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

SHF HFNEF

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 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/dt max at invasive catheterization The -dP/dt max, 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 LV pressure Grade 1 Grade 2 Grade 3 Grade 4 Mitral flow Tissue Doppler Pulmonary vein E/e’ E e’ < >15>15

Nagueh et al: JACC, 1997 Ommen et al: Circ, 2000 Annulus e Mitral E E/e As LV filling pressure 

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