HEART FAILURE WITH PRESERVED EJECTION FRACTION

1. Heart Failure with
Preserved Ejection
Fraction
Gopal C Ghosh

2. Yancy et al. 2013 ACCF/AHA Heart Failure Guideline

3. HFpEF vs Diastolic Heart Failure
What’s in a Name?
• Patient with HF -----> minimal diastolic dysfunction
• Diastolic dysfunction features --- > but no HF
(Hypertensive heart disease)
• Key non-diastolic features such as limited systolic
reserve, abnormal volume regulation, and
maladaptive ventricular–arterial interaction
• In other words, a normal-range EF did not imply
normal systolic function

4. Figure : Average Longitudinal and Circumferential Systolic StrainAverage longitudinal strain (red bars) and
circumferential systolic strain (green bars) among normal controls (n = 50), hypertensive heart disease (HHD) patients (n =
44), heart failure with pre...
Impaired Systolic Function by Strain Imaging in Heart Failure With Preserved Ejection Fraction
Journal of the American College of Cardiology, Volume 63, Issue 5, 2014, 447–456

5. Impaired Systolic Function by Strain
Imaging in Heart Failure With Preserved
Ejection Fraction
• Strain imaging detects impaired systolic function
despite preserved global LVEF in HFpEF that may
contribute to the pathophysiology of the HFpEF
syndrome
• Frankly elevated filling pressure based on an E/E’
ratio 15 or more was present in only 49% of the
patients

6. Scheme for diagnosis of heart failure with preserved ejection fraction
Michel Komajda, and Carolyn S.P. Lam Eur Heart J
2014;35:1022-1032
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author
2014. For permissions please email: journals.permissions@oup.com

7. Working definition
• Clinical diagnosis of congestive heart failure
Framingham criteria – 2 major or 1 major + 2 minor
Ejection fraction normal (>50%)
• No consensus in US on need for DD or hypertrophy
• No significant valvular abnormalities by echocardiography
Major Minor
PND or orthopnea DOE
Rales Nocturnal cough
HJR Tachycardia
S3 Ankle edema
JVD (or elevated CVP) Hepatomegaly
CXR pulmonary edema CXR engorged pulm vessels
Cardiomegaly Pleural effusion
10lb weight loss with diuretics Decreased vital capacity
HPI
PE
Imaging
Empiric!
Yancy et al. 2013 ACCF/AHA Heart Failure Guideline

8. Arguments for heart failure with preserved ejection fraction as a transitory stage to heart failure with
reduced ejection fraction (left) vs. heart failure with preserved ejection fraction as a distinct entity from
heart failure with reduced ejection fraction (right).
Michel Komajda, and Carolyn S.P. Lam Eur Heart J
2014;35:1022-1032
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author
2014. For permissions please email: journals.permissions@oup.com

9. Epidemiology
Prevalence, hospitalizations, mortality

10. • The mortality rate among patients with diastolic
heart failure ranges from 5 to 8 percent annually, as
compared with 10 to 15 percent among patients
with systolic heart failure
• Heart failure developed within five years in 11 to 15
percent of persons older than 65 years of age who
had no clinical evidence of heart disease but had
Doppler evidence of left ventricular diastolic
dysfunction
Aurigemma GP et al: The Cardiovascular Health Study.
J Am Coll Cardiol 2001;37:1042-1048

12. Increasing proportion of HFpEF
Owan TE et al. N Engl J Med 2006;355:251-259.

14. Admissions for HFPEF vs HFREF
Owan TE et al. N Engl J Med 2006;355:251-259.

15. Mortality for patients with HF-PEF (heart failure with preserved left ventricular ejection
fraction) and HF-REF (heart failure with low left ventricular ejection fraction), adjusted for age,
gender, aetiology of heart failure, hypertension, diabetes, atrial fibrillation.
Meta-analysis Global Group in Chronic Heart Failure
(MAGGIC) Eur Heart J 2012;33:1750-1757
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author
2011. For permissions please email: journals.permissions@oup.com

16. CONTs......
• Hong Kong: HFpEF accounts for 67% of HF admissions
• Clinical outcome same as HFrEF (Inhospital, 30 days & 1 year
mortality)
• 40% of deaths are non-cardiac
Yip GW et al. Am J Cardiol. 1999;84:563–567
Sharma K et al. Circulation Research.2014; 115: 79-96

17. Pathophysiology and
management

18. Physiologic definition
• Elevated LVEDP (filling pressure)
• Especially during exacerbation or exertion
• Increased stiffness (LV EDPVR)
Systolic dysfunction
Impaired contractility
Diastolic dysfunction
Impaired relaxation
Higher LVEDP
Burkhoff. Heart Failure With a Normal Ejection Fraction: Is It Really a Disorder of Diastolic Function? Circulation. 2003; 107:656-658

20. Poor exercise tolerance – fatigue
and DOE
• Why does exercise make anyone tired?
• VO2max ~ CO x O2 extraction
• Ventilation/lactate threshold
• Normally CO increases with HR, SV, contractility while
simultaneously decreasing stiffness to improve filling to match
needs
• In HFPEF, HR limits diastolic filling time, stiffness (EDPVR)
paradoxically worsens
Larger LVEDP
necessary,
causes DOE
Limited HR and limited
LVEDV results in non-optimal
use of Frank-Starling curve,
reduces CO (and thus
VO2max) and causes fatigue
Abudiab. Cardiac Output Response to Exercise in Relation to Metabolic Demand in heart Failure with Preserved Ejection Fraction. Eur J Heart Fail. 2013; (15):776-785

21. Pathogenesis
What mediates stiffening / fibrosis?
No theory is definitive, but many acknowledge high
burden of comorbidities

22. Microvascular inflammation
endothelium
cardiomyocyte
interstitial fibrosis
cardiomyocyte stiffening
Paulus. A Novel Paradigm for Heart Failure with Preserved Ejection Fraction. 2013; 62(4)

23. Inside the cardiomyocyte
Kavita Sharma, and David A. Kass Circulation Research. 2014;115:79-96

24. Non-cardiac mechanisms
Kavita Sharma, and David A. Kass Circulation Research. 2014;115:79-96

26. HFpEF a uniform syndrome?
• HFpEF is not homogeneous, but is rather a
heterogeneous condition consisting of several
pathophysiological subtypes

28. MANAGEMENT

30. Hong Kong trial
• 150 patients with HFNEF (LVEF >45%) were
randomised
• QoL (Minnesota Heart Failure Symptom
Questionnaire), 6-minute walk test (6MWT) and
Doppler echocardiography were performed at
baseline, 12, 24 and 52 weeks

31. Hong Kong trial
• ACE(Ramipril) vs. ARB(Irbesartan) vs. diuretics
Yip GWK, et al. Heart 2008;94;573-580.

32. PEP-CHF STUDY
• 53 european centres
• Mean follow up 26.2
months
• EF 40% or more(Or
wall motion score
index >1.4)

33. Kaplan–Meier curves showing time to first occurrence of the primary endpoint, all-cause
mortality or unplanned heart failure related hospitalization, for the entire duration of the study.
John G.F. Cleland et al. Eur Heart J 2006;27:2338-2345
© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail:
journals.permissions@oxfordjournals.org

35. I-PRESERVE
• 4128 patients who had heart failure with a preserved
ejection fraction(EF>45%)
• Rates of hospitalisations were also same

37. CHARM PRESERVED TRIAL
• n=3023; LVEF >40%
• Patients were randomized to candesartan, titrated to
32 mg QD, or placebo and were followed up for a
median of 37.7 months

39. Figure Time to cardiovascular death or hospital admission for CHF
Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-
Preserved Trial
The Lancet, Volume 362, Issue 9386, 2003, 777 - 781

40. CHARM Preserved Trial
CV Mortality or
CHF hospitalization
HR 0.89
p=0.118
22.0%
24.3%
0%
10%
20%
30%
Candesartan Placebo
11.2% 11.3%
0%
5%
10%
15%
Candesartan Placebo
European Society of Cardiology 2003
CV Mortality
HR 0.99
p=0.918

42. VALIDD Trial: supporting antihypertensive Tx
Valsartan In Diastolic Dysfunction
Lowering blood pressure improves
diastolic function irrespective of
the type of antihypertensive
agent used.
Solomon SD. Lancet 2007; 369: 2079–87

43. OPTIMIZE HF Registry

44. From: Clinical Effectiveness of Beta-Blockers in Heart Failure: Findings From the OPTIMIZE-HF
(Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure)
Registry
J Am Coll Cardiol. 2009

45. OPTIMIZE – HF: Betablockers
Hernandez, et al. JACC. 2009 Jan 13;53(2):184-92
Diastolic heart failure Systolic heart failure

46. SENIORS

47. Trial profile.
Marcus D. Flather et al. Eur Heart J 2005;26:215-225
European Heart Journal vol. 26 no. 3 © The European Society of Cardiology 2005; all rights
reserved.

48. SENIORS: Nevibolol
Study of the Effects of Nebivolol Intervention on Outcomes and Hospitalisation in
Seniors with Heart Failure)
Ghio S, et al. Eur Heart J. 2006;27: 562–568

49. SWEDIC

50. SWEDIC: Carvedilol
Bergstrom A. Eur J Heart Fail. 2004;6:453-61.
Swedish Doppler-echocardiographic study

51. ALDO-CHF
• Men and Women aged >50 years , had current heart
failure symptoms consistent with New York Heart
Association (NYHA) class II or III, left ventricular
ejection fraction (LVEF) of 50% or greater
• ECHO evidence of diastolic dysfunction

52. Date of download: 3/13/2016
Copyright © 2016 American Medical
Association. All rights reserved.
From: Effect of Spironolactone on Diastolic Function and Exercise Capacity in Patients With Heart Failure With
Preserved Ejection Fraction: The Aldo-DHF Randomized Controlled Trial
JAMA. 2013;309(8):781-791. doi:10.1001/jama.2013.905
Error bars indicate 95% CI. P values describe comparisons of the changes in the placebo or spironolactone group at the respective
time point vs baseline. No further improvement by spironolactone occurred between the 6-month and 12-month visits (P = .39 for
E/e′).
Figure Legend:

53. TOPCAT
• Patients 50 years of age or older
• Clinically defined signs and symptoms
• Left ventricular ejection fraction of 45% or more
• Spironolactone 15-45 mg

54. Incidence Rates of the Primary Composite
Outcome, Its Components, and Additional
Secondary Outcomes
Pitt B et al. N Engl J Med 2014;370:1383-1392.

55. Kaplan–Meier Plots of
Two Components of the
Primary Outcome

56. RAAM PEF-EPLERENONE
• Exercise capacity- improves
• Markers of collagen turnover-decreased
• Diastolic function- improves
• DIG-PEF trial
• RELAX trial

57. Statins in diastolic HF

58. Figure : Kaplan-Meier survival and survival without cardiovascular (CV) hospitalization in
propensity-matched patients grouped by statin therapy.
Hidekatsu Fukuta et al. Circulation. 2005;112:357-363
Copyright © American Heart Association, Inc. All rights reserved.

59. Role of NO—cyclic guanosine 3′,5′-monophosphate (cGMP)—protein kinase-G activity (PKG)
pathway in heart failure with preserved ejection fraction.
Michel Komajda, and Carolyn S.P. Lam Eur Heart J
2014;35:1022-1032
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author
2014. For permissions please email: journals.permissions@oup.com

60. Key points
• Relatively recent term, HFPEF = clinical dx of CHF
+ preserved EF
• Half of all CHF, just as lethal
• Characterized by abnormal stiffness (up+left shift of
LV end diastolic pressure-volume relationship – LV
EDPVR)
• Especially fragile exercise capacity, fatigue, DOE
• Unclear how it happens, comorbidities likely key
• No tx strategy for HFREF has worked in HFPEF