heart failure with preserved ef (hfpef) · there is a lack of unity in diagnosing hfpef. a...
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Heart failure with preserved EF (HFpEF):
Otmar Pfister
Kardiologie
• Tatsachen
• Problem: Diagnose (Definition)
• Problem: Therapie
- was funktioniert nicht
- was könnte funktionieren
• Warten auf Paragon HF
HFpEF: Nur Probleme…
HFpEF
40 %
Optimize HF-Registry (n = 41‘267)
Fonarow G et al. J Am Coll Cardiol 2007
Das Schlaraffenland, Pieter Bruegel um 1567
Prädisponierende Faktoren für HFpEF
Körperliche
Inaktivität
AdipositasArterielle
Hypertonie
Diabetes
Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) Eur Heart J 2012;33:1750-1757
Prognose HFpEF versus HFrEF
Todesursachen bei Patienten mit HFpEF
Henkel et al, Circ Heart Fail 2008
Olmsted County Register (n=1063)
HFpEF: Biologische Phänotypen
Lewis G.A et al. J Am Coll Cardiol 2017
• Mikrovaskuläre Dysfunktion
• Linksventrikuläre Hypertrophie
• Endotheliale Dysfunktion
• Abnormes Calcium Handling
• Titin Dysfunktion
• Myokardiale Fibrose
• Mitochondriale Dysfunktion
Compliance Störung der grossenGefässe
Xanthopoulos et al. Trends in Cardiovascular Medicine 2018
• Tatsachen
• Problem: Diagnose (Definition)
• Problem: Therapie
- was funktioniert nicht
- was könnte funktionieren
• Warten auf Paragon HF
HFpEF: Nur Probleme…
• 68-jährige Frau mit Dyspnoe NYHA III
• Arterielle Hypertonie, Diabetes mellitus Typ 2, Adipositas
(BMI 38), VHF, HF: 78/min, Blutdruck: 156/74 mmHg
• Labor: NT-proBNP 827 ng/L, Kreatinin 140 mmol/L
• Echo: Konzentrisch hypertropher linker Ventrikel, LVEF
52%, dilatierte Vorhöfe (LAVI 46ml/m2), sPAP 42mmHg
• ACE-Hemmer, Betablocker, Diuretikum
Fall Vignette 1
• 76-jährige Frau mit Dyspnoe NYHA III
• Koronare 2-GE, BMI 28, HF – 84/min, Blutdruck –
143/78 mmHg
• Labor: NT-proBNP 513 ng/L, Kreatinin 118 mmol/L
• Echo: LVEF 58%, konzentrisches LV Remodelling, E/e’
13, LAVI 31 ml/m2, sPAP nicht sicher bestimmbar
• ACE-Hemmer, BB
Fall Vignette 2
Dilemma number 1: Diagnosis
ESC Guidelines Acute and chronic HF, Eur Heart J 2016
NTproBNP > 125ng/L
BNP >35 pg/L
NTproBNP > 125ng/L
BNP >35 pg/L
HFpEF
Functional
septal e’ < 7 cm/s* orlateral e’ < 10 cm/s*
orAverage E/e’ ≥ 15M
ajo
rM
inor
Morphological Biomarker (SR) Biomarker (AF)
LAVI > 34 ml/m2+or
LVMI ≥ 149/122 g/m2 (m/w)and
RWT > 0.42 #
NT-proBNP > 220 pg/mlor
BNP > 80 pg/ml
NT-proBNP > 660 pg/mlor
BNP > 240 pg/ml
Average E/e’ 9–14or
TR velocity > 2.8 m/sor
GLS < 16 %
LAVI 29–34 ml/m2
orLVMI > 115/95 g/m2 (m/w)
or RWT > 0.42
orLV wall thickness ≥ 12 mm
NT-proBNP 125–220 pg/mlor
BNP 35–80 pg/ml
NT-proBNP 365–660 pg/mlor
BNP 105–240 pg/ml
Major Criteria: 2 points
Minor Criteria: 1 point
≥ 5 points: HFpEF2–4 points: Diastolic Stress Test or Invasive Haemodynamic Measurements
Pieske B. Presentation at Heart Failure 2018, 26 - 29 May 2018, Vienna, Austria
ESC-HFA consensus (preliminary, not published)
LVEF ≥ 50% and exertional dyspnoea
Diagnostische Wertigkeit von Echo Parameter (Unterscheidung HFpEF / Hypertensive Herzkrankheit)
Lam CS et al, J Am Coll Cardiol 2009
PASP: Optimal cut-off: 35mmHg (83% Sensitivity, 92% Specificity)
H2FPEF-Score (first validated score)
Criterion Points
Atrial fibrillation 3
BMI > 30kg/m2 2
Age > 60 years 1
≥ 2 antihypertensive drugs 1
E/e’ > 9 (echo) 1
Estimated sPAP > 35 mmHg (echo) 1
0-1
HFpEF unlikely
6-9
HFpEF likelyinvasive hemodynamics
Reddy et al. Circulation 2018
LVEF ≥ 50% and exertional dyspnoea
• Tatsachen
• Problem: Diagnose (Definition)
• Problem: Therapie
- was funktioniert nicht
- was könnte funktionieren
• Warten auf Paragon HF
HFpEF: Nur Probleme…
Dilemma number 2: Therapy
55%50%45%40%
CHARM preserved
PEP-CHF
I-PRESERVE
TOPCAT
EDIFY
PARAGON HF
normal EF
HFmrEF HFpEFHFrEF
Different LVEF cut-off’s in large HFpEF trials
HR=0.82 (0.69-0.98)
HR=1.10 (0.79-1.51)
US, Canada,
Argentina, Brazil
Russia, Rep Georgia
TOPCAT: possible benefit of spironolactone
CV
de
ath
or
HF
ho
sp
ita
liza
tio
n
Spironolactone
Placebo
Pitt B et al, NEJM [email protected]
Novel drug targets to maintain cGMP levels
cGMP
NO NPs
sGC rGC
PKG
↓ CMC hypertrophy
↓ CMC stiffening
↓ Interstitial fibrosis
↓ Endothelial dysfunction
…
Organic or
inorganic nitrates
sGC stimulators
PDE5 inhibitors
Neprilysin
inhibitors
PDE9 inhibitors
Kardiologie
Kuster G and Pfister O, SMW 2019 in press
Redfield MM et al. N Engl J Med 2015 Borlaug BA et al. JAMA 2018
INDIE-HFpEF: (inorganic nitrite) NEAT-HFpEF: (organic nitrite)
No benefit of nitrates in HFpEF
accelometer units/d Peak oxygen consumption (VO2max)
Elke S. Hoendermis et al. Eur Heart J 2015;36:2565-2573
PD5-Inhibition (Sildenafil) unwirksam
Benefit from beta-blocker across the EF range
Cleland JGF et al., Eur Heart J 2018
Kardiologie
no benefit of
beta-blocker
in HFpEF
Ivabradine = selective If channel
blocker
179 HFpEF patients (LVEF > 45%)
sinus node
Main results
no change in diastolic function (E/e’)
no change in exercise capacity (6 minute walk)
no change in NT-proBNP
DiFrancesco D et al. Drugs 2004
Ivabradine (EDIFY Trial)
Novel drug targets to maintain cGMP levels
cGMP
NO NPs
sGC rGC
PKG
↓ CMC hypertrophy
↓ CMC stiffening
↓ Interstitial fibrosis
↓ Endothelial dysfunction
…
Organic or
inorganic nitrates
- NEAT-HFpEF
- INDIE-HFpEF
sGC stimulators
- SOCRATES-preserved
PDE5 inhibitors
- RELAX Trial
Neprilysin
inhibitors
- PARAMOUNT
- PARAGON
PDE9 inhibitors
- preclinical data
Kardiologie
Kuster G and Pfister O, SMW 2019 in press
Interatrial shunt device
Hasenfuss G et al., Cardiovasc Med 2018
Kardiologie
TTE: subcostal view
Zinman B et al New Engl J Med 2015
SGLT2-Inhibitors reduce HF-hospitalisations
Registry Data (Real World)
SGLT-2 superior alternative superior
Kosiborod M et al J Am Coll Cardiol 2018
- 35%
- 33%
Neal B et al New Engl J Med 2017
Exercise
Hypertension
(ACE-Inhibitor /
ARB /
CA-Antagonists)
Ischemia
Revascularisation
betablocker
Volemia
(diuretics)
Comorbidities
adipositas /
diabetes / iron
deficiency ?
HFpEF: Treatment targets
Atrial fibrillation
Optimal HR ( 70-
90 bpm),
maintain sinus
rhythm ?
There is a lack of unity in diagnosing HFpEF. A universal
definition of diagnostic criteria remains to be established
So far there is no proven therapy except of regular
exercise
Therapies that might work: Spironolactone, Neprilysin
inhibition, SGLT2 inhibition, interatrial shunt device
HFpEF is a heterogenous disorder associated with
comorbidities. Future therapeutic strategies should be
tailored to specific HFpEF phenotypes
Conclusion
