04/08/23

Heart Failure with Normal Ejection Fraction (HFNEF): What the hospitalist

needs to know

Moises Auron, MD FAAP FACPMoises Auron, MD FAAP FACP

Hospital MedicineHospital Medicine

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Outline

• Diagnostic Criteria• Epidemiology• Etiology• Physiology and Patophysiology• Clinical Manifestations• Diagnosis• Prognosis• Treatment

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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

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Outline

• Diagnostic Criteria• Epidemiology• Etiology• Physiology and Patophysiology• Clinical Manifestations• Diagnosis• Prognosis• Treatment

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Epidemiology

• 20% to 60% of patients with HF

• Increasing prevalence

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

Owan T, et al. NEJM. 2006;355:251-9

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Epidemiology

Increased prevalence with age:

Age Prevalence

50 15%

50-70 33%

> 70 50%

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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

04/08/23Masoudi FA. JACC. 2003; 41(2): 217-23.Yancy CW, JACC. 2006; 47(1):76-84

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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

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

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• Elderly patients associated disorders – CAD– DM– Aortic stenosis– Atrial fibrillation– Obesity – Sex-specific women

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Aging and HF with preserved EF

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

04/08/23

Outline

• Diagnostic Criteria• Epidemiology• Etiology• Physiology and Patophysiology• Clinical Manifestations• Diagnosis• Prognosis• Treatment

04/08/23 Ouzounian M. Nature Clin Pract Cardiovasc Med. 2008; 5(7): 375-8604/08/23

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Structural abnormalities

• Chamber remodeling– Normal EDV– ↑ wall thickening– ↑ ratio myocardial mass/cavity volume– ↑ ratio wall thickness/chamber radius

• ↑ Cardiomyocyte diameter

• ↑ Collagen and extracellular matrix

04/08/23 Aurigemma GP, et al. Circulation 2006; 113: 296–304

04/08/23 Aurigemma GP, et al. Circulation 2006; 113: 296–304

Systolic HF

Normal heart

Diastolic HF

Structural abnormalities

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Myocardial disorders associated with HF and normal LVEF

• Restrictive cardiomyopathy

• Obstructive hypertrophic cardiomyopathy

• Nonobstructive hypertrophic cardiomyopathy

• Infiltrative cardiomyopathies

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

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Restrictive Cardiomyopathy

04/08/23NEJM. 1997;336(4):267-76.

04/08/23Hunt, et al. 2009 ACCF/AHA Heart Failure Guidelines. (Circulation. 2009;119:e391-e479.

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Outline

• Diagnostic Criteria• Epidemiology• Etiology• Physiology and Patophysiology• Clinical Manifestations• Diagnosis• Prognosis• Treatment

04/08/23

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

04/08/23Zile MR. Circulation. 2002; 105(12):1503-8.Gerull B. Nat Genet. 2002; 30(2):201-4

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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

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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

Hunt, et al. 2009 ACCF/AHA Heart Failure Guidelines. (Circulation. 2009;119:e391-e479.04/08/23

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Pathophysiology

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

Cliger C, et al. AJGC. 2006;15:50–5704/08/23

04/08/2304/08/23

Little WC. Heart Failure Reviews. 2000;5:301-6.Kitzman DW. JACC. 1991;17(5):1065-72,

04/08/23 Chattopadhyay S. Circ Heart Fail. 2010;3:35-43.

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Pathophysiology

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

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Single syndrome hypothesis

Ouzounian M. Nature Clin Pract Cardiovasc Med. 2008; 5(7): 375-8604/08/23

04/08/23

Diastolic CHF?

Understanding nondiastolic mechanisms of Heart Failure with Normal Ejection Fraction may provide further answers and, more importantly, lead to more therapeutic advances.

Myocardial systolicVentricular

Vascular

Renal

Neurohumoral

Non-CV

Normal EF Heart Failure

Bench T, et al. Current Heart Failure Reports 2009, 6:57–6404/08/23

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Non-diastolic mechanisms

• Volume overload

• Venoconstriction/volume redistribution

• Ventricular vascular coupling abnormalities

• Chronotropic incompetence

• Endothelial dysfunction

Bench T, et al. Current Heart Failure Reports 2009, 6:57–6404/08/23

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Volume overload

Maurer MS. J. Am. Coll. Cardiol. 2007;49;972-98104/08/23

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Prolonged QRS and mortality

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

N=872

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Prolonged QRS and mortality

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

N=872

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Outline

• Diagnostic Criteria• Epidemiology• Etiology• Physiology and Patophysiology• Clinical Manifestations• Diagnosis• Prognosis• Treatment

04/08/23

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

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

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Outline

• Diagnostic Criteria• Epidemiology• Etiology• Physiology and Patophysiology• Clinical Manifestations• Diagnosis• Prognosis• Treatment

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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.

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

04/08/23

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Echocardiography

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

E = early filling

A = atrial contraction04/08/23

04/08/23 Bursi F, et al. JAMA 2006;296:2209-2216.04/08/23

E = early filling e’ = Early tissue doppled lengthening velocity

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Pulmonary vein flow

04/08/23 Redfield MM. JAMA. 2003;289(2):194-202.

S – systolic flow – LA relaxationD – diastolic flow – forward flow from Pulmonary veins into LAAR – atrial systole – retrograde flow into Pulmonary veins

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Echocardiography

Sm = peak systolic velocity

septal side of the mitral valve annulus or base.

Em = peak early diastolic velocityAm = peak atrial contraction velocity

Sanderson JE. Prog Cardiov Dis. 2006;49(3): 196-20604/08/23

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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.

Sanderson JE. Prog Cardiov Dis. 2006;49(3): 196-20604/08/23

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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.

Circumferential strain at the LV apical level in a patient with a LAD-related MI. Reduced systolic shortening (strain) in the anterior, septal, andinferior segments, with marked postsystolic contraction (white arrows). Early septal systolic stretching indicating dyskinesis (red arrow). Normal contraction is seen in the lateral segments.

Edvardsen T. Prog Cardiov Dis. 2006;49(3): 207-14.04/08/23

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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.)04/08/23

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Cardiac MRI vs. Echocardiography

Rademakers FE. Prog Cardiov Dis. 2006;49(3): 215-27.04/08/23

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Diagnosis: BNP

• Levels > 62 pg/ml– 85% sensitivity– 83% specificity

04/08/23 Lubien E. Circulation. 2002;105(5):595-601

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Diagnosis: ESC algorithm

04/08/23Maeder 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

04/08/23

Prognosis

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

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

Bhatia RS. NEJM. 2006;355:260-9.04/08/23

Adjusted HR for death 0.96; P = 0.01

N = 6076; 47% EF > 50% N = 2802; 31% EF > 50%

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Prognosis

Somaratne JB. Eur J Heart Fail. 2009;11:855-6204/08/23

N= 24,501

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Outline

• Diagnostic Criteria• Epidemiology• Etiology• Physiology and Patophysiology• Clinical Manifestations• Diagnosis• Prognosis• Treatment

04/08/23

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)

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

04/08/23

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Completed trials for HF with preserved EF

Lam CSP. Ann Acad Med. 2009;38(8): 663-666.04/08/23

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Hong Kong trial• ACE vs. ARB vs. diuretics

Yip GWK, et al. Heart 2008;94;573-580.04/08/23

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VALIDD Trial: supporting antihypertensive TxValsartan In Diastolic Dysfunction

Lowering blood pressure improves diastolic function irrespective of the type of antihypertensiveagent used.

Solomon SD. Lancet 2007; 369: 2079–8704/08/23

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SWEDIC: Carvedilol

Bergstrom A. Eur J Heart Fail. 2004;6:453-61.

Swedish Doppler-echocardiographic study

04/08/23

N = 113

No change in:

•Deceleration time

•Isovolumic relaxation time

•Pulmonary vein flow velocity

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

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

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N = 1359 N = 752

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OPTIMIZE – HF: Betablockers

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

Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure

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N = 7154 elderly

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OPTIMIZE – HF: Betablockers

Hernandez, et al. JACC. 2009 Jan 13;53(2):184-9204/08/23

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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

Klingbeil AU. Am J Med. 2003;115:41– 46.

80 trials

N = 3767 (treatment)

N = 346 (placebo)

8%6%

11% 10% 13%

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Statins in diastolic HF

Fukuta H. Circulation. 2005;112:357-363

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

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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

ClinicalTrials.gov: NCT0009430204/08/23

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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.

04/08/23Hunt, et al. 2009 ACCF/AHA Heart Failure Guidelines. (Circulation. 2009;119:e391-e479.

04/08/23

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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