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

http://www.fac.org.ar/scvc/llave/echo/roeland/roelandi.htm

• 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

http://www.fac.org.ar/scvc/llave/echo/roeland/roelandi.htm

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

THANKS ….