Post on 22-Feb-2016
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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 relationship-
unaltered 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 Frank-Starling 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 PPaulus 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
LVpressure
Grade 1 Grade 2 Grade 3 Grade 4
Mitral flow
TissueDoppler
Pulmonaryvein
E/e’
E
e’
< 10 10 -15 >15 >15
Nagueh et al: JACC, 1997 Ommen et al: Circ, 2000
Annulus e
Mitral E
E/e
As LV fillingpressure
• 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 UAAhmed 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