Heart Failure with Normal Ejection

Fraction (HFNEF): What the hospitalist

needs to know

Moises Auron, MD FAAP FACP

Hospital Medicine

11/02/21
 Outline
• Diagnostic Criteria
• Epidemiology
• Etiology
• Physiology and Patophysiology
• Clinical Manifestations
• Diagnosis
• Prognosis
• Treatment
11/02/21
 Diagnostic Criteria
• Symptoms and signs compatible with
heart failure
• Left ventricular ejection fraction >50%
• Exclusion of severe valvular disease and
pericardial disease
• Diastolic dysfunction

Hunt SA et al. ACC/AHA 2005 Guideline Update for the Diagnosis and
Management of Chronic Heart Failure in the Adult. Circulation 112: e154–e235

11/02/21
 Outline
• Diagnostic Criteria
• Epidemiology
• Etiology
• Physiology and Patophysiology
• Clinical Manifestations
• Diagnosis
• Prognosis
• Treatment
11/02/21
 Epidemiology
• 20% to 60% of patients with HF
• Increasing prevalence

11/02/21 Hunt, et al. 2009 ACCF/AHA Heart Failure Guidelines. (Circulation. 2009;119:e391-e479.
Owan T, et al. NEJM. 2006;355:251-9
 Epidemiology
Increased prevalence with age:
Age Prevalence
50 15%
50-70 33%
> 70 50%

Zile MR. Circulation. 2002; 105(11): 1387-93.

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 Epidemiology
• More frequent in elderly female
– Diastolic HF – 79%
– Systolic HF – 49%
• Asymptomatic – more frequent presentation
• ADHERE
– Elderly - Female
– HTN - ↓ previous MI
– ↓ ACEI/ARB - ↓ in-hospital mortality
Masoudi FA. JACC. 2003; 41(2): 217-23.
11/02/21 Yancy CW, JACC. 2006; 47(1):76-84
 Aging and HF with preserved EF
• Decrease in the elastic properties of the heart
and great vessels
• Subsequent increase in SBP an increase in
myocardial stiffness.
• Decrease in ventricular filling due to:
– structural changes in the heart (fibrosis)
– decline in relaxation and compliance.
– decrease in beta-adrenergic receptor density
– decline in peripheral vasodilator capacity

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Hunt, et al. 2009 ACCF/AHA Heart Failure Guidelines. (Circulation. 2009;119:e391-e479.
 Aging and HF with preserved EF
• Elderly patients associated disorders
– CAD
– DM
– Aortic stenosis
– Atrial fibrillation
– Obesity
– Sex-specific  women

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Hunt, et al. 2009 ACCF/AHA Heart Failure Guidelines. (Circulation. 2009;119:e391-e479.
 Outline
• Diagnostic Criteria
• Epidemiology
• Etiology
• Physiology and Patophysiology
• Clinical Manifestations
• Diagnosis
• Prognosis
• Treatment
11/02/21
11/02/21 Ouzounian M. Nature Clin Pract Cardiovasc Med. 2008; 5(7): 375-86
 Structural abnormalities
• Chamber remodeling
– Normal EDV
– ↑ wall thickening
– ↑ ratio myocardial mass/cavity volume
– ↑ ratio wall thickness/chamber radius
• ↑ Cardiomyocyte diameter
• ↑ Collagen and extracellular matrix

11/02/21 Aurigemma GP, et al. Circulation 2006; 113: 296–304

 Structural abnormalities

Systolic HF

Normal heart

Diastolic HF

11/02/21 Aurigemma GP, et al. Circulation 2006; 113: 296–304

 Myocardial disorders associated
with HF and normal LVEF

• Restrictive cardiomyopathy
• Obstructive hypertrophic cardiomyopathy
• Nonobstructive hypertrophic
cardiomyopathy
• Infiltrative cardiomyopathies

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Hunt, et al. 2009 ACCF/AHA Heart Failure Guidelines. (Circulation. 2009;119:e391-e479.
 Restrictive Cardiomyopathy

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NEJM. 1997;336(4):267-76.
11/02/21
Hunt, et al. 2009 ACCF/AHA Heart Failure Guidelines. (Circulation. 2009;119:e391-e479.
 Outline
• Diagnostic Criteria
• Epidemiology
• Etiology
• Physiology and Patophysiology
• Clinical Manifestations
• Diagnosis
• Prognosis
• Treatment
11/02/21
 Physiologic mechanisms
• Lusitropism – dependent on Ca2+ efflux
• Dependent on ATP – impaired in ischemia
– ACEI improves diastolic dysfunction in HCM
• Na2+ gradient (outward  inward) promotes Ca2+
efflux
• Digitalis impairs Na2+/K+ ATPase
• Β-agonists
– Inotropic: Ca2+ influx
– Lusitropic: Ca2+ re-uptake
• Titin – recoil/ Ca2+ de-sensitizer

Zile MR. Circulation. 2002; 105(12):1503-8.

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Gerull B. Nat Genet. 2002; 30(2):201-4
 Physiologic mechanisms
• Diastole – determined by:
– Myocardial relaxation
• Prior to Aortic valve closure
• Isovolumetric relaxation
• “Untwisting” of LV  Suction with LA/LV P gradient
• Promotes rapid early diastolic filling
– LV elasticity and distensibility
• In late diastole  relaxed myocytes
• LV: compliant and distensible  minimal resistance
– Atrial contraction - 20-30% of LV filling volume

11/02/21
 Pathophysiology
• Reduced ventricular compliance (myocardial
stiffness) and fluid retention
• Abnormal renal sodium handling and arterial
stiffness, in addition to myocardial stiffness
• The majority of patients have a history of
hypertension
• Most of the patients have evidence of LVH on
echocardiography.
• More frequent in elderly women

11/02/21 Hunt, et al. 2009 ACCF/AHA Heart Failure Guidelines. (Circulation. 2009;119:e391-e479.
 Pathophysiology

Aurigemma GP. NEJM. 2004;351:1097-105.

11/02/21
Cliger C, et al. AJGC. 2006;15:50–57
 Little WC. Heart Failure Reviews. 2000;5:301-6.
11/02/21 Kitzman DW. JACC. 1991;17(5):1065-72,
11/02/21 Chattopadhyay S. Circ Heart Fail. 2010;3:35-43.
 Pathophysiology

11/02/21 Ting Tan Y, et al. JACC. 2009;54(1):36–46

 Single syndrome hypothesis

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Ouzounian M. Nature Clin Pract Cardiovasc Med. 2008; 5(7): 375-86
 Diastolic CHF?
Ventricular
Myocardial systolic Vascular

Normal EF Heart Failure

Renal
Non-CV

Neurohumoral

Understanding nondiastolic mechanisms of Heart

Failure with Normal Ejection Fraction may provide
further answers and, more importantly, lead to
more therapeutic advances.
11/02/21
Bench T, et al. Current Heart Failure Reports 2009, 6:57–64
 Non-diastolic mechanisms
• Volume overload
• Venoconstriction/volume redistribution
• Ventricular vascular coupling
abnormalities
• Chronotropic incompetence
• Endothelial dysfunction

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Bench T, et al. Current Heart Failure Reports 2009, 6:57–64
 Volume overload

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Maurer MS. J. Am. Coll. Cardiol. 2007;49;972-981
 Prolonged QRS and mortality
N=872

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Hummel SL, et al. J Cardiac Fail 2009;15:553-60.
 Prolonged QRS and mortality
N=872

Hummel SL, et al. J Cardiac Fail 2009;15:553-60.

11/02/21
 Outline
• Diagnostic Criteria
• Epidemiology
• Etiology
• Physiology and Patophysiology
• Clinical Manifestations
• Diagnosis
• Prognosis
• Treatment
11/02/21
 Clinical manifestations
• Most frequent: Asymptomatic
• Less severe presentation
– Decreased exercise capacity
• Increased LA/PVP
• Poor tolerance to tachycardia and Afib
• HTN/LV stress  Flash pulmonary edema
– Neurohumoral activation
– Decreased Quality of Life

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 Clinical manifestations
• Restrictive CM
– Increased JVP
– Kussmaul’s sign
– S3
• Abrupt cessation of rapid ventricular filling
– Functional MR/TR

http://www.radrounds.com/photo/cardiac-amyloidosis-cardiac-2

11/02/21
 Outline
• Diagnostic Criteria
• Epidemiology
• Etiology
• Physiology and Patophysiology
• Clinical Manifestations
• Diagnosis
• Prognosis
• Treatment
11/02/21
 Diagnosis
• ↓ Slow rate of ventricular relaxation
• ↑ LV filling pressure in a patient with normal LV
volumes and contractility.
– LVEF > 50%
– LVEDP < 97 ml/m2
• Clinical diagnosis - HF in a patient who is shown
to have a normal LVEF and no valvulopathy
• Doppler echocardiography (TTE)
• BNP levels in addition to TTE improve diagnostic
accuracy.

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Hunt, et al. 2009 ACCF/AHA Heart Failure Guidelines. (Circulation. 2009;119:e391-e479.
 Echocardiography

E = early filling
A = atrial contraction
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Aurigemma GP. NEJM. 2004;351:1097-105.
E = early filling e’ = Early tissue doppled lengthening velocity

11/02/21 Bursi F, et al. JAMA 2006;296:2209-2216.

 Pulmonary vein flow

S – systolic flow – LA relaxation

D – diastolic flow – forward flow from Pulmonary veins into LA
AR – atrial systole – retrograde flow into Pulmonary veins

11/02/21 Redfield MM. JAMA. 2003;289(2):194-202.

 Echocardiography
Sm = peak systolic
velocity

Em = peak early
diastolic velocity
Am = peak atrial
contraction velocity

septal side of the mitral valve annulus or base.

11/02/21
Sanderson JE. Prog Cardiov Dis. 2006;49(3): 196-206
Systolic dysfunction with normal EF
• New doppler echocardiography techniques
reveals abnormal ventricular function
particularly in the long axis and midwall
fractional shortening .
– 30-50% cases
– Motion of basal LV
• Ejection is relatively preserved because of
increased radial function.

11/02/21
Sanderson JE. Prog Cardiov Dis. 2006;49(3): 196-206
 Myocardial strain and torsion:
Speckle-tracking echocardiography
Circumferential strain from the apical LV level in a
healthy individual. Homogenous circumferential
distribution of normal systolic strain.
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Edvardsen T. Prog Cardiov Dis. 2006;49(3): 207-14.
Circumferential strain at the LV apical level in a
patient with a LAD-related MI. Reduced systolic
shortening (strain) in the anterior, septal, and
inferior segments, with marked postsystolic
contraction (white arrows).
Early septal systolic stretching indicating
dyskinesis (red arrow). Normal contraction is seen
in the lateral segments.
 Doppler tissue imaging – validated
with MRI

“The present study has shown that DTI can quantify LV torsional deformation over
time. This novel method may facilitate noninvasive quantification of LV torsion in
clinical and research settings.”

Notomi Y. Circulation. 2005;111:1141-1147.)

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 Cardiac MRI vs. Echocardiography

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Rademakers FE. Prog Cardiov Dis. 2006;49(3): 215-27.
 Diagnosis: BNP
• Levels > 62 pg/ml
– 85% sensitivity
– 83% specificity

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Lubien E. Circulation. 2002;105(5):595-601
 Diagnosis: ESC algorithm

Maeder M. State of the Art: HFNEF. JACC. 2009:53(11): 905-18

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 Outline
• Diagnostic Criteria
• Epidemiology
• Etiology
• Physiology and Patophysiology
• Clinical Manifestations
• Diagnosis
• Prognosis
• Treatment
11/02/21
 Prognosis
N = 6076; 47% EF > 50% N = 2802; 31% EF > 50%

HR 1.13; (95%CI 0.94-1.36; P= 0.18)

Adjusted HR for death 0.96; P = 0.01

Owan TE. NEJM. 2006;355:251-9.

Bhatia RS. NEJM. 2006;355:260-9.
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 Prognosis
N= 24,501

Somaratne JB. Eur J Heart Fail. 2009;11:855-62

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 Outline
• Diagnostic Criteria
• Epidemiology
• Etiology
• Physiology and Patophysiology
• Clinical Manifestations
• Diagnosis
• Prognosis
• Treatment
11/02/21
 Treatment
• Limited evidence.
• Similar drugs as for systolic CHF justified
by co-morbid conditions:
– Atrial fibrillation, HTN, DM, CAD
• Treatment is based on the control of
physiological factors (BP, HR, blood
volume, and myocardial ischemia)

11/02/21
Hunt, et al. 2009 ACCF/AHA Heart Failure Guidelines. (Circulation. 2009;119:e391-e479.
Completed trials for HF with preserved EF

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Lam CSP. Ann Acad Med. 2009;38(8): 663-666.
 Hong Kong trial
• ACE vs. ARB vs. diuretics

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Yip GWK, et al. Heart 2008;94;573-580.
VALIDD Trial: supporting antihypertensive Tx
Valsartan In Diastolic Dysfunction

Lowering blood pressure

improves diastolic function
irrespective of the type of
antihypertensive
agent used.

11/02/21
Solomon SD. Lancet 2007; 369: 2079–87
 SWEDIC: Carvedilol
Swedish Doppler-echocardiographic study

N = 113

No change in:
•Deceleration time
•Isovolumic relaxation time
•Pulmonary vein flow velocity

11/02/21 Bergstrom A. Eur J Heart Fail. 2004;6:453-61.

 SENIORS: Nevibolol
Study of the Effects of Nebivolol Intervention on Outcomes and Hospitalization
in Seniors with Heart Failure) Age > 70 y/o.

N = 1359 N = 752

van Veldhuisen DJ, et al. JACC. 2009;53(23):2150–8

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 OPTIMIZE – HF: Betablockers
Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients
With Heart Failure

N = 7154 elderly

11/02/21 Hernandez, et al. JACC. 2009 Jan 13;53(2):184-92

 OPTIMIZE – HF: Betablockers

11/02/21 Hernandez, et al. JACC. 2009 Jan 13;53(2):184-92

 Calcium channel blockers
• Verapamil
– Lusitropic effect
– Negative chronotropic
– Anti-ischemic
– Small studies
• Increased peak LV
diastolic filling in
HCM

Bonow, RO. Circulation. 1985; 72(4):853-64.

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 Hypertension treatment and LVH

11% 10% 13%

8%
6%

80 trials
N = 3767 (treatment)
N = 346 (placebo)
Klingbeil AU. Am J Med. 2003;115:41– 46.
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 Statins in diastolic HF

RR death [95% CI] 0.20 [0.06 to 0.62]; P=0.005

11/02/21 Fukuta H. Circulation. 2005;112:357-363

 Ongoing trials: Spironolactone
• Trial of Aldosterone Antagonist Therapy in
Adults With Preserved Ejection Fraction
Congestive Heart Failure (TOPCAT)
• Start Date: August 2006
• Estimated Completion Date: July 2013
• Spironolactone vs. placebo
• N = 4500

11/02/21 ClinicalTrials.gov: NCT00094302

New ventures: Isosorbide/Hydralazine

• Improved HTN, diastolic function and

exercise capacity.
• Decreased soluble V-CAM1 levels.
• No reductions in LVH, cardiac fibrosis, or
pulmonary congestion.
Wilson RM. Hypertension. 2009;54:583-590.
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11/02/21
Hunt, et al. 2009 ACCF/AHA Heart Failure Guidelines. (Circulation. 2009;119:e391-e479.
 HFNEF: What the hospitalist need
to know
• Recognize HFNEF as a cause for AHF
– Elevated filling pressures
– Exercise intolerance / Flash pulmonary
edema
• Recognize HFNEF subtypes
• Distinguish the etiologies of restrictive CM
• Optimize treatment of:
– HTN, ischemia, volume overload
– HCM
11/02/21