HFpEF

• # 50% of all HF pts

• Heterogeneous

Populations & etiologies, pathophysiology (complex)…

• Comorbidities

Age, HBP, diabetes, CKD, COPD, SAS, AF, metabolic syndrome…

• High readmission/mortality rates

More readmissions (for non-CV causes) & lower CV mortality

10-30% death/yr (50-70% CV)

• No evidence that any treatment alters its natural history

• HFPEF accounts for half the cases of HF

• Increasing incidence

• High mortality and morbidity (< than HFREF)

• Lack of effective therapies

• Surrounded by controversy

Diastolic dysfunction

HF with normal systolic function

HF with preserved ejection fraction

Eur Heart J 2012;33:150-57

Definition

•Signs and symptoms of heart failure

• If available and significantly elevated –

BNP/Pro-BNP

Normal or mildly abnormal LV ejection

fraction (>50%)

•Evidence of diastolic LV dysfunction:

•Invasive - LV end-diastolic pressure

>16 mm Hg or mean pulmonary

capillary wedge pressure >12 mm Hg

•Or Noninvasive

PATOPHYSIOLOGY

Diastolic dysfunction central role

• Longitudinal systolic dysfunction

• Impaired ventricular-arterial coupling

• Chronotropic incompetence

• Limited systemic vasodilator reserve

• Pulmonary hypertension

• Extracardiac causes of volume overload

Pathophysiological features of

HFPEF

• Abnormal passive elastic properties of

the LV

• Increased myocardial mass

• Alterations in the extramyocardial

collagen network

• Increased stiffness of the LV

NEW PARADIGM OF HFPEF

EXTENSIVE COMORBIDITIES

SYSTEMIC PRO-INFLAMMATORY STATE

OXIDATIVE STRESS IN ENDOTHELIUM

↓ NO

BIOAVAILABILITY

↓ PKG ACTIVITY

JACC 2013;62:263-71

IMPORTANT DIAGNOSTIC AND THERAPEUTIC IMPLICATIONS

LV HYPERTROPHY AND ↑ STIFFNESS

Meta-Analysis Global Group In Chronic Heart Failure

(MAGGIC)

HF PEF HF REF

n = 10347 n = 31625

Age 71 66 < 0.001

Female gender % 50 28 < 0.001

History hypertension % 51 41 < 0.001

Ischaemic aetiology % 43 59 < 0.001

Atrial fibrillation % 27 18 < 0.001

Eur Heart J, 2011

p-value

MAGGIC

European Heart Journal 2011

A case of true “diastolic” heart failure

CLINICAL PRESENTATION

EXERCISE-INDUCED HFPEF

• Exertional dyspnea • Exercise test central role

• No volume overload • BNP normal or mildly ↑

• Usually ambulatory • Lowest risk

HF WITH VOLUME OVERLOAD

• Signs and symptoms of HF •Acute presentation

• Inpatients or previous HF • ↑↑ BNP hospitalizations • High mortality and morbidity

RIGHT HEART FAILURE AND PULMONARY HYPERTENSION

• Right heart failure • Highest risk

• +/- pulmonary arterial HTN • ↑↑↑ BNP

Diagnostic Criteria

Major

• PND or orthopnea

• JVD >16 mm Hg

• Rales or acute pulmonary edema

• Cardiomegaly

• Hepatojugular reflex

• Response to treatment (weight loss >4.5 kg)

Framingham criteria: Two major or one major

and two minor criteria

Minor

• Ankle edema

• Nocturnal cough

• Exertional dyspnea

• Pleural effusion

• Hepatomegaly

• Tachycardia >120

bpm

Biomarkers – ACC/AHA Guidelines, 2013

Insuffisance cardiaque diastolique

The Good the Bad and The Ugly

Reversibility of the restrictive pattern

Temporelli JACC 98;31:1591

144 pts with congestive heart failure and DT < 125 ms

n = 327

n = 122

n = 49

Shim Heart 11;97:1417

n=498 pts with diastolic stress test; PH = SPAP > 50 mmHg at 50 W

Events = death + infarction + HF hospitalisation

Kirpatrick J et al, JACC, 2007

E/e’ may predict LV filling

pressure

Nagueh et al JACC, 2007

New markers of

diastolic function:

E/e’sr as prognostic factor

Ersboll EHJ 2014;35:648; 1048 pts w myocardial infarction

Death, stroke, afib, HF hosp.

New markers of

Santos

EHJHF

2014;16:1096

135 HFpEF pts

40 controls

diastolic function:

Paulus W J et al. Eur Heart J 2007;28:2539-2550

ESC Consensus Statement

Symptoms or signs of HF

LVEF > 50% and LVED VI < 97 ml/m²

Abnormal LV relaxation, filling, diastolic distensibility and stiffness

PCWP > 12 mm Hg or LVEDP > 16 mm Hg

E/E’ > 15 15 > E/E’ > 8

NT proBNP > 220 pg/ml or BNP > 200 pg/ml . LA dilation . LVH . A Fib.

From Paulus, Eur. Heart J., 2007

NT proBNP > 220 pg/ml

TD E / E’ > 8

TD

BNP > 200 pg/ml

Echo blood flow Doppler : . E/A DT . Pulmonary vein flow

HFpEF

ASE/EAE recommendations: estimation of filling

pressures in patients with normal EF

E/E’

Sep. E/E’ > 15

or

E/E’ < 8

(Sep, Lat, or

Av.)

Normal LA volume LA >34 ml/m2

Ar – A < 0 ms Ar – A > 30 ms

Valsalva E/A < 0.5 Valsalva E/A > 0.5

PAS <30 mmHg PAS >35 mmHg

IVRT/TE-E’ >2 IVRT/TE-E’ <2

Normal LAP Normal LAP LAP

Lat. E/E’ > 12

or E/E’ 9-14

Av. E/E’ > 13.5

LAP

IF

LAVI < 34 mL/m2 OR

e’ sep > 8 cm/s AND

e’ lat > 10 cm/s

no constrictive pericarditis

IF

LAVI > 34 mL/m2 AND

e’ sep < 8 cm/s OR

e’ lat < 10 cm/s

Grade I Grade II

E/A < 0.8 E/A 0.8 – 1.5

dec.time > 200 ms dec.time 160-200 ms

Avg E/e’ < 9 Avg E/e’ 9 - 12

(or hypovolemia

without diastolic

dysfunction)

If inconclusive, consider:

SPAP ↑, pulmonary venous S/D < 1, onset e’ later than onset E, LV wall

hypertrophy, and other signs

Flachskampf et al. JACC CV Img 2015, in press

no diastolic dysfunction

diastolic dysfunction

Grade III

E/A > 2

dec.time < 160 ms

Avg E/e’ > 12

Longitudinal function:

contractility from the base to the apex

Radial function:

contractility from the outer to the center of the LV cavity

Twist

Complexity of LV Anatomy and Functions

Rotation, Torsion & Twist

Speckle Tracking vs. Vector Velocity

Imaging

Kirpatrick J et al, JACC, 2007

HF-PEF: an evidence-free zone

EVIDENCE

Key large trials in HF-PEF

Cleland et al Eur Heart J. 2006;27:2338-45 Yusuf et al Lancet 2003;362:777-81

Massie et al N Engl J Med 2008;359:2456-67 Pitt et al N Engl J Med. 2014;370:1383-92

CHARM-Preserved: Primary outcome CV death or CHF hospitalisation

(%) 30 Placebo Treatment Group

25

20

15

10

5 HR 0.89 (95% CI 0.77-1.03), p = 0.118

0 p = 0.545

0 Number at risk : Candesartan 1514 1458 1377 833 182 Placebo 1509 1441 1359 824 195

I-PRESERVE: Primary Endpoint Death or protocol specified CV hospitalization 40 - Placebo 30 - Irbesartan 20 - P 0

P C Log-rank p=0.35 0 - HR = 0.89 (0.77-1.04), p = 0.138 0 No. at Risk Irbesartan 2067 1929 1812 1730 1640 1569 1513 1291 1088 816 497

Placebo 2061 1921 1808 1715 1618 1539 1466 1246 1051 776 446

Months 72 48 60

Perindopril Placebo

HR 0.92; 95% CI 0.70 to 1.21;

(years)

12 24 36

40

10

0 1 2 3

0

Placebo

Spironolactone

0 HR (95% CI) = 0.95 (0.86-1.05)

0 0 Number at risk:

PEP CHF AC mortality / HF Hosp Time to first occurrence of total mortality and unplanned HF 50 366 (24.3%)

Candesartan 30 333 (22.0%) 20

Adjusted HR 0.86, p = 0.051 P

1 2 3 3.5 years 0 Time Patients at risks : Perindopril 424 374 184 70 Placebo 426 356 186 69

TOPCAT (CV Death, HF Hosp., or Resuscitated Cardiac Arrest) (Mean follow-up 49.5 months)

0 351/1723 (20.4%) 0

0 320/1722 (18.6%)

10 -

0

6 12 18 24 30 36 42 48 54 60 Months from Randomization Spiro 1722 1502 1168 870 614 330 53 Placebo 1723 1462 1145 834 581 331 53

Disappointing randomized clinical studies • Digoxin DIG-PEF (Ahmed, 2006)

• Carvedilol J-DHF (Yamamoto, 2013)

Nebivolol ELANDD (Conraad, 2012)

SENIORS (VanVeldhuisen, 2009)

• Perindopril PEP-CHF (Cleland, 2006)

• Candesartan CHARM-preserved (Yusuf, 2003)

Irbesartan I-PRESERVE (Massie, 2008)

Olmesartan SUPPORT (Sakata, 2015)

• Spironolactone ALDO-DHF (Edelmann, 2013)

TOPCAT (Shah 2013, Pitt 2014)

Eplerenone RAAM-PEF (Deswaal, 2012)

• Sildenafil RELAX (Redfield, 2013)

PARAGON-HF Prospective comparison of ARni with Arb Global Outcomes in heart failure with preserved ejectioN fraction

PARAGON-HF: study design

Target patient population: 4300 patients with symptomatic HF (NYHA Class II–IV) and LVEF 45%

Active run-in period

LCZ696 200mg BID

Screening

Valsartan 160mg BID

On top of optimal background medications for

co-morbidities (excluding ACEis and ARBs)

up to 2 weeks 3–8 weeks ~240 weeks

Primary outcome: CV death and total

(first and recurrent) HF hospitalisations

(anticipated ~1721 primary events) *Valsartan 40mg BID (up to 2 weeks) followed by valsartan 80mg BID as an optional starting run-in dose for those patients being treated with less than the minimum dose of ACEi or ARB at Visit 1. ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; BID, twice daily; CV, cardiovascular; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association

ClinicalTrials.gov Identifier: NCT01920711 (https://clinicaltrials.gov/ct2/show/NCT01920711)

Randomisation 1:1

Double-blind treatment period

Valsartan LCZ696

80mg BID* 100mg BID

ACCF - AHA Guidelines

Pharmacological treatment, Stage C

Recommendations COR LOE

Systolic and diastolic blood pressure should be controlled according to

published clinical practice guidelines.

Diuretics should be used for relief of symptoms due to volume overload. I C

Coronary revascularization for patients with CAD in whom angina or

demonstrable myocardial ischemia is present despite GDMT.

Management of AF according to published clinical practice guidelines

for HFpEF to improve symptomatic HF

Use of beta-blocking agents, ACE inhibitors, and ARBs for hypertension

in HFpEF

ARBs might be considered to decrease hospitalizations in HFpEF IIb B (589)

Nutritional supplementation is not recommended in HFpEF.

ACE indicates angiotensin-converting enzyme; AF, atrial fibrillation; ARBs, angiotensin-receptor blockers; CAD, coronary artery disease; COR, Class or Recommendation; GDMT, guideline-directed medical therapy; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; LOE; and Level of Evidence.

C

I B (27,91)

IIa C

IIa C

IIa C

III: No

Benefit

What do the guidelines say

• Congestion Diuretic

Management of concomitant conditions+++

• Hypertension Betablocker/ACE-I/ARB

• Ischemia Betablocker/Revasc.

• AF preserve SR or control HR (digoxin)

• HBP, ischemia, AF Verapamil, Diltiazem

• Overweight/diabetes Diet, Exercise, Drugs

Beta-blocker†

Ventricular rate Ventricular rate controlled ? controlled ?

No Yes Yes No

Add digoxin Add digoxin

Ventricular rate Ventricular rate controlled ? controlled ?

Rate control in CHF

ESC Guidelines

2012 controlled ? controlled ?

No Yes No

Seek specialist advice, Seek specialist advice, including consideration of including consideration of AV node ablation AV node ablation

HF REF HF PEF

Substitute beta-blocker (or rate-limiting CCB) for digoxin

Rate-limiting CCB° (or Beta-blocker)

No Yes Yes No

Substitute amiodarone for digoxin

Ventricular rate Ventricular rate

Yes

Maintenance therapy

Management: Future expectations

EXERCISE TRAINING

DRUGS

• Advance glycation end-products cross-link breakers/alagebrium

• Guanosine Triphosphate binding proteins blockers/statins

• Selective sinus node If channel inhibitor/ivabradine (EDIFY, EUDRA)

• Angiotensin receptor-neprilysin inhibitor/LCZ696 (PARAGON-HF)

• Soluble guanylate cyclase stimulator/vericiguat (SOCRATES)

• Selective inhibitor of the late sodium (INa+)current /ranolazine

• Specific mRNA blockers

DEVICES

• Renal denervation; Vagal nerve/Baroreceptor stimulation

• Wireless PAP monitoring (CHAMPION)