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HFpEF: Classification into Phenotypes

Nancy K. Sweitzer, MD, PhDProfessor of MedicineChief of Cardiolovascular MedicineDirector, Sarver Heart CenterEditor-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

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Mrs. R

• Weight: 115 pounds• HR 72 bpm, BP 152/78• JVP 14 cm H2O• Chest clear• Nl PMI, regular, nl S1, physiologic splitting

of 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.Bisa62yo manwithexertional dyspnea• Oxygen-dependentCOPD• Obesityhypoventilationsyndrome• SleepapneatreatedwithCPAP• Referredbyhispulmonologist

Mr. B

• Weight225(height5’7”)• HR96,BP122/78• JVP6• Chestclearwithoutrales• PMInotpalpable,distanthearttones,butnoobviousmurmurorgallop

• Liverspannormal,noHJR,noedema• EchowithnormalLV,E/A0.8,e’8,E/e’8,RVH

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Mr. B, RHC

• RA4,PA55/20,CWP12• Bicycleexerciseonthecath labtable

– RA6,PA98/45,CWP32

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.

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Causes of 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

DiastolicDysfunction

IVRT Rapid Filling

Diastasis AtrialFilling

Left ventricle

Left atriumLeft atrium

RELAXATION

ELASTIC RECOILPASSIVE ELASTICITY

Diastole is divided into 4 phases

DiastolicDysfunction

IVRT Rapid Filling

Diastasis Atrial Filling

Left ventricle

Left atrium

Impaired relaxation

Leftatrium

Increased stiffness

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Diastolic Function Assessment

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

Diastolic Dysfunction is not HFpEF

Redfieldetal,JAMA.2003;289:194-202

HFpEF is not Diastolic Dysfunction

0

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Enrolled Patients: CHARM - Preserved

Severe DDModerate DDMild DDNormalIndeterminate

Persson et al JACC 2007; 49:687-94

HFpEF is not Diastolic Dysfunction

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Control Hypertensive LVH

HFpEF

Severe DDModerate DDMild DDNormalIndeterminate

Melenovsky et al, 2007; 49:198-207

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Cardiovascular Stressors Produce Symptoms in Patients with HFpEF

• Exercise• Hypertension• AtrialArrhythmias• Ischemia• Tachycardia(pneumonia,pain,acuteillness)

Diastolic Filling: Effects of Heart Rate

75bpm 92bpm

Exercise Responses in HFpEF

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aryCapillaryW

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Volume(ml)

Peakexercise

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HFpEF

FailureoftheFrank-StarlingRelationship

Kitzman etal,JACC1991

Filling Pressures in HFpEF

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DHF-Rest DHF-24 hour

RV systolic pressure

Estimated PAD

Zile etal.,2008,JournalCardFailure.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

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Control HFpEF

Dobutamine

Baseline

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

Ejec

tion

Frac

tion

Mechanisms of HFpEF:Abnormal Contractility

• During times of increased demand, such as exercise, the ventricles of these patients seem unable to increase output.

“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

organs 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

• Ifwereducereflectedwaves,canweincreasestrokevolume

• Ifwereducereflectedwaves,canweimproveventricularrelaxation

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Variable Baseline BNP p value

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?

870 American Journal of Hypertension 26(7) July 2013

Sweitzer et al.

ventricular contractility, may have equal or greater effects on stroke volume as acute changes in arterial properties in older patients, particularly in the presence of age-related arterial and ventricular stiffening. This conclusion is supported by data from Sagawa et  al.21 that demonstrated that at physiological heart rates, total arterial elastance and preload are more important determinants of stroke volume than arterial compliance, provided input impedance is unchanged. In our study, arterial elastance was not changed significantly by either drug treatment despite the change in AI.

Careful consideration of invasively obtained left ventric-ular pressure–volume curves provides a possible explana-tion for the phenomenon we observed (i.e., a drop in stroke volume when preload and late systolic loading are simulta-neously reduced). The end-diastolic pressure volume rela-tion is markedly less steep than the end-systolic pressure volume relation in normal hearts. Therefore, even modest changes in end-diastolic pressure may have a greater effect on stroke volume than large changes in end-systolic pressure

(the parameter most affected by pressure augmentation), as illustrated in Figure 1. Changes in the slopes of the end-sys-tolic and end-diastolic pressure–volume relations will alter this interdependence. Although we did not directly meas-ure preload in this study, this provides at least a theoreti-cal explanation for the failure of a reduction in late systolic pressure augmentation to lead to improved cardiac output through improved ventricular–vascular interaction.

Our data reinforce the view that AI is not a reliable marker of central arterial stiffness and should not be used in clini-cal decision making about therapies affecting arterial prop-erties. Our data demonstrate that changes in ventricular performance may have significant effects on AI. In addi-tion, more direct measures of arterial stiffness, such as pulse wave velocity and aortic characteristic impedance, were not reduced in these participants despite the fall in AI, suggest-ing that AI is measuring something other than arterial prop-erties. For example, a reduction in stroke volume after a drop in preload may result in a decrease in augmentation in the

Table 4. Cardiac variables 

Variable Baseline BNP P value Baseline Hydralazine P value

Mitral E wave, cm/s 67.0 ± 10.5 58.1 ± 8.2 0.003 69.7 ± 14.0 69.4 ± 16.3 0.63

Mitral A wave, cm/s 76.0 ± 23.4 76.3 ± 23.5 0.95 74.8 ± 24.7 82.1 ± 25.6 0.46

E/E’ 7.1 ± 2.4 6.7 ± 1.5 0.41 8.0 ± 3.1 7.5 ± 3.5 0.38

Data are displayed as mean ± SD. Abbreviation: BNP, B-type natriuretic peptide.

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Figure 1. Theoretical pressure volume loops generated using mean data from the study population for central arterial pressure, end-systolic elastance (Ees), and stroke volume in participants in this study before and after B-type natriuretic peptide (BNP), demonstrating the fall in stroke volume that may occur due to the relatively greater effect of a fall in preload on ventricular volume. The open loop represents baseline conditions, whereas the shaded loop represents data obtained during BNP infusion. The horizontal arrows mark stroke volume in the 2 conditions. ∆Ped, change in end-diastolic pressure between the 2 conditions; ∆Pes, change in end-systolic or aortic pressure between the 2 conditions.

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

NEAT Trial

n engl j med 373;24 nejm.org December 10, 2015 2321

Isosorbide Mononitr ate in Heart Failure

using accelerometer-derived data might be more sensitive to the overall effect of a therapy than intermittent repetition of coached exercise tests or memory-dependent quality-of-life questionnaires. Accelerometer data are high-density, quantitative, and collected continuously under conditions of daily living.18,19 Furthermore, the ultimate goal of therapies that are prescribed to improve exer-cise tolerance is indeed to facilitate activity. In-activity promotes further deconditioning and frailty among patients with heart failure3 and is independently associated with both the incidence and deleterious outcomes of heart failure.26-28

If behavioral or environmental factors promi-nently influence a patient’s willingness or ability to be active, improved exercise tolerance may not lead to increased activity. However, our patients indicated that their activity was primarily limited by their heart-failure symptoms. Furthermore, we observed a decrease in activity levels with isosorbide mononitrate, rather than no change. The decrease in activity occurred in the absence of adverse effects on submaximal exercise capac-ity or perceptive exercise tolerance, as assessed on the 6-minute walk test and in association

with directionally adverse, albeit not significant, effects on quality-of-life scores. These findings suggest that activity levels were sensitive to ad-verse effects of isosorbide mononitrate beyond the numerically higher rate of overt symptoms requiring study-drug discontinuation.

Absolute values for accelerometer units and the activity time per day that is based on such units are highly sensitive to the device design, body location, data-acquisition mode, analytics, activity threshold values, and patient popula-tion.18,19 Thus, a comparison with other studies is difficult. During the 120-mg phase, patients who received isosorbide mononitrate were active for 0.3 hours (18 minutes) less per day than were those who received placebo. Observational stud-ies using uniaxial, chest-worn accelerometer data from implanted pacing or defibrillator devices in patients with heart failure and a reduced ejection have shown that even a 10-minute reduction in activity per day was associated with adverse out-comes.28 These data would suggest that the re-ductions in activity with isosorbide mononitrate that we observed were clinically relevant. Each accelerometer was calibrated during production,

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

Shown are the absolute values and differences between the two treatments (isosorbide mononitrate minus placebo) for the average daily arbitrary accelerometer units (Panel A) and hours of activity per day (Panel B) during the 120-mg phase and for daily arbitrary accelerometer units for all three doses (30 mg, 60 mg, and 120 mg) combined (Panel C). The arbitrary accelerometer units were stored as 15-minute cumulative accelerometer units (96 data points per day) and were totaled over a 24-hour period to provide daily accelerometer units. The I bars indicate 95% confidence intervals.

No.

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nits

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B Hours of Activity per Dayin 120-mg Dose Phase

C Average Daily Accelerometer Unitsin Three Dose Phases Combined

A Average Daily Accelerometer Unitsin 120-mg Dose Phase

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P=0.02P=0.02P=0.06

The New England Journal of Medicine Downloaded from nejm.org at University of Arizona on March 20, 2016. For personal use only. No other uses without permission.

Copyright © 2015 Massachusetts Medical Society. All rights reserved.

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

Solomonetal.2007,Lancet.369:2079-87

VALIDD Study

Solomonetal.2007,Lancet.369:2079-87

VALIDD Study

Solomonetal.2007,Lancet.369:2079-87

VALIDD Study

Solomonetal.2007,Lancet.369:2079-87

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Known Knowns

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

Known Unknowns

ShahSJ,JAmColl Cardiol.2013;62:1339-1342

Unknown Unknowns274 Circulation January 20, 2015

Association of Phenogroups With Adverse OutcomesTo provide external clinical validity of our phenomapping tech-niques, we studied the relationship between phenogroups and adverse outcomes. As shown in Table 5 and Figures 3 and 4, outcomes varied significantly by phenogroup, with a step-wise increase in risk profile going from lowest risk (phenogroup 1) to highest risk (phenogroup 3). Phenogroup 3 in particular repre-sented a high-risk subset, independently of BNP (known to be one of the most potent risk markers in HF) and the MAGGIC HF risk score, which comprises 13 traditional clinical parameters. Table 6 shows that the phenomapping technique created phenogroups

with differential risk profiles that provided better discrimination compared with clinical parameters (ie, the MAGGIC risk score) and BNP. On the basis of the integrated discrimination improve-ment, net reclassification improvement, and likelihood ratio tests, the phenogroup assignment provided prognostic information above and beyond traditional clinical variables. In addition, the association between phenogroup membership and outcomes per-sisted after adjustment for HF duration.

Validation of the Phenomapping AnalysesTo validate our phenomapping results, we prospectively enrolled an additional 107 patients in the HFpEF program. For the most

Figure 1. Phenotype heat map (phenomap) of heart failure with preserved ejection fraction. Columns represent individual study participants; rows, individual phenotypes. Red indicates increased value of a phenotype; blue, decreased value of a phenotype. BMI indicates body mass index; BNP, B-type natriuretic peptide; BUN, blood urea nitrogen; Cr, creatinine; DBP, diastolic blood pressure; Echo RAP, echocardiographic right atrial pressure; ESV, end-systolic volume; GFR, glomerular filtration rate; Hgb, hemoglobin; HR, heart rate; IVRT, isovolumic relaxation time; LAV, left atrial volume; LV, left ventricular; LVEDV, left ventricular end-diastolic volume; PASP, pulmonary artery systolic pressure; Plt, platelet count; PP, pulse pressure; PRSW, preload recruitable stroke work; PWT, posterior wall thickness; RA, right atrial; RDW, red cell distribution width; RV, right ventricular; RVFAC, right ventricular fractional area change; SV, stroke volume; TAPSE, tricuspid annular plane systolic excursion; Vcf, velocity of circumferential fiber shortening; and WBC, white blood cell count.

ShahSJetal,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

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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 HeartCenter

Thank You!