Download Diastolic LV function and HFNEF

Diastolic LV function and HFNEF
FRIJO JOSE A
• Approximately 50% of pts with HF have a
normal or near normal LVEF
Mayo Clinic registry
•
•
•
•
•
•
Women
Hypertension (up to 88%)
Obesity (BMI >30 kg/m2 → 40%)
Renal failure
Anemia
AF
• Diabetes (30%)
• CAD (40%-50%)
similar to that in HF patients with impaired LVEF
• Lower overall mortality in HFNEF v/s SHF
patients (2.8% vs 3.9%; P = 0.005)
• Symptom burden, duration of ICU stay &
hospital stay, long-term mortality – similar
ADHERE database- 52,187 patients
Clinical ∆ of HF (Framingham criteria) and an
LVEF > 50%
• True- typically excluded
– “significant” CAD(most often clinically assessed)
– Hypertrophic cardiomyopathy
– Valvular heart disease
Morphologic Features
• Higher cardiomyocyte diameter
• Higher myofibrillar density
• Collagen volume fraction was similar
D/D to the Syndrome of HFNEF
Diastolic function
• Major factors influencing relaxation
– Cytosolic Ca level must fall- requires ATP &
phosphorylation of phospholamban
– Inherent viscoelastic properties of myocard –
(hypertrophied heart -↑fibrosis, relaxation –
slower)
– ↑ phosphorylation of troponin I
– Influenced by systolic load- ↑ the systolic load,
the faster the rate of relaxation
Diastolic function
• SHF pts →LV pressure–volume analysis →less
steep slope of end-systolic LV pressure–
volume relationship
• HFNEF pts →
– Upward and leftward shifted end-diastolic
pressure–volume relationship
– End-systolic pressure–volume relationshipunaltered or even steeper
HFNEF
• ↑LV stiffness
– Very small changes in LVEDV→ Marked ↑ in
LVEDP & pulm venous P→ dyspnea during
exercise, even pulm edema
– Impaired LV filling and inability to use FrankStarling mech→ Failure to ↑CO during exercise→
Exercise intolerance
Is diastolic dysfunction the only explanation?
• TDI - ↓ systolic mitral annular amplitudes—in
HFNEF pts V/S controls
• These changes – not as pronouncd as in SHF pts
• ? initial abn compensated for by ventri
hypertrophy & neurohormonal activation
→hypercontractile LV state with abn relaxation
→resistance to LV filling →progress →phenotype
characteristic of SHF
• However, data lacking & progression have been
shown to occur rarely
• 2,042 participants
• Incidence of mod-sev LV diast dysf in presence
of an LVEF >50% - 5.6%
• Only ~ 1% of study population had symptoms
of HF & an LVEF >50%.
Redfield MM et al. JAMA 2003;289:194 –202.
– 37 HFNEF pts (prev pulm edema, LVEF >50%)
– 40 pts with hypertensive LVH without HF
– 56 control subjects
• HFNEF V/S HTN LVH and control - ↑LV mass
index, ↑conc LV geometry, ↑E/E’ ratio, ↑LA
volume
• Distinguished HFNEF pts very well from
control but not from asymptomatic
hypertensive LVH
• Product of LV mass index and LA volume highest accuracy for predicting HFNEF
Melenovsky V et al. J Am Coll Cardiol 2007;49:198–207
• Anemia, renal dysf
• ? Volume overload rather than an intrinsic abn
of LV diastolic function -pathophysio of HFNEF
LV systolic function
• LVEF as a measure of LV systolic function questioned-load dependence
• Annular peak syst velocity (TDI) ↓in HFNEF
• Still controversial- whether LV syst function is
N in HFNEF
Ventriculovascular coupling in HFNEF
• Effective art elastance- global measure of art stiffness(LVESP/SV)- ↑ HFNEF pts
• Combined ventri-art stiffening contributes to HFNEF
Mechanisms
– 1) exaggerated↑ SBP after small ↑ in LVEDV
– 2) a marked ↑ SBP after a further ↑ in art elastance in
presence of a high ES elastance
– 3) limited systolic reserve due to ↑ baseline ES elastance
– 4) ↑ cardiac work to deliver a given CO
– 5) a direct influence of ↑ art elastance on LV diast functn
First 2 also explain sensitivity of these pts to overdiuresis & aggr vasodilator
therapy
Role of Atrial Fibrillation
Atria
• Blood-receiving reservoir chamber
• Contractile chamber
• Conduit
• Volume sensor of the heart, releasing ANP in
response to intermittent stretch
• Contains receptors for afferent arms of various
reflexes
– mechanoreceptors that ↑sinus discharge rate,
thereby contributing to the tachycardia of exercise as
the venous return increases (Bainbridge reflex)
Role of Atrial Fibrillation
• The prevalence of AF in HFNEF ≈ 20% to 30%
• Fung et al- HFNEF pts with AF (29%) had ↓ functional
class & quality of life than without AF
• CHARM - AF →adv CV outcomes irrespective of
baseline LVEF
– High HR, loss of atrial systole, irr cycle length with implications of the
Frank-Starling mechanism, episodic nature
• Echocardiographic assess challenging
– Fung et al - similar E/E’ ratios in HFNEF with and without
AF but larger LA size in AF
– Melenovsky et al - LA emptying fraction ↓in HFNEF pts
than hypertensive LVH & during handgrip, late diastolic
annular tissue velocity - unchanged in HFNEF but ↑ in
control (5% vs. 35%)
Role of Coronary Artery Disease
• Ischemia affects early diastole by ↑ Tau
• Reversed after removal of ischemic burden by
CABG
?Considerable no of pts with atypical
presentation of ischemia (silent/dyspnea)
labeled as HFNEF
• 15% incidence of hospital admission due to
UA in pts previously ∆ with HFNEF -38/12
Volume overload
• HF with either ↓/N EF is a Na-sensitive
condition
• HFNEF- ↑ likely to have multiple
comorbidities that may contribute to volume
overload
– Renovascular disease, obesity, OSAHS, anemia
• Plasma volumes of HTN HFNEF - ↑ by an
average of 16% compared with N controls
despite daily diuretic use
• UNLOAD -ultrafiltration -186 pts -45 NEF→½
ultrafiltration, other ½ IV diuretics
• Volume expansion precedes sympt, volume
removal alleviates sympt without inducing
hypotension/end-organ dysf
• HFNEF → ↑ risk of recur of fluid overload
• A/c pulm edema - common manifestation of
HFNEF→ diuretics remain mainstay
• Diuretics & dietary salt restrict- paramount to
care of HFNEF pts
Venoconstriction/volume redistribution
• ≈ 85% of blood vol- venous circulation
• Small alterations in venous tone & capacitance
(esp splanchnic bed) → impact the distri of
intravasc vol - imp determinant of LVED filling P
– Data lacking
– Most imp drugs used in a/c pulm edema →
venodilators & diuretics
? Improvements-at least partly due to ↓autonomic
tone & resulting ↑in venous capacitance
Diagnosis of HFNEF
2007- European Working Group on HFNEF
3 conditions must be fulfilled
– 1) symptoms & signs of HF
– 2) LVEF >50% in a nondilated LV (LVEDV<97 ml/m2)
– 3) evidence of ↑LV filling P
3 ways to ∆ ↑ LV filling P
– invasive measurements
– unequivocal TDI findings
– combination of ↑natriuretic peptides & echo indices
of LV diastolic function/LV filling P
Paulus Wjet al -European Society of Cardiology. Eur Heart J 2007;28:2539 –50
Symptoms & Signs of HF
Invasive Diagnostics
• Prolonged & ↑ Tau- require sophist
measurement
• ↑ LVEDP /PCWP - suggested to be appropriate
for ∆ of HFNEF in the presence of HF sympts &
LVEF>50%
• The rate of isovolumic relaxation - best measured by
negative dP/dtmax at invasive catheterization
• The -dP/dtmax, which gives the isovolumic relaxation
rate- measured either invasively or by a CW Doppler
velocity spectrum in AR
• Isovolumic relaxation is ↑when rate of Ca uptake into
the sarcoplasmic reticulum (SR) is ↑
• Tau- time constant of relaxation- describes rate of fall
of LV pressure during isovolumic relaxation -also req
invasive for precise determination
Isovolumic pressure decay
• Simplest way of quantifying the time course of LV
pressure decline - peak -dp/dt
• Peak -dp/dt - altered by myo relaxation &
changes in loading conditions
– For eg, LV peak -dp/dt ↑ when Ao pressure ↑ - ie, ↑
in LV peak -dp/dt from -1,500 to -1,800 mm Hg/sec
could be caused by an ↑ in rate of myo relaxation, a
rise in Ao pressure, or both
• LV peak -dp/dt is ↓during myo ischemia & is ↑ in
response to – β adr stimulation &
phosphodiesterase inhibitor milrinone
• It is not ↑ by digitalis glycosides
Echocardiography
• Currently most sensitive & widely available
technique for assessment of LV diastolic function
–TDI
• Whereas the ratio of early to late diastolic peak
mitral inflow velocities exhibits a J-shaped
relationship with LVEDP, TDI velocities
continuously decline from N to advanced LV
diastolic dysfunction
• As a consequence, E’ ↓ & E/E’ ratio continuously
↑with advanced LV diastolic dysfunction
• E/E ’ ratio >15 → mean diastolic LV pressure
>12 mm Hg
• E/E ’ ratio >15 - ∆ of ↑ LV filling pressure and
thus HFNEF
• An E/E ’ ratio 8 – 15- asso with very wide
range of mean LV diastolic pressures, thus,
further measurements suggested
• Values for E ’ at the lateral annulus are
generally higher than at medial annulus,
resulting in lower E/E ’ ratios at the lateral
annulus
Diastolic Dysfunction
Grade 1
Grade 2
Grade 3
Grade 4
LV
pressure
Mitral flow
Tissue
Doppler
E
e’
Pulmonary
vein
E/e’
< 10
10 -15
>15
>15
As LV filling
pressure 
Mitral E
Annulus e
E/e
Nagueh et al: JACC, 1997 Ommen et al: Circ, 2000
• Measurement of velocity of mitral annular
ascent during early diastole (e′vel) with TDI →
relatively preload-independent measure of LV
relaxation that correlates inversely with tau
• E/e′ ratio is a fairly accurate predictor of the
presence of elevated filling pressures
Area-length method for
calculation of LV mass
LVmass=1.05[5/6(A1xL1)-5/6(A2xL2)]
Divide by body surface area to get LV mass index
Reichek et al. Circulation 1983;67:348-52
Natriuretic peptides
• BNP & NT-proBNP- established tools for
exclusion of possible HF in patients presenting
to the emergency room with dyspnea of
unclear origin
• Among patients with preserved LVEF but not
necessarily HF, BNP & NT-proBNP levels –
related to severity of LV diastolic dysfunction
• Used to distinguish a N from a
“pseudonormal” LV filling pattern
Treatment
• Aggressive treatment of hypertension and
diabetes
• Diuretic therapy & dietary salt restrictions is
paramount
• Compelling indication for ACEI/ARBs in many
patients (DM +LVH), But,
– Candesartan (the CHARM-PRESERVED trial)
– Irbesartan (the I-PRESERVED)
– Perindopril (the PEP-CHF)
Did not reveal a survival benefit
VALIDD [VALsartan In Diastolic Dysfunction] study)
• SBP lowering in pts with HTN & LV diastolic
dysfunction
• Either with a valsartan-based regimen or a
regimen not including inhibitors of the RAAS
• Similar reduction in BP & an ↑diastolic
relaxation
• Suggests that BP control may be a key factor in
determining the response to treatment
Solomon SD et al. Lancet 2007;369:2079–87
• The Digitalis Investigation Group
• Evaluated effects of digoxin on all-cause mortality
and HF hospitalization in patients with HF
regardless of EF
• LVEF >45% (n = 988) –ancillary study parallel to
main trial
• Digoxin - no effect on all-cause mortality/CV
hospitalization
• Trend toward a ↓ in HF related hospitalizations
↔↑in hospitalizations for UA
Ahmed A et al. Circulation 2006, 114:397–403.
TOPCAT trial
• A trial for HF pts with preserved systolic
function
• Multi-center, international, randomized,
double blind placebo-controlled trial
• Spironolactone
• 4500 adults with HF &LVEF >45%
• Enrollment started -Aug 2006 & is ongoing
ACC/AHA Guidelines for Treatment of Patients with Heart
Failure and Normal Left Ventricular Ejection Fraction-2005
update
Class l
• Control systolic & diastolic HTN
• Control ventricular rate in pts with AF
• Diuretics to control pulm congestion & periph
edema
Class lla
• Cor revascularization in pts with CAD in
whom sympt/demonstrable myo ischemia is
judged to be having an adverse effect on
cardiac function
• Restoration & maintenance of SR in pts with
AF might be useful to improve symptoms
• Class llb
• Use of β-blockade, ACEIs, ARBs, or CCA may
minimize heart failure sympt
• Use of digitalis to minimize sympt is not well
established
HFNEF—the Future?
• Elucidate the mech responsible for HFNEF
– Ischemia, uncontrolled HTN, AF must be clearly
defined
– In particular, inducible ischemia must be searched
actively
Possible therapeutic strategies
• Active relaxation - Ca uptake into the sarc
reticulum - sarc reticulum Ca ATP-ase type 2
– Gene transfer –suggested possible strategy
– Percutaneous delivery of a modified
phospholamban encoded in an adenovirus
Studeli R et al. Am J Transplant 2006;6:775– 82
• Passive LV stiffness - Advanced glycation end
products cross-links breaker, Alagebrium- Pilot
study in 23 HFNEF pts - ↓LV mass & an ↑ in E‘
-currently evaluated in a multicenter study
Little WC et al. J Card Fail 2005;11:191–5.
• Role of Sympath nervous system & RAAS in
HFNEF is largely unknown given that LVH is
asso with ↑sympath activity & more severe
LVH seems to be asso with ↑ likelihood of
HFNEF
• Sympathetic NS may play a role in the
pathogenesis of HFNEF
• Candesartan has been shown to ↓ the
sympath activity
• Β-blockers & negatively chronotropic CCBs –
HR lowering & prolongation of diastole results
in better LV filling and output
• Study evaluating purely HR-lowering agent
ivabradine in HFNEF is currently ongoing