Voorjaarsvergadering 2021 HFpEF: putting the puzzle together!

Voorjaarsvergadering 2021

HFpEF: putting the puzzle together!

Medicatie bij HFpEFLoek van Heerebeek, Cardiologist, MD, PhD, MSc, FESC

Disclosures

(Potentiële) belangenverstrengeling

Consultancy: Astrazeneca, Bayer

Voor bijeenkomst mogelijk relevantie relaties met bedrijven

Research grant: Astrazeneca

Honorarium of andere (financiële) vergoeding

Speaker fees: Abbott, Astrazeneca, Bayer, Boehringer Ingelheim, Novartis, Servier, Vifor

Welke medicatie adviseert u voor de behandeling van HFpEF?

Vraag 1 Wordcloud

HFpEF

Heart failure: Treatment

*SGLT2-I

*sGC

stimulator

ESC ACC/

AHA

Diuretics IB IC

Comorbidities IC IB

(HT)

MRA - IIb

ARB - IIb

Cardiac comorbidities

BB, ACE-I, ARB

(Hypertension)

- IIa

Afib - IIa

Revascularization - IIa

LV filling:“Suction”

Diastolic LV (dys)function

Nagueh SF et al. Eur J Echocardiogr 2009:10:165; Oh. Circulation 2009;120:802

Normal diastolic function

LV filling:“Pushing”

Diastolic dysfunction

Diuretics in HFpEF

HFpEF:

Stiff LV coupled to

stiff arteries

Borlaug, Eur Heart J 2011;32:670

Small volume increase: Large LVFP

Small volume depletion: RR and renal dysf

HFpEF1) HF symptoms 2) LVEF ≥ 50% 3) Diastol dysfunction; NT-proBNP; Struct. abnorm. (LVH; LAE)

HFpEF: a heterogeneous syndrome

Cardiomyopathy

*Amyloidosis

*Sarcoidosis,

*Hemochromatosis

*Fabry

*HCM/RCM

RV EMB HFpEF: 14% amyloid

Amyloidosis

Hahn VS, JACC Heart Fail 2020;8:712

HFpEF1) HF symptoms 2) LVEF ≥ 50% 3) Diastol dysfunction; NT-proBNP; Struct. abnorm. (LVH; LAE)

Cardiomyopathy

*Amyloidosis

*Sarcoidosis,

*Hemochromatosis

*Fabry

*HCM/RCM

Condition Disease

Endocardium EMF

Pericardium Constrictive

pericarditis

Autoimmune SLE, RA

Endocrine Thyroid, Addison,

Cushing

Valvular AoS

Coronary CAD

HFpEF: a heterogeneous syndrome

Targeted therapy

Miscellaneous

Targeted therapy

Comorbidities

Shah S…van Heerebeek L, Paulus WJ. Circulation 2016;134:73

Comorbidities drive myocardial structural and function remodeling

through coronary endothelial dysfunction

Metabolic/inflammatory

(Obesity) HFpEF

phenotype

Voor welke medicatie ziet u een rationale bij een patient

met metabool HFpEF subphenotype?

Vraag 2 Wordcloud

HFpEF: Targeting obesity- HFpEF phenotype

Na+ retention

and plasma

volumeObesity

HFpEF

LV volumes

with cardiac

overfilling

Interstitial and perivascular

fibrosis

Microvascular

inflammation/rarefaction

High cardiomyocyte

stiffness

↓ Cardiac

distensibility

Neprilysin

inhibitors

Mineralocorticoid

receptor antagonists

SGLT2

inhibitors

Sacubitril/valsartan and MRA in phase 3 HFpEF trials

Pitt B et al. NEJM 2014;370:1383

TOPCAT: HFpEF (n=3445; LVEF ≥45%);

→ Prim EP: Composite of CV death, aborted

cardiac arrest or HFH

Solomon SD et al. NEJM 2019;381:1609

Valsartan (n=2389)

1009 events;14.6/100 pt yrs

Saccubitril/valsartan (n=2407)

894 events;12.8/100 pt yrs

HR 0.87 (95% CI 0.75-1.01)

P = 0.059

HFpEF pts (n=4822; LVEF ≥45%; NYHA II-IV)

randomized 1:1 sacubitril/valsartan vs valsartan

→ Prim EP: Composite of CV death and HFH

Bhatt DL et al. NEJM 2020;Nov 16

SOLOIST-WHF trial

T2DM WHF pts (n=1222); HFrEF (80%), HFpEF

(20%) (ACE-I/ARB 82%, ARNI 15%, BB 92% MRA

65%); sotagliflozin or placebo; Prim EP: total events

of CV death, HFH, urgent HF visits

First occurrence of

CV death or HFH

↓Vasodilation

SGLT-2 inhibitors and cardiorenal effects

Newman JD et

al. JACC

2018;72:1856

Verma S et al. Diabetologia 2018;61:2108

↓Glomerular hyperfiltration

Cardiac pleiotropic effects

GLP1-RA?

Withaar et al. Cardiovasc Res 2020

Welke niet-medicamenteuze interventie adviseert u bij een

patient met HFpEF?

Vraag 3 Wordcloud

Life style and exercise training

Kitzman JAMA 2016;315:36

Obese (BMI 39 kg/m2) HFpEF pts (n=100)

randomized to aerobic exerc training (AT)

caloric restriction (CR) or both

for 20 weeks;

Prim EP: peak VO2 and quality of life

HFpEF – HD monitoring devices

Adamson Circ Heart Fail 2014;7:935

CardioMEMS HD guided HF management improves HF hosp in HFpEF

*Hosp rate >6 mths: 46% lower; hosp rate at 18 mths: 50% lower

*More therapeutic changes in vasodilators/diuretics in HD guided group

Sondergaard et al. Eur J Heart Fail 2014;16:796; Feldman T et al. Circulation 2018;137:364

Interatrial shunt device to lower LA pressures

Phase 2, multicenter RCT; HF pts(n=44; EF ≥40%),

NYHA III-IV, exercise PCWP ≥25 mmHg; 1:1 to IASD vs

sham procedure.

*Prim EP: exercise PCWP 1 mth

Peak PCWP ↓ by 3.5 ± 6.4 mmHg in IASD vs

0.5 ± 5.0 mmHg in control.

No peri-procedural or 1-mth MACCE

Kaye DM Circ Heart Fail 2016;9:e003662; Shah SJ et al JAMA Cardiol 2018;3:968

Interatrial shunt device to lower LA pressures

REDUCE LAP I 1-yr outcomes; HF pts(n=64; EF ≥40%), NYHA II-IV, PCWP >15 mmHg

or ≥25 mmHg with exercise

*Prim EP: exercise PCWP 1 mth

IASD: greater reduction in exercise PCWP (p=0.028); No peri-procedural or 1-mth

MACE

HFpEF1) Diuretics 2) Comorbidities 3) Hypertension, Afib, Coronary disease (ACC/AHA)

Condition Disease

Endocardium EMF

Pericardium Constrictive

pericarditis

Autoimmune SLE, RA

Endocrine Thyroid, Addison,

Cushing

Valvular AoS

Coronary CAD

HFpEF: a heterogeneous syndrome: no “one size fits all” approach

Miscellaneous

Targeted therapy

Cardiomyopathy

*Amyloidosis

*Sarcoidosis,

*Hemochromatosis

*Fabry

*HCM/RCM

Targeted therapy

Comorbidities

SGLT2-I, ARNI, MRA, GLP1-RA?

“Devices”?

Myofilament

dysfunction

Endothelial dysfunctionAbnormal calcium

handling

Myocardial

fibrosis

Mitochondrial

dysfunction

*↑cGMP/PKG sign

*Heat shock proteins

*PDE modulation

*Cross-bridge modulation

(mavacamten)

*↓Inflammation

*↓Oxidative stress

*Endothelial-

cardiomyocyte signaling

*↓Fibrosis

(Pirfenidone)

*↑ Metabolism

(Iron, trimetazidine,

elamipretide,

perhexilene)

HFpEF: Current ongoing myocardial research targets

Lewis GA et al. JACC 2017;70:2186

In summary…..

HFpEF:

• Heterogeneous syndrome; no “one size fits all” therapeutic approach

• Identify etiology to enable targeted therapy

• Paradigm: comorbidities induce structural and functional cardiac remodeling

through coronary microvascular endothelial inflammation

• Hypothesis: Metabolic HFpEF phenotype may respond more favourably to

current HF drugs