyperlipidemia Hyperlipidemia (%)(%) 8 (32.0)8 (32.0) 9 (36.0)9 (36.0) 0.770.77

Current Smoker Current Smoker (%)(%) 14 (56.0)14 (56.0) 15 (60.0)15 (60.0) 0.770.77

Recanalization time (h)Recanalization time (h) 3.7 3.7 1.5 1.5 3.9 3.9 1.8 1.8 0.670.67

Effects of Intravenous Atrial Natriuretic Peptide on Cardiac Sympathetic Nerve Activity and Left Ventricular Remodeling in Patients with

First Anterior Acute Myocardial Infarction: Clinical Characteristics


First Anterior Acute Myocardial Infarction: Clinical Characteristics



CharacteristicCharacteristic ANP ANP (n=25)(n=25)


TIMI flow grade 2 TIMI flow grade 2 (%)(%) 23 (92.0)23 (92.0) 23 (92.0)23 (92.0) 1.001.00

TIMI flow grade 3 TIMI flow grade 3 (%)(%) 2 (8.0)2 (8.0) 2 (8.0)2 (8.0) 1.001.00

Stent Stent (%)(%) 23 (92.0)23 (92.0) 22 (88.0)22 (88.0) 0.640.64

Peak CPK (IU/U)Peak CPK (IU/U) 29592959±±16481648 3187±18913187±1891 0.650.65

In-hospital medicationsIn-hospital medications ACE inhibitor ACE inhibitor (%)(%)

ARB ARB (%)(%)

Beta-blocker Beta-blocker (%)(%)

Loop diuretics Loop diuretics (%)(%)

Spironolactone Spironolactone (%)(%)

23 (92.0)23 (92.0)5 (20.0)5 (20.0)

21 (84.0)21 (84.0)5 (20.0)5 (20.0)2 (8.0)2 (8.0)

23 (92.0)23 (92.0)6 (24.0)6 (24.0)

22 (88.0)22 (88.0)6 (24.0)6 (24.0)2 (8.0)2 (8.0)

1.001.000.730.730.680.680.730.731.001.00


First Anterior Acute Myocardial Infarction: Clinical Characteristics (cont.)


First Anterior Acute Myocardial Infarction: Clinical Characteristics (cont.)




with First Anterior Acute Myocardial Infarction: Primary Endpoint


with First Anterior Acute Myocardial Infarction: Primary Endpoint

0

1

2

3

4

5

6

7

8

9

10

ANP ISDN

0

1

2

3

4

5

6

7

8

9

10

ANP ISDN

TD

ST

DS

0

5

10

15

20

25

30

35

40

ANP ISDN0

5

10

15

20

25

30

35

40

ANP ISDN

H/M

ra

tio

H/M

ra

tio

n = 25 n = 25 n = 25 n = 25 n = 25 n = 25 n = 25 n = 25


Extent Score of Extent Score of 99m99mTc-PYPTc-PYP

p=1.00 p=1.00

Total Defect Score of Total Defect Score of 201201T1 T1

p<0.01 p<0.01 9 9 ± 3± 3 9 9 ± 4± 4

27 27 ± 7± 7

32 32 ± 6± 6


•The The 201201T1 and T1 and 99m99mTc-PYP dual single-photon emission Tc-PYP dual single-photon emission computed tomography (SPECT) imaging were performed to computed tomography (SPECT) imaging were performed to evaluate the area of initial myocardial damage 3 to 5 days evaluate the area of initial myocardial damage 3 to 5 days after primary angioplasty.after primary angioplasty.

•The extent score was similar in both groups; therefore the The extent score was similar in both groups; therefore the initial area at risk was probably similar for both groups. initial area at risk was probably similar for both groups.

•However, defect scores were significantly lower in the ANP However, defect scores were significantly lower in the ANP group than in the ISDN group (p<0.01).group than in the ISDN group (p<0.01).

•Therefore, the intravenous administration of ANP may have Therefore, the intravenous administration of ANP may have increased the amount of salvaged myocardium after increased the amount of salvaged myocardium after reperfusion therapy in patients with AMI.reperfusion therapy in patients with AMI.

Effects of Intravenous Atrial Natriuretic Peptide on Cardiac Sympathetic Nerve Activity and Left Ventricular Remodeling in Patients with First Anterior Acute Myocardial Infarction: Primary Endpoint (cont.)

Effects of Intravenous Atrial Natriuretic Peptide on Cardiac Sympathetic Nerve Activity and Left Ventricular Remodeling in Patients with First Anterior Acute Myocardial Infarction: Primary Endpoint (cont.)


CharacteristicCharacteristic ANPANP(n=25)(n=25)


LV end diastolic LV end diastolic pressure (mm Hg)pressure (mm Hg) 11.2 11.2 4.3 4.3 12.1 12.1 6.8 6.8 0.580.58

LV end diastolic LV end diastolic volumevolume

85.5 85.5 28.528.5 106.3 106.3 39.4 39.4 <0.05<0.05

LV ejection fractionLV ejection fraction 47.9 47.9 10.210.2 41.5 41.5 11.8 11.8 <0.05<0.05


First Anterior Acute Myocardial Infarction: Secondary Endpoint


First Anterior Acute Myocardial Infarction: Secondary Endpoint

LV Parameters 2 weeks after treatmentLV Parameters 2 weeks after treatment


• LV end diastolic volume was significantly lower and LV ejection LV end diastolic volume was significantly lower and LV ejection fraction was significantly higher in the ANP group than in the ISDN fraction was significantly higher in the ANP group than in the ISDN group.group.

• However, LV end diastolic pressure was similar in both groups. However, LV end diastolic pressure was similar in both groups.



with First Anterior Acute Myocardial Infarction: Tertiary Endpoint


with First Anterior Acute Myocardial Infarction: Tertiary Endpoint

0

10

20

30

40

50

60

ANP ISDN

0

10

20

30

40

50

60

ANP ISDN

p < 0.05p < 0.05

TD

S

0

0.5

1

1.5

2

2.5

ANP ISDN0

0.5

1

1.5

2

2.5

ANP ISDN

p < 0.p < 0. 0505H

/M r

atio

H/M

rat

io

0

10

20

30

40

50

60

ANP ISDN0

10

20

30

40

50

60

ANP ISDN

p < 0.005 p < 0.005

WR

WR

n = 25 n = 25 n = 25 n = 25 n = 25 n = 25 n = 25 n = 25 n = 25n = 25 n = 25 n = 25

41± 841± 8

1.96 ± 0.181.96 ± 0.18

1.74 ± 0.231.74 ± 0.23

34 ± 834 ± 835 ± 8%35 ± 8%

44 ± 12%44 ± 12%

Total Defect ScoreTotal Defect Score Washout RateWashout RateHeart/Mediastinum Heart/Mediastinum count (H/M) ratiocount (H/M) ratio


123123I-MIGB scintigraphic findings 3 weeks after treatmentI-MIGB scintigraphic findings 3 weeks after treatment



with First Anterior Acute Myocardial Infarction: Limitations


with First Anterior Acute Myocardial Infarction: Limitations

• The study had a small number of patients with AMI The study had a small number of patients with AMI (n=50).(n=50).

• This study used a fixed ANP dose, but future studies This study used a fixed ANP dose, but future studies should assess the dose-response effects of ANP on should assess the dose-response effects of ANP on 123123I-MIBG scintigraphic findings and LV parameters. I-MIBG scintigraphic findings and LV parameters.

• Swan-Ganz catheterization was not performed to Swan-Ganz catheterization was not performed to measure hemodynamic parameters after treatment; measure hemodynamic parameters after treatment; however, the LV end diastolic pressure was similar in however, the LV end diastolic pressure was similar in the two groups.the two groups.

• The study had a small number of patients with AMI The study had a small number of patients with AMI (n=50).(n=50).

• This study used a fixed ANP dose, but future studies This study used a fixed ANP dose, but future studies should assess the dose-response effects of ANP on should assess the dose-response effects of ANP on 123123I-MIBG scintigraphic findings and LV parameters. I-MIBG scintigraphic findings and LV parameters.

• Swan-Ganz catheterization was not performed to Swan-Ganz catheterization was not performed to measure hemodynamic parameters after treatment; measure hemodynamic parameters after treatment; however, the LV end diastolic pressure was similar in however, the LV end diastolic pressure was similar in the two groups.the two groups.




with First Anterior Acute Myocardial Infarction: Summary


with First Anterior Acute Myocardial Infarction: Summary

• The TDS, H/M ratio, and WR as determined by The TDS, H/M ratio, and WR as determined by cardiac cardiac 123123I-MIGB scintigraphy were better in the I-MIGB scintigraphy were better in the ANP group than in the ISDN group.ANP group than in the ISDN group.

• The ES determined by The ES determined by 99m99mTc-PYP was similar in the Tc-PYP was similar in the two groups.two groups.

• Two weeks after treatment, LV parameters were Two weeks after treatment, LV parameters were better in the ANP group than in the ISDN group.better in the ANP group than in the ISDN group.

• The TDS, H/M ratio, and WR as determined by The TDS, H/M ratio, and WR as determined by cardiac cardiac 123123I-MIGB scintigraphy were better in the I-MIGB scintigraphy were better in the ANP group than in the ISDN group.ANP group than in the ISDN group.

• The ES determined by The ES determined by 99m99mTc-PYP was similar in the Tc-PYP was similar in the two groups.two groups.

• Two weeks after treatment, LV parameters were Two weeks after treatment, LV parameters were better in the ANP group than in the ISDN group.better in the ANP group than in the ISDN group.




with First Anterior Acute Myocardial Infarction: Summary (cont.)


with First Anterior Acute Myocardial Infarction: Summary (cont.)

• These findings demonstrate for the first time These findings demonstrate for the first time that intravenous administration of ANP could that intravenous administration of ANP could improve cardiac sympathetic nerve activity improve cardiac sympathetic nerve activity and prevent left ventricular remodeling to a and prevent left ventricular remodeling to a larger extent compared with ISDN after larger extent compared with ISDN after reperfusion therapy in patients with first reperfusion therapy in patients with first anterior AMI.anterior AMI.

• These findings demonstrate for the first time These findings demonstrate for the first time that intravenous administration of ANP could that intravenous administration of ANP could improve cardiac sympathetic nerve activity improve cardiac sympathetic nerve activity and prevent left ventricular remodeling to a and prevent left ventricular remodeling to a larger extent compared with ISDN after larger extent compared with ISDN after reperfusion therapy in patients with first reperfusion therapy in patients with first anterior AMI.anterior AMI.


Kasama et al. JACC. 2007 Feb 13; 49(6):667-74 .

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Transcript of Kasama et al. JACC. 2007 Feb 13; 49(6):667-74 .