heart failure with preserved ef: a clinician’s guide to ... · a clinician’s guide to...
TRANSCRIPT
Heart Failure with Preserved EF: A Clinician’s Guide to Relaxation
Jonathan R. Lindner, M.D. Professor of Medicine
Cardiovascular Division Oregon Health & Science University
Diastolic Dysfunction - Scope of the Problem
• 5 million patients with CHF in the U.S.
• 600,000 new cases of CHF each year
• 50,000 deaths from CHF alone each year (20% increase in last 10 yrs yet death rate down 2%)
• Medicare beneficiary costs of $4-5 billion per year
Distribution of LVEF in 11,327 Patients Hospitalized or Dying from CHF
Cleland J et al. Eur Heart J 2003;24:442
Survival After Discharge: OPTIMIZE-HF Registry
Fonarow GC, et al. JACC 2007;40:768
Problems Investigating HFPEF
Lack of unified definition
A syndrome, not disease
Pathophysiology defined in terms of molecular, histologic, and hemodynamic alterations
Ventricular filling not exclusively a ventricular event (atrial compliance, pressures, and systolic function)
Difficulty distinguishing age-related changes
Ao
LV
LA
Pre
ssur
e (m
m H
g)
relaxation stiffness
IC S IR D
mitral flow
0
20
40
60
80
100
120
140
Ao
LV
LA
Pres
sure
(mm
Hg)
relaxation 1. molecular events 2. mechanodynamic properties
“So that the coming together depends on the going apart, the systole depends on the diastole, the flow depends on the ebb.”
D. H. Lawrence (1885-1930)
Famous Quotes on Diastolic Dysfunction I.
Mechanodynamics in Early Diastole
Elasticity - recovery properties of a deformed material
spring
+ inotropy
resting LV
equilibrium
0
20
40
60
80
100
120
140
Ao
LV
LA
Pres
sure
(mm
Hg)
Time
peak negative dp/dt
T1/2
P=P0e-τ/t
MDP
-20
-10
0
10
-10 0 10 20 30 40-20
-10
0
10
-100 -80 -60 -40 -20 0
r=0.93 r=0.93
Change in EF (%) Change in end-systolic volume (%)
Cha
nge
in T
1/2 (
ms)
isoproterenol pacing
Evidence for Elastic Recoil - effect of positive inotropy
Udelson J, et al. Circulation 1990
Regional Presssure Gradients During Relaxation
LA
LV
Time
Pre
ssur
e (m
m H
g)
Diastolic Calcium Flux
PL
SR
kinases
cAMP
P
SERCA CS
Ca++
ATP
3 Na+
mitochondria
Na+
Sensitivity?
Abnormal Calcium Flux in Diastolic Failure
SERCA ↓ Phospholamban ↑ Na/Ca exchanger ↓ ATP ↓
Molecular Alterations
Age Ischemia/reperfusion Hypertrophy/afterload Diabetes mellitus Cardiomyopathy Hypothyroidism
Associated Conditions
0
20
40
60
80
100
120
140
Ao
LV
LA
Pres
sure
(mm
Hg)
stiffness 1. distensibility 2. compliance
Pre
ssur
e
Volume Volume Volume
↓ distensibility ↓ compliance
Pressure-Volume Relations
Inflammatory processes Myocarditis Ischemia Vasculitis Diabetes
Myocyte hypertrophy/disarray Hypertension
Hypertrophic cardiomyopathy Aortic stenosis
Age
Abnormal Infiltration Amyloidosis
Hemachromatosis Storage diseases
Collagen Infiltr. Fibroelastosis
Ischemia
Perimysium
Endomysium
Normal
LVH with Htn
Collagen in Cardiovascular Disease
Izawa H, et al, Circulation 2005;112:2940
Collagen Volume Fraction in Humans Relation to Compliance and Relaxation
ATII ET-1
Catecholamines
DGF IGF-1 PDGF
IL-1β CT-1
TNF-a TGFβ
Gq Gs Gi STK TK CR
Nuclear transcription factors/substrates
Myocyte hypertrophy
Mediators of Hypertrophy and Collagen Synthesis
Matrix remodeling
EES
EES
LV Stiffness in Moderate-Severely Symptomatic Pts.
Westermann D, et al, Circulation 2008;117:2051
Diagnosis
History - Htn -DM - ESRD -OSA Physical Exam: - S4 and S3 (late) - Diffuse, prominent, and sustained PMI (LVH) - Other manifestations of Htn (retinopathy) - Manifestations of other disease processes (ie: amyloid) ECG/Lab - LVH on ECG - Low voltage with cardiomegaly on CXR - Elevated BNP, NT-ProBNP
Lubien E, et al. Circulation 2002
BNP and Doppler Data
Echocardiography
1. Excludes systolic dysfunction (global or segmental)
2. Diagnosis of specific disease states (amyloidosis, HOCM, eosinophilic myocarditis)
3. Doppler parameters of filling dynamics 4. Tissue velocity and strain measurements 5. Excludes other non-myocardial causes of diastolic
filling abnormalities (constriction, mitral valve dz, tamponade, masses)
Color Doppler M-mode: Propagation Velocity (45 cm/sec)
0
40
80
120
Ao
LV
LA
PW Doppler
Doppler Echocardiography
LAP normal
Mitral PW
PV PW
E A
S D A
Doppler Echocardiography
Tissue Doppler: Longitudinal Tracking
Borges AC, et al., JASE 2003
E – relaxation & filling pressure E' - relaxation
Nagueh, et al., JACC 1997
Advanced Systolic Heart Failure (Mullens W, et al., Circulation 2009;119:62)
HFPEF (Bhella PS, et al., Circulation 2009;119:62)
Advanced Echo Hemodynamics: Have Some Skepticism
Strain Echocardiography
Treatment Concepts Treat the underlying cause (Htn, AS)
Maintain fluid balance: low-sodium diet, volume restriction, diuretics, dialysis
Avoid tachycardia: β-blockers, CCBs
Restore/maintain sinus rhythm
Promote remodeling: ACE-I, ARBs, aldosterone antagonists, endothelin antagonists
Relieve ischemia
aggressive Rx of diabetes? PPAR-γ agonists?
Treatment Concepts- 2 There are no convincing data to guide decisions with regards to initial therapy – most important thing is to control BP (except not alpha blocker)
ACE-I and ARBs have best record for reducing collagen, although outcomes trials have been mixed (CHARM-Preserved, I-PRESERVE were negative; Swedish registry trial positive)
Some interesting studies will soon be completed evaluating angiotensin receptor – neprilysin inhibitors (LCZ696)