Application of Diagnostic Algorithms for Heart Failure with Preserved Ejection Fraction to

the Community: The ARIC Study

S. Selvaraj and P.L. Myhre et al.

Supplementary Material

SUPPLEMENTARY METHODS

Definition of comorbidities

Hypertension was defined by a systolic blood pressure ≥140 mmHg or diastolic

blood pressure ≥90 mmHg, or currently taking antihypertensive medication. Diabetes

mellitus was defined by a self-report of physician diagnosis of diabetes mellitus, fasting

serum glucose of ≥126 mg/dl, a non-fasting glucose ≥200 mg/dl, or pharmacologic

treatment for diabetes mellitus. Prevalent coronary heart disease was defined by

electrocardiographic evidence of myocardial infarction, or self-reported history of

myocardial infarction or revascularization at visit 1 or an adjudicated event between visits

1-5. Atrial fibrillation and flutter were defined by electrocardiographic evidence at each

visit or hospitalization for atrial fibrillation or flutter by the end of visit 5.

Prevalent HFpEF at visit 5 was defined by preserved EF (≥50%) and at least one

of the following: 1) any adjudicated HF event, 2) any first position International

Classification of Diseases-9th Revision (ICD-9) code of 428.x before 2005, or 3) any

physician report of HF on or prior to visit 5 (1). Criteria could also be satisfied using data

collected after the most current physician report of “No” HF with either of the following:

1) Non-1st position ICD-9 code of 428.x before 2005, or 2) repeated instances of self-

reported HF or self-reported HF meds (or if only 1 instance of self-reporting observed,

then N-terminal pro-B-type natriuretic peptide [NT-proBNP value] >125 ng/L from Visit

4 or 5 was required) (2).

Laboratory testing

Laboratory testing was conducted on blood samples drawn at visit 5. NT-proBNP

and serum high sensitivity cardiac troponin T (hs-cTnT) concentrations were analyzed

from frozen serum samples using a sandwich immunoassay method on an Elecsys 2010

Analyzer (Roche Diagnostics, Indianapolis, IN). The NT-proBNP assay has a lower

measurable limit of 5 ng/L, and participants with NT-proBNP below the limit were

assigned a value of 2.5 ng/L. The hs-cTnT assay has a lower measurable limit of 3 ng/L

(3), and participants with hs-cTnT below the limit were assigned a value of 1.5 ng/L.

Dyspnea survey

A modified version of the British Medical Research Council (mMRC) instrument

(4) administered at Visit 5 was used to define dyspnea severity. The mMRC is an

activity-based scale using 5 grades of dyspnea. We defined participants as having

dyspnea if they had ≥grade 2 dyspnea (dyspnea when walking at one’s own pace on level

ground) (5).

Echocardiography and spirometry

Comprehensive echocardiograms were performed at visit 5 according to a study-

specific protocol and were analyzed in a core laboratory (6). Left ventricular mass was

indexed to height to the 2.7 power to account for challenges of interpretation in the

setting of obesity. Left ventricular strain was assessed by means of speckle-tracking

echocardiography (TomTec Imaging Systems) (7). Significant left-sided valvular disease

was excluded as discussed in the main publication. Specifically, we excluded at least

moderate aortic stenosis (aortic valve peak velocity > 3m/s) and at least moderate mitral

regurgitation (jet area/left atrial area ratio from the apical 4 and 2 chamber views >0.20).

Severity of aortic regurgitation and mitral stenosis were determined by review of 2-

dimensional, color Doppler, and spectral Doppler imaging by board-certified

echocardiographer over-readers. Pulmonary artery systolic pressure was calculated as

4*(peak tricuspid regurgitation velocity)2 + 5 mmHg (8). Echocardiographic assessments

were performed by persons blinded to participants' clinical characteristics. Spirometry

was performed according to American Thoracic Society guidelines using previously

defined protocol (9).

SUPPLEMENTARY REFERENCES

1. Rosamond WD, Chang PP, Baggett C et al. Classification of heart failure in the

atherosclerosis risk in communities (ARIC) study: a comparison of diagnostic

criteria. Circ Heart Fail 2012;5:152-9.

2. Atherosclerosis Risk in Communities Visit 5 Derived Variable Dictionary 2018.

3. Matsushita K, Kwak L, Yang C et al. High-sensitivity cardiac troponin and

natriuretic peptide with risk of lower-extremity peripheral artery disease: the

Atherosclerosis Risk in Communities (ARIC) Study. Eur Heart J 2018;39:2412-

2419.

4. Fletcher CM, Elmes PC, Fairbairn AS, Wood CH. The significance of respiratory

symptoms and the diagnosis of chronic bronchitis in a working population. Br

Med J 1959;2:257-66.

5. Santos M, Kitzman DW, Matsushita K, Loehr L, Sueta CA, Shah AM. Prognostic

Importance of Dyspnea for Cardiovascular Outcomes and Mortality in Persons

without Prevalent Cardiopulmonary Disease: The Atherosclerosis Risk in

Communities Study. PLoS One 2016;11:e0165111.

6. Shah AM, Cheng S, Skali H et al. Rationale and design of a multicenter

echocardiographic study to assess the relationship between cardiac structure and

function and heart failure risk in a biracial cohort of community-dwelling elderly

persons: the Atherosclerosis Risk in Communities study. Circ Cardiovasc Imaging

2014;7:173-81.

7. Cheng S, Larson MG, McCabe EL et al. Reproducibility of speckle-tracking-

based strain measures of left ventricular function in a community-based study. J

Am Soc Echocardiogr 2013;26:1258-1266 e2.

8. Selvaraj S, Shah SJ, Ommerborn MJ et al. Pulmonary Hypertension Is Associated

With a Higher Risk of Heart Failure Hospitalization and Mortality in Patients

With Chronic Kidney Disease: The Jackson Heart Study. Circ Heart Fail 2017;10.

9. Silvestre OM, Nadruz W, Jr., Querejeta Roca G et al. Declining Lung Function

and Cardiovascular Risk: The ARIC Study. J Am Coll Cardiol 2018;72:1109-

1122.

SUPPLEMENTARY FIGURE LEGENDS

Supplementary Figure S1

Title: Flow Diagram of Study Inclusion and Exclusion Criteria

Caption:

Of the initial 6,538 participants attending Visit 5, there were 5,466 participants with

available data needed to calculate the H2FPEF and ESC HFA-PEFF scores. After

excluding those with cardiac, pulmonary, and hematologic causes of dyspnea, as well as

those missing components of the H2FPEF Score, there were 4,892 participants included

in the analysis. We separated participants into 5 categories for each scoring system:

asymptomatic, known HFpEF, and tertiles of the diagnostic score among those with

unexplained dyspnea. ARIC, Atherosclerosis Risk in Communities; ESC, European

Society of Cardiology; HFpEF, Heart Failure with Preserved Ejection Fraction; PASP,

pulmonary artery systolic pressure; TR, tricuspid regurgitation).

Supplementary Figure S2

Title: Relationship between H2FPEF Score and BMI among those with Unexplained

Dyspnea and Known HFpEF

Caption:

Despite the fact that the H2FPEF score includes BMI as part of its algorithm, participants

with unexplained dyspnea had a higher BMI at most scores compared to those with

known HFpEF. 3 knots were used for the spline curves, and dashed lines indicate 95%

confidence intervals. BMI, body mass index; HFpEF, heart failure with preserved

ejection fraction.

Supplementary Figure S3

Title: Cumulative Incidence Curves for Heart Failure Hospitalization or Death.

Caption:

Cumulative incidence curves for each of the study outcomes by symptoms (unexplained

dyspnea) and diagnostic score at Visit 5. Left panel: 1) asymptomatic, 2) symptomatic

and H2FPEF-score <6, 3) symptomatic and H2FPEF score ≥6, and 5) known HFpEF.

Right panel: 1) asymptomatic, 2) symptomatic and HFA-PEFF score 0-2, 3) symptomatic

and HFA-PEFF score 3, 4) symptomatic and HFA-PEFF score 4-6 and 5) known HFpEF.

HFpEF, heart failure with preserved ejection fraction; HFH, heart failure hospitalization.

Supplementary Figure S4

Title: Cumulative Incidence Curves for Heart Failure Hospitalization or Death

Among Diagnostic Score Groups of Unexplained Dyspnea.

Caption:

Among participants with unexplained dyspnea, shown are cumulative incidence curves

by classification of risk by H2FPEF score and HFA-PEFF scores. The only pairwise

comparisons that are significantly different at p=0.05 are the comparisons of the

H2FPEF<6 and HFA-PEFF<5 group (lower risk for both scores) versus all other groups.

HFpEF, heart failure with preserved ejection fraction; HFH, heart failure hospitalization.

SUPPLEMENTARY TABLE 1. Clinical Characteristics of the Study Sample at Visit 5 among Participants with Unexplained Dyspnea by

Diagnostic Score Groups

Unexplained

Dyspnea: HFA-

PEFF <5,

H2FPEF<6

N=435

Unexplained

Dyspnea: HFA-

PEFF <5,

H2FPEF≥6*

N=42

Unexplained

Dyspnea: HFA-

PEFF≥5,

H2FPEF<6*

N=137

Unexplained

Dyspnea: HFA-

PEFF≥5,

H2FPEF≥6

N=27

Global P-

value

P-value

Comparing

Columns

marked by *

Age, years 75.8 ± 5.1 76.8 ± 5.1 78.0 ± 5.1 77.8 ± 5.9 < 0.001 0.18

Women, n (%) 292 (67.1%) 29 (69.0%) 95 (69.3%) 17 (63.0%) 0.91 0.97

Black race, n (%) 167 (38.4%) 11 (26.2%) 25 (18.2%) 6 (22.2%) < 0.001 0.26

Physical Exam

Systolic blood pressure (mm

Hg)131 ± 17 129 ± 24 135 ± 20 132 ± 19 0.08 0.08

Diastolic blood pressure

(mm Hg)67 ± 10 67 ± 11 65 ± 11 66 ± 13 0.25 0.41

Heart rate (beats/minute) 67 ± 11 67 ± 11 63 ± 10 64 ± 13 < 0.001 0.009

Body mass index (kg/m2) 31.7 ± 7.2 35.9 ± 6.5 30.6 ± 6.8 33.1 ± 5.9 < 0.001 < 0.001

Comorbidities, n (%)

Hypertension 338 (78.2%) 38 (90.5%) 114 (84.4%) 24 (88.9%) 0.08 0.33

Diabetes mellitus 207 (47.6%) 29 (69.0%) 55 (40.1%) 15 (55.6%) 0.009 0.001

Coronary heart disease 39 (9.2 %) 9 (22.0%) 26 (19.4%) 5 (18.5%) 0.003 0.72

Current smoker 30 (6.9 %) 1 (2.4 %) 14 (10.4%) 0 (0.0 %) 0.13 0.1

Paroxysmal or permanent

atrial fibrillation or flutter9 (2.1 %) 33 (78.6%) 4 (2.9 %) 16 (59.3%) < 0.001 < 0.001

Medication Use

Number of anti-hypertensive

medications1.6±1.2 2.4±1.1 2.0±1.3 1.4±1.2 <0.001 <0.001

Aspirin (n, %) 302 (69.4%) 32 (76.2%) 106 (77.4%) 19 (70.4%) 0.29 0.87

Statin (n, %) 239 (54.9%) 26 (61.9%) 75 (54.7%) 12 (44.4%) 0.57 0.41

Anticoagulation (n, %) 16 (3.7 %) 16 (38.1%) 8 (5.8 %) 12 (44.4%) < 0.001 < 0.001

Glucose lowering medication

(n, %)125 (28.7%) 18 (42.9%) 33 (24.1%) 9 (33.3%) 0.29 0.018

Laboratory Testing

Hemoglobin (mg/dL) 13.1 ± 2.0 13.2 ± 1.7 12.8 ± 1.2 12.4 ± 1.2 0.57 0.11

Hemoglobin A1c (%) 6.2 ± 1.0 6.3 ± 1.0 6.1 ± 1.0 6.0 ± 0.6 0.5 0.18

Estimated glomerular

filtration rate (mL/min/1.73

m2)

71 ± 17 65 ± 22 62 ± 19 57 ± 18 < 0.001 0.43

High sensitivity C-reactive

protein (mg/L)*2.40 [1.10 , 5.37

2.55 [1.20 ,

7.36

1.97 [0.99 ,

4.50

3.48 [1.93 ,

6.850.15 0.15

N-terminal pro-B-type

natriuretic peptide (ng/L)*100 [58 , 164 275 [119 , 672 374 [252 , 654

1157 [448 ,

1989]< 0.001 0.022

High sensitivity cardiac

troponin T (ng/L)*11 [7 , 16 14 [9 , 21 15 [10 , 22 15 [11 , 26 < 0.001 0.56

Low density lipoprotein

(mg/dL)104 ± 34 94 ± 33 98 ± 33 93 ± 35 0.05 0.56

Spirometry

FEV1 (% predicted) 88 ± 26 88 ± 19 90 ± 25 85 ± 21 0.78 0.58

FEV1/FVC 96 ± 17 98 ± 12 94 ± 19 98 ± 13 0.61 0.3

Electrocardiography and

Echocardiography

QRS duration (ms) 94 ± 20 100 ± 22 100 ± 23 106 ± 34 0.003 0.96

LV end-diastolic diameter

(cm)4.3 ± 0.5 4.7 ± 0.6 4.4 ± 0.5 4.5 ± 0.5 < 0.001 0.023

LV end-diastolic volume 77.9 ± 19.8 81.9 ± 23.4 84.3 ± 23.6 84.9 ± 22.2 0.012 0.59

(mL)

Mean LV wall thickness

(cm)1.0 ± 0.1 1.1 ± 0.1 1.1 ± 0.2 1.1 ± 0.3 < 0.001 0.42

LV mass index (g/m2) 76.4 ± 15.9 86.8 ± 18.4 90.8 ± 24.7 95.2 ± 44.9 < 0.001 0.35

LV hypertrophy (n, %) 69 (16.2%) 15 (36.6%) 55 (40.4%) 9 (33.3%) 0.001 0.66

LV ejection fraction (%) 66 ± 6 65 ± 5 67 ± 6 64 ± 7 0.1 0.13

Average LV global

longitudinal strain (%)-18.0 ± 2.4 -17.2 ± 3.5 -17.8 ± 2.5 -16.6 ± 3.9 0.013 0.23

Left atrial volume index

(mL/m2)23 ± 6 30 ± 10 33 ± 10 40 ± 10 < 0.001 0.07

Tricuspid annular peak

systolic velocity (cm/s)11.8 ± 3.0 10.8 ± 2.8 12.0 ± 3.6 10.9 ± 2.3 0.1 0.07

Peak tricuspid regurgitation

velocity (cm/s)2.36 ± 0.26 2.65 ± 0.39 2.43 ± 0.26 2.84 ± 0.32 < 0.001 <0.001

E wave deceleration (ms) 206 ± 45 191 ± 49 216 ± 52 172 ± 42 < 0.001 0.006

E-a ratio 0.79 ± 0.21 0.87 ± 0.25 0.87 ± 0.33 1.27 ± 0.72 < 0.001 0.96

Septal e’ velocity (cm/s) 5.51 ± 1.35 6.40 ± 1.68 5.10 ± 1.28 6.09 ± 1.83 < 0.001 <0.001

Septal E/e’ ratio 12.2 ± 3.8 13.2 ± 4.5 14.8 ± 6.2 15.9 ± 6.3 < 0.001 0.12

ESC, European Society of Cardiology; HFpEF, heart failure with preserved ejection fraction; FEV1, forced expiratory volume in 1 second; FVC,

forced vital capacity; LV, left ventricular.

*Presented as median [25th-75th percentile]

SUPPLEMENTARY TABLE 2. Sensitivity Analysis using Complete Case Analysis of Pulmonary Artery Systolic Pressure for Event

Rates for Combined Endpoint

Outcomes, n (%) Asymptomatic

N=2173

Symptomatic,

H2FPEF Score

1-2

N=93

Symptomatic,

H2FPEF Score

3-4

N=140

Symptomatic,

H2FPEF Score

≥5

N=126

Known HFpEF

N=293

Heart failure hospitalization or

death

● Event rate (per 1000

person-years)

22.2 (19.7, 25.1) 21.9 (12.1, 39.6) 60.7 (44.7, 82.4) 45.0 (31.2 64.7) 77.6 (64.2, 93.7)

● Hazard ratio (95% CI) Ref 0.99 (0.54, 1.81) 2.78 (2.00, 3.87) 2.05 (1.39, 3.00) 3.60 (2.88, 4.51)

HFpEF, heart failure with preserved ejection fraction.

SUPPLEMENTARY TABLE 3. The HFA-PEFF score and H2FPEF score, and its Components, in Association to Incident

Heart Failure among 641 Participants with Unexplained Dyspnea

*All

participants

were >60

years

HR (95% CI) P-value Harrell’s

C-statistics

HFA-PEFF score 1.68 (1.34-2.10) <0.001 0.68

Functional domain score (0-2) 0.84 (0.31-2.24) 0.72 0.51

Morphological domain score (0-2) 1.67 (1.11-2.50) 0.014 0.60

Biomarker domain score (0-2) 2.05 (1.47-2.87) <0.001 0.67

H2FPEF score 1.25 (1.07-1.46) 0.006 0.59

Body mass index >30 kg/m2 1.12 (0.64-1.96) 0.69 0.50

2 or more antihypertensive medicines 2.59 (1.36-4.95) 0.004 0.61

Atrial fibrillation 2.18 (1.02-4.65) 0.044 0.54

Pulmonary Artery Systolic Pressure >35

mmHg

3.40 (1.70-6.81) 0.001 0.57

Age >60 years N/A* - -

E/e’ >9 0.95 (0.46-1.95) 0.88 0.50

SUPPLEMENTARY TABLE 4. Sensitivity Analysis for Risk of HFpEF Hospitalization for Each Diagnostic Score Algorithm

H2FPEF Score

Outcomes, n (%) Asymptomatic

N=3749

Unexplained

Dyspnea,

H2FPEF Score

1-2

N=150

Unexplained

Dyspnea,

H2FPEF Score

3-4

N=264

Unexplained

Dyspnea,

H2FPEF Score

≥5

N=227

Known HFpEF

N=502

HFpEF hospitalization

● Event rate (per 1000

person-years)

2.0 (1.5, 2.7) 2.5 (0.6, 10.2) 6.9 (3.6, 13.2) 10.7 (6.1, 18.8) 11.3 (7.5, 17.2)

● Hazard ratio (95% CI) Ref 1.27 (0.31, 5.27) 3.42 (1.66, 7.04) 5.32 (2.79,

10.13)*

5.59 (3.32, 9.40)*

HFA-PEFF Score

Outcomes, n (%) Asymptomatic Unexplained

Dyspnea, HFA

Unexplained

Dyspnea, HFA

Unexplained

Dyspnea, HFA

Known HFpEF

N=3749 PEFF Score 0-2

N=117

PEFF Score 3

N=214

PEFF Score 4-6

N=310

N=502

HFpEF hospitalization

● Event rate (per 1000

person-years)

2.0 (1.5, 2.7) 0 2.7 (0.9, 8.4) 13.1 (8.5, 20.3) 11.3 (7.5, 17.2)

● Hazard ratio (95% CI) Ref NA 1.36 (0.42, 4.39) 6.54 (3.82,

11.18)**

5.59 (3.32,

9.40)**

HFpEF, heart failure with preserved ejection fraction; CI, confidence interval

*p=0.89 comparing unexplained dyspnea with H2FPEF Score ≥ 5 versus known HFpEF.

**p=0.61 comparing unexplained dyspnea with HFA-PEFF Score 4-6 versus known HFpEF.

Supplementary Figure 1. Flow Diagram of Study Inclusion and Exclusion Criteria

Participants attending ARIC Visit 5 (n= 6,538)

Missing dyspnea data (n=482)Missing NT-proBNP data (n=118) Missing echocardiographic data (n=420) (PASP was imputed for n=2,101 with

missing TR jet) Missing clinical data for calculation of

H2FPEF score (n=52)

Cardiac causes of dyspnea- LV ejection fraction <50% (n= 184)

- Valvular disease (n= 49)  Pulmonary causes of dyspnea (n=613)  Hemoglobin <10 mg/dl (n=84)

Known HFpEF (n=502)

Eligible for inclusion (n= 5,466)

Available for analysis (n=4,892)

Asymptomatic (n=3,749)

Symptomatic, H2FPEF Tertile 1 (n=150)

Symptomatic, H2FPEF Tertile 3 (n=227)

Symptomatic, H2FPEF Tertile 2 (n=264)

Known HFpEF (n=502)

Asymptomatic (n=3,749)

Symptomatic, ESC HFA Tertile 1 (n=117)

Symptomatic, ESC HFA Tertile 3 (n=310)

Symptomatic, ESC HFA Tertile 2 (n=214)

SUPPLEMENTARY FIGURE 2.

SUPPLEMENTARY FIGURE 3.

SUPPLEMENTARY FIGURE 4. Cumulative Incidence Curves for Heart Failure Hospitalization or Death Among Diagnostic Score

Groups of Undifferentiated Dyspnea