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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)