Donald Rumsfeld HFpEF: Classification into Phenotypes Nancy K. - - PDF document

12/1/17 1

HFpEF: Classification into Phenotypes

Nancy K. Sweitzer, MD, PhD Professor of Medicine Chief of Cardiolovascular Medicine Director, Sarver Heart Center Editor-in-Chief, Circulation Heart Failure

Donald Rumsfeld

Donald Rumsfeld & the Scientific Method

Case 1

• Mrs. R is a 72 yo woman with a history of

hypertension sent to you for worsening dyspnea.

• She has no other significant medical history.
• She reports shortness of breath with making the

beds, but not with dressing or showering.

• She recently went on a cruise, and noticed a

profound increase in shortness of breath, and new ankle swelling

• Medications: Chlorthalidone

12/1/17 2

• Mrs. R
• Weight: 115 pounds
• HR 72 bpm, BP 152/78
• JVP 14 cm H2O
• Chest clear
• Nl PMI, regular, nl S1, physiologic splitting
• f S2, no audible murmur, +S4
• Enlarged liver, + HJR
• 1+ edema bilaterally to mid-shin, nl cap

refill, warm

• Mrs. R
• Echo:

– EF 72%, no RWMA – LV thickness 13 mm – LA size: moderately enlarged – PA pressures estimated at 50 mmHg – Mild MR, mild TR – RV size and function normal

• Cath: No CAD

Case 2

• Mr. B is a 62 yo man with exertional dyspnea
• Oxygen-dependent COPD
• Obesity hypoventilation syndrome
• Sleep apnea treated with CPAP
• Referred by his pulmonologist
• Mr. B
• Weight 225 (height 5’7”)
• HR 96, BP 122/78
• JVP 6
• Chest clear without rales
• PMI not palpable, distant heart tones, but no
• bvious murmur or gallop
• Liver span normal, no HJR, no edema
• Echo with normal LV, E/A 0.8, e’ 8, E/e’ 8, RVH

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• Mr. B, RHC
• RA 4, PA 55/20, CWP 12
• Bicycle exercise on the cath lab table

– RA 6, PA 98/45, CWP 32

Overview

• Definitions, Epidemiology
• Diastolic Dysfunction and HFpEF
• Mechanistic Insights
• Improving Diagnostic Precision

HFpEF: Definition

• Clinical Definition:

– A patient with the clinical syndrome of heart failure, normal left ventricular ejection fraction, and no other etiology of the symptoms, is said to have “heart failure with preserved ejection fraction” or HFpEF. – Historically called diastolic heart failure based on the supposition that if contraction is normal, then relaxation must be abnormal.

• Pathophysiological Definition:

Filling of the LV to normal end diastolic volume to produce normal cardiac output occurs only at higher than normal pressures under some conditions.

Epidemiology

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

12/1/17 4 Ca Causes of HF HFpEF

• Diastolic dysfunction
• Impaired left ventricular relaxation
• Myocardial ischemia
• Hypertrophy, including aortic stenosis, hypertension, hypertrophic cardiomyopathy
• Systolic dysfunction
• Diabetes mellitus
• Aging
• Increased myocardial stiffness
• Infiltrative disorders (amyloidosis, sarcoidosis, hemochromatosis)
• Endomyocardial fibrosis
• Ventricular interaction or pericardial restraint
• Right Ventricular pressure or volume overload
• Acute pulmonary embolism
• Acute mitral regurgitation or tricuspid regurgitation
• Pericardial disease
• Abbreviated left ventricular filling time
• Atrial tachyarrhythmias, especially atrial fibrillation
• Moderate sinus tachycardia with LBBB
• Multifactorial
• High output heart failure (thyrotoxicosis, arteriovenous fistula, pheochromocytoma)
• Renal dysfunction
• Volume overload states
• Obesity

Mechanisms of HFpEF Diastolic Dysfunction

IV IVRT Ra Rapi pid d Fi Filling ng Di Diastasis At Atrial al Fi Filling ng

Left ventricle Left atrium Left atrium

RELAXATION ELASTIC RECOIL PASSIVE ELASTICITY

Diastole is divided into 4 phases

Diastolic Dysfunction

IV IVRT Ra Rapi pid d Fi Filling ng Di Diastasis At Atrial al Fi Filling ng

Left ventricle Left atrium Impaired relaxation Left atrium Increased stiffness

12/1/17 5 Diastolic Function Assessment

Redfield, et al. JAMA. 2003;289:194-202

Diastolic Dysfunction is not HFpEF

Redfield et al, JAMA. 2003;289:194-202

HFpEF is not Diastolic Dysfunction

20 40 60 80 100 Enrolled Patients: CHARM - Preserved Severe DD Moderate DD Mild DD Normal Indeterminate

Persson et al JACC 2007; 49:687-94

HFpEF is not Diastolic Dysfunction

20 40 60 80 100 Control Hypertensive LVH HFpEF Severe DD Moderate DD Mild DD Normal Indeterminate

Melenovsky et al, 2007; 49:198-207

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Cardiovascular Stressors Produce Symptoms in Patients with HFpEF

• Exercise
• Hypertension
• Atrial Arrhythmias
• Ischemia
• Tachycardia (pneumonia, pain, acute illness)

Diastolic Filling: Effects of Heart Rate

75 bpm 92 bpm

Exercise Responses in HFpEF

35 30 25 10 15 20 5

Pulmonary Capillary Wedge Pressure (mmHg)

60 80 100 120 140 160

Left Ventricular End-Diastolic Volume (ml)

Peak exercise

Control

Rest Peak exercise

HFpEF Failure of the Frank-Starling Relationship

Kitzman et al, JACC 1991

Filling Pressures in HFpEF

10 20 30 40 50 60 70 DHF-Rest DHF-24 hour RV systolic pressure Estimated PAD

Zile et al., 2008, Journal Card Failure. 14: 816-23.

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HFpEF Physiology

Volume Pressure

Kawaguchi et al, Circ 2003;107:714-20.

Mechanisms of HFpEF: Abnormal Ventricular Stiffness

• Traditionally attributed to changes in

extracellular matrix, including:

– Increased collagen deposition – Interstitial fibrosis

• Recent studies suggest much of this is

attributable to altered phosphorylation and increased stiffness of titin Mechanisms of HFpEF: RAAS System Activation

• Angiotensin and aldosterone are pro-

fibrotic in both the heart and blood vessels, increasing stiffness.

• Hypertrophied hearts have increased ACE

in the myocardium, leading to locally high angiotensin II levels.

• Trials of angiotensin system blockade in

diastolic HF have been disappointing.

• CHARM, PEP-CHF, I-PRESERVE

Mechanisms of HFpEF: Abnormal Contractility

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Systolic Function in HFpEF

Norman et al, JCardFail 2011; 17:301-8

Systolic Function in HFpEF

10 20 30 40 50 60 70 80 90 100 Control HFpEF Dobutamine Baseline

Norman et al, JCardFail 2011; 17:301-8

Ejection Fraction

Mechanisms of HFpEF: Abnormal Contractility

• During times of increased demand,

such as exercise, the ventricles of these patients seem unable to increase

• utput.

“Impaired contractile reserve”

Systolic Dysfunction in HFpEF

Shah AM et al, Circ 2015; 32:402-414.

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Mechanisms of HFpEF:

Arterial Stiffening and Altered Ventricular-Vascular Interaction

Physiology of Arteries

• Compliance or cushioning function – To

transform pulsatile into continuous flow

• Conduit function – Deliver an adequate

supply of blood to body tissues

– Maintain adequate mean arterial pressure

• Minimize energy losses

Mechanisms of HFpEF:

Arterial Stiffening and Altered Ventricular-Vascular Interaction

• Altered wave travel in the arteries leads to

altered load on the ventricle.

• Wave travel in the aorta is altered by

arterial stiffening.

• This impacts ventricular systolic and

diastolic function.

Arterial Hemodynamics in Humans

• Unique Nature of Humans:

– We are upright animals – Proximal aorta interacts directly with heart – Short arteriolar beds exist between aorta and

• rgans without much autoregulation (brain

and kidney)

• Wave reflection is extremely important

(after age 17)

• Non-invasive assessment is useful

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Wave Travel in Arteries Reflected Pressure Waves Reflected Pressure Waves Reflected Pressure Waves

With aging, and nearly all identified cardiovascular risk factors, pulse wave velocity and amplification increase

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Coupling of the LV to the Circulation

Ventricular Performance

ØDuring a normal contraction, at peak force, there is little calcium left in the myocyte. ØNew crossbridges cannot be formed.

Ventricular Vascular Coupling

• If we reduce reflected waves, can we

increase stroke volume

• If we reduce reflected waves, can we

improve ventricular relaxation

12/1/17 12

Va Variable Ba Baseline BN BNP p p value ue Augmentation Index, % 11.4 ± 8.9

• 0.2 ± 14.7

0.02 E’ velocity 10.0 ± 2.5 8.8 ± 2.0 0.06 Stroke volume, mL 68.5 ± 18.3 60.9 ± 8.1 0.02

Sweitzer NK et al, Am J Hypertens 2013; 26:866-71

Reduction of Augmentation What Happened?

Pressure (mmHg)

160 140 120 100 80 60 40 20 10 30 70 90 130 150 Ees ∆P ∆P

Volume (mL)

50 110

ed es

• 1. Theoretical pressure volume loops generated using mean data from the study population for central arterial pressure,

Sweitzer NK et al, Am J Hypertens 2013; 26:866-71

NEAT Trial

Figure 1. Primary and Secondary End Points for Activity Levels.

• No. of Units

10,000 8,000 9,000 7,000 6,000 5,000 −500 −1000

B Hours of Activity per Day

in 120-mg Dose Phase

C Average Daily Accelerometer Units

in Three Dose Phases Combined

A Average Daily Accelerometer Units

in 120-mg Dose Phase Placebo Isosorbide Mononitrate Treatment Difference

• No. of Hours

10.0 8.0 9.0 7.0 6.0 5.0 −0.5 −1.0 Placebo Isosorbide Mononitrate Treatment Difference

• No. of Units

10,000 8,000 9,000 7,000 6,000 5,000 −500 −1000 Placebo Isosorbide Mononitrate Treatment Difference P=0.02 P=0.02 P=0.06

Redfield MM et al, NEJM 2015; 373:2314-24

HFpEF: Treatment

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VALIDD Study

§ Age ≥ 45 § Stage 1 or 2 essential hypertension § No HF admissions X 1 year § EF > 50% § Abnormal diastolic relaxation velocity on tissue Doppler imaging

Solomon et al. 2007, Lancet. 369:2079-87

VALIDD Study

Solomon et al. 2007, Lancet. 369:2079-87

VALIDD Study

Solomon et al. 2007, Lancet. 369:2079-87

VALIDD Study

Solomon et al. 2007, Lancet. 369:2079-87

12/1/17 14

Known Knowns

Shah & Pfeffer, Nat. Rev. Cardiol. 2012; 10.1038

Known Unknowns

Shah SJ, J Am Coll Cardiol. 2013;62:1339-1342

Unknown Unknowns

Shah SJ et al, Circ 2015; 131:269-79

Promise of Precision Medicine in HFpEF

• Proteomic analysis of 1400 serum

samples from HFpEF patients

• Will investigate “phenogroups” and

apply machine learning de novo to groups

• Perhaps biologically distinct groups can

be distinguished

12/1/17 15 HFpEF

• Heterogeneous
• Impaired relaxation common, especially

in hypertensives, but likely neither necessary nor sufficient for HFpEF

• Multifactorial etiology likely, particularly

in the elderly

• Until we are better able to target

mechanisms, unlikely to make progress.

HFpEF

• Questions?

Sarver Heart Center

Thank You!