considerar otros diagnósticos
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Considerar otros
diagnósticos
normalDeterminar la presencia de
cardiopatía mediante ECG, RX-tórax,
Péptidos natriuréticos
Guías para el diagnóstico de IC aguda de la ESC
Guías para el diagnóstico de IC aguda de la ESC
Nieminen MS et al. Eur Heart J 2005; 26:384
Sospecha de IC en base a signos y síntomas
anormal
Ecocardiografía-Doppler
..continuar
ANP y BNP: comparación fisiológicaANP y BNP: comparación fisiológica
InestableEstableEstabilidad mRNA
RápidaLentaRespuesta de la transcripción genética al estímulo
++++Aumento en relación con la insuficiencia cardíaca
(+)++Secreción cardíaca basal
BajaElevadaConcentración auricular
Aurícula y ventrículo AurículaLocalización cardíaca
BNPANP
cardiomiocito
pre-proBNP
sangre
signalproBNP
NT-proBNP BNP
-26 amino acid 108
-26 -11 108
1 76 77 108
Péptidos natriuréticos: SintesisPéptidos natriuréticos: Sintesis
BNP- Diagnosis of acute dyspneaBNP- Diagnosis of acute dyspnea
Maisel et al, NEJM 2002;347:161
BNP Study:Breathing Not Properly
Estudio ICONEstudio ICON
• Número total=1256 pacientes
• No ICC=536 pacientes
– Antecedentes de ICC=55– No antecedentes de ICC=481
• IC aguda=720 pacientes
Diagnostico y NT-proBNP ICONICON
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 0.2 0.4 0.6 0.8 11 - Specificity (false positives)
Sen
siti
vity
(tr
ue
po
siti
ves)
Area under the curve=0.94P<0.00001
Optimal cut: 1160 pg/ml
Effect of Age on Cut-point Performance
• Age <50 yearsAge <50 years
– 84% sensitive/97% specific84% sensitive/97% specific
• Age 50-75 yearsAge 50-75 years
– 85% sensitive/85% specific85% sensitive/85% specific
• Age >75 yearsAge >75 years
– 94% sensitive/59% specific94% sensitive/59% specific
ICONICON
ROC Analysis: Age<50 yearsROC Analysis: Age<50 years
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 0.2 0.4 0.6 0.8 11 - Specificity (false positives)
Sens
itiv
ity
(tru
e p
osit
ives
)
Area under the curve=0.99P<0.00001
Optimal cut: 450 pg/ml97% sensitive, 93% specific
ROC Analysis: Age 50-75 yearsROC Analysis: Age 50-75 years
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 0.2 0.4 0.6 0.8 11 - Specificity (false positives)
Sen
siti
vity
(tr
ue
pos
itiv
es)
Area under the curve=0.93P<0.00001
Optimal cut: 900 pg/ml89% sensitive, 82% specific
ROC Analysis: Age >75 yearsROC Analysis: Age >75 years
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 0.2 0.4 0.6 0.8 11 - Specificity (false positives)
Sens
itiv
ity
(tru
e p
osit
ives
)
Area under the curve=0.86P<0.00001
Optimal cut: 1800 pg/ml85% sensitive, 73% specific
0.0041.00-1.021.01Frecuencia cardiaca
<0.00011.3-1.81.6Edad
<0.00011.7-4.02.6Ausencia de fiebre
<0.00011.7-4.62.8Antecedentes de ICC
<0.00011.8-4.42.8Uso de diuréticos de asa
<0.000012.0-4.53.0Crepitantes pulmonares
<0.000012.2-5.53.5Ortopnea
0.00021.85-7.73.7Ausencia de tos
<0.00013.5-12.86.7Edema intersticial en RX
<0.00001<0.0000112.6-39.312.6-39.324.224.2NT-proBNP elevadoNT-proBNP elevado**
P95% CIORPredictor
*NT-proBNP elevado definido como >450 para pacientes <50 años, >900 pg/ml para pacientes 50-75 años, y >1800 pg/ml para pacientes >75 años
Análisis de regresión logística MV
ICONICON
22%
36%
Rule Out Cutoff PointsRule Out Cutoff Points
International NT-proBNP Collaboration
300 pg/ml, age independent
99% sensitive60% specific
98% NPV
Punto de corte recomendado en las nuevas guías de la ESC
Patient attending the ED with breathlessness
History taking, physical exam, ECG, chest X-ray and NTproBNP
Acute CHF
unlikely
Acute CHFlikely
Acute CHF less likely
Additional tests
NTproBNP<300pg/mL
NTproBNPbetween 2 cut-
points
NTproBNP>450g/mL - patients <50 a>900pg/mL - patients 50-75 a>1800pg/mL - patients >75a
Understanding NT-proBNP in Obesity
Understanding NT-proBNP in Obesity
The obesity paradox ¿?
• Plasma levels of natriuretic peptides appear inversely associated with BMI in both subjects with and without HF.
• Natriuretic peptides are lower in overweight and obese patients compared with lean patients
Mehra MR et al. JACC 2004;43:1590Kistorp C et al. Circulation 2005;112:1756.StPeter JV. Clin Chemistry 2006;52:680Rivera M et al. Eur J Heart Fail 2005;7:1168.
Mechanisms of low NP in obesity Is it a matter of Increased degradation?
Mechanisms of low NP in obesity Is it a matter of Increased degradation?
22 pts underwent bariatric surgery
Parallel increases of BNP and NT-proBNP after weight loss
These data refutes the hypothesis that negative correlation between BNP and BMI is due to upregulation of NPR-C
because NPR-C do not clear NT-proBNP
Mechanisms of low NP in obesityMechanisms of low NP in obesity
• Increased degradation– BNP is cleared by NPR-C, abundantly expressed in human
adipocytes.– NT-proBNP is not cleared by NPR-C
• Reduced synthesis• altered neurohormonal interactions ¿?• Sex steroid hormones ¿?• Substance produced in the lean mass that
suppresses either synthesis or release of NP from cardiomyocytes ¿?
Das SR et al. Circulation 2005;112:2163van Kimmenade R et al. JACC 2006;47:886
Obesity, NT-proBNP and DiagnosisObesity, NT-proBNP and Diagnosis
How obesity affects NT-proBNP in the diagnosis of acute HF?
ICON BMI- substudy
How obesity affects NT-proBNP in the diagnosis of acute HF?
ICON BMI- substudy
BMI, NT-proBNP and diagnosisBMI, NT-proBNP and diagnosis
ROC curves for NT-proBNP / BMIROC curves for NT-proBNP / BMI
Utility of recommended NT-proBNP rule-in and rule-out HF cut-points as a function of
BMI
Utility of recommended NT-proBNP rule-in and rule-out HF cut-points as a function of
BMI
NP and obesity for diagnosing acute HF
NP and obesity for diagnosing acute HF
• Age-adjusted rule-in and age-independent rule-out cut-points for NT-proBNP are equally useful for obese and lean patients
Bayes-Genis et al. Arch Intern Med 2006: In press
• BMI influences the selection of cut-points for BNP in diagnosing acute HF:
• 170 ng/L - lean• 54 ng/L - obese
Daniels LB et al. Am Heart J 2006;151:999
Obesity, NT-proBNP and PrognosisObesity, NT-proBNP and Prognosis
How obesity affects the prognostic value of NT-proBNP
ICON BMI - substudy
How obesity affects the prognostic value of NT-proBNP
ICON BMI - substudy
BMI, NT-proBNP and prognosisBMI, NT-proBNP and prognosis
Hazard ratios across BMI adjusted for NT-proBNP > 986 ng/L
Hazard ratios across BMI adjusted for NT-proBNP > 986 ng/L
Optimal long-term (1 year) NT-proBNP cut-point: 986ng/L
Januzzi JL et al. Arch Intern Med 2006;166:315
K-M survival curves across BMI categories
K-M survival curves across BMI categories
Bayes-Genis et al. Arch Intern Med 2006: In press
What about BNP?What about BNP?
BMI, BNP and prognosisBMI, BNP and prognosis
Horwich TB et al. JACC 2006;47:85
Diferent prognostic cut-points across BMI
Diferent prognostic cut-points across BMI
Horwich TB et al. JACC 2006;47:85
• One single prognostic cut-point for NT-proBNP (986ng/L) is useful across all BMI categories.
Januzzi JL et al. Arch Intern Med 2006;166:315
Bayes-Genis A et al. Arch Intern Med 2006;In press
• Optimal BNP cut-points for prediction of death or urgent transplantation are different in the three BMI strata:
• 590 ng/L - lean • 491 ng/L - overweight• 343 ng/L - obese
Horwich TB et al. JACC 2006;47:85
NP and obesity for long-term risk stratification
NP and obesity for long-term risk stratification
In univariable analysis, higher BMI was an independent predictor of survival, with a 4% reduction in the risk of death with every increase of 1 BMI unit (95% CI=0.94-0.99, p=0.002). However, greater BMI was not significantly associated with 1-year mortality once age was added to the model.
Thus, the apparent obesity paradox in HF represents an association that is unlikely to be
causal
The obesity paradoxREVISITED
Riñón y NT-proBNPRiñón y NT-proBNP
Subestudio Renal de ICONSubestudio Renal de ICON
• 720 pacientes con IC aguda
• FGR calculado mediante ecuación MDRD
• Supervivencia a 60 días• 84 pacientes fallecieron• 606 pacientes vivos
Levey et al. Ann Intern Med 1999;130:461-470
Supervivencia a 60 díasSupervivencia a 60 díasCharacteristic Alive
(n=606)Deceased
(n=84)p-value
Age (mean±SD) 74.4±11.7 78.5±10.6 0.002
Male Gender 51.2% 52.4% 0.833
Past medical history HT CAD Prior MI Prior HF Prior COPD
62.0%50.7%33.3%51.7%29.3%
51.2%65.5%42.2%54.8%26.2%
0.0560.0110.1120.5930.561
Symptoms/signs Orthopnea Edema NYHA Class 4
51.6%46.5%44.2%
48.4%45.2%50.0%
0.6350.8230.319
Characteristic Alive (n=606)
Deceased (n=84)
p value
Physical Examination Pulse rate (mean±SD) Jugular venous distension S3 gallop Rales
92.8±25.848.8%6.9%
68.7%
95.5±26.056.0%8.3 %
67.9 %
0.3810.2220.6390.882
Chest X-ray findings Infiltrate Pleural effusion Cardiomegaly
11.7%26.6%37.0%
16.7%22.6%39.3%
0.1960.4400.680
ECG findings AF/AFl LBBB LVH
34.5%15.0%10.7%
32.1%25.0%8.3%
0.6710.0200.499
Supervivencia a 60 díasSupervivencia a 60 días
Characteristic Alive (n=606)
Deceased (n=84)
p value
Laboratory findings Creatinine, mg/dl (median, IQR) GFR (ml/min/1.73m²)(median, IQR) TropT >0.01 ng/ml NT-proBNP, pg/ml (median, IQR)
1.12 (0.87-1.50)61 (43-79)
47.5%4077 (1740-9989)
1.41 (1.02-2.10) 44 (31-64)
77.3% 9448 (3805-22179)
<0.001<0.001<0.001<0.001
Supervivencia a 60 díasSupervivencia a 60 días
• Los pacientes fueron dicotomizados
– Según los niveles de NT-proBNP– Concentración mediana = 4647 pg/mL (=548 pmol/L)
– Según FGR – > / < 60 ml/min/1.73m²
– 51.8% had GFR < 60 ml/min/1.73m²
Subestudio Renal de ICONSubestudio Renal de ICON
Predictores independientes de mortalidad en el análisis multivariado
Predictores independientes de mortalidad en el análisis multivariado
Predictor Odds Ratio
95% CI P Value
Age 1.02 0.99 -1.05 0.08
Prior HF 0.78 0.48-1.27 0.31
Prior MI 1.36 0.84-2.22 0.22
NYHA class 1.26 0.86-1.86 0.24
Hemoglobin 0.94 0.88-1.01 0.07
GFR < 60 ml/min/1.73 m² 2.03 1.18-3.49 <0.01
NT-proBNP > 4647 pg/mL 2.67 1.58-4.51 <0.01
Predictor Odds Ratio 95% CI P Value
Age 1.02 0.99 -1.05 0.06
Prior HF 0.78 0.48-1.27 0.31
Prior MI 1.37 0.84-2.24 0.20
NYHA class 1.24 0.84-1.83 0.28
Hemoglobin 0.94 0.88-1.01 0.07
GFR < 60 ml/min/1.73 m² &
NT-proBNP > 4647 pg/mL 3.46 2.13-5.63 <0.001
Predictores independientes de mortalidad en el análisis multivariado
Predictores independientes de mortalidad en el análisis multivariado
Curvas de K-M según FGR y NT-proBNPCurvas de K-M según FGR y NT-proBNP
Van Kimmenade R et al. JACC 2006 In Press
NT-proBNP monitoringNT-proBNP monitoring
ER ER ER7 d 7 d 7 d
Death ofCV origin
Death ofnon CV
origin
Survivors
P=0.004
- 15% - 75% - 50%
Percent NTproBNP reduction during admission and prognosisPercent NTproBNP reduction during admission and prognosis
1 - Specificity
1,00,80,50,30,0
Sen
sitiv
ity
1,0
0,8
0,5
0,3
0,0
AUC 0.79 (0.69-0.94)p=0.001
ROC for NTproBNP reduction during hospitalizationROC for NTproBNP reduction during hospitalization
Sens: 70%
Spec: 84%
PPV: 47%
NPV 94%
Accuracy 82%
- 30%
Prognosis of NTproBNP reduction during hospitalization for CHF
Prognosis of NTproBNP reduction during hospitalization for CHF
Bettencourt P et al. Circulation 2004;110:2168
N=182
Decrease 30% - 25%
Decrease <30% - ~50%
Increase 30% - 80%
6 months
A
Baseline W1 W2 W3 W4 M3
UneventfulFollow-up
LVEDD: 69 mmLVEF: 16%
Patient with no events during follow-upPatient with no events during follow-up
Baseline W1 W2 W3 W4 M3
Hospitaladmission
deathLVEDD: 73 mmLVEF: 20%
Patient with events during follow-upPatient with events during follow-up
What’s next?What’s next?
Worsening HF
Good prognosisoutpatient follow-up
Adverse prognosis
Resynchronization?i.v. inotropes?
???????
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