Study Population

Consecutive patients were prospectively recruited from the outpatient clinic of the Northwestern University HFpEF program between March 2008 and January 2011 as part of a systematic observational study of HFpEF ( ClinicalTrials.gov ID NCT01030991 ). Patients were initially identified through an automated daily query of the inpatient electronic medical record at Northwestern Memorial Hospital using the following search criteria: (1) diagnosis of HF or the term heart failure in the hospital notes, (2) B-type natriuretic peptide (BNP) > 100 pg/mL, or (3) the administration of two or more doses of intravenous diuretics. The list of patients generated was screened daily, and only those patients who had LV ejection fractions (LVEFs) > 50% and who met Framingham criteria for HF were offered postdischarge follow-up in a specialized HFpEF outpatient program. Once a patient was evaluated as an outpatient in the HFpEF clinic, the diagnosis of HF was confirmed by a cardiologist who specializes in HF. The diagnosis of HFpEF was based on previously published criteria that require both an LVEF > 50% and an LV end-diastolic volume index < 97 mL/m ² . In line with a large population-based study of HFpEF, patients with hemodynamically significant valvular disease (defined as greater than moderate in severity), prior cardiac transplantation, history of overt LV systolic dysfunction (LVEF < 40%), or diagnoses of constrictive pericarditis were not recruited into the study. Patients were excluded in the present study if they had ventricular paced rhythms.

In the Northwestern HFpEF program, all study procedures (including laboratory testing, electrocardiography, and echocardiography) are performed in the outpatient setting. All study participants gave written, informed consent, and the institutional review board at Northwestern University approved the study.

Clinical Characteristics

We collected and analyzed demographics and clinical data (including comorbidities and medications) in all study subjects. We also documented New York Heart Association functional class and several laboratory parameters, including BNP. Estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease equation.

Electrocardiography

All subjects underwent 12-lead electrocardiography (Marquette MAC 5000 Resting ECG System; GE Healthcare, Milwaukee, WI). Electrocardiograms were analyzed by a single trained reader blinded to all other data, including echocardiographic data and outcomes. We measured the PR interval, QRS duration, QT interval, QRS axis, and T-wave axis according to published guidelines. The corrected QT (QTc) interval was calculated using Bazett’s formula (QTc). We verified computer-generated axes from the electrocardiographic report by manual overread. T-wave inversion was defined by a negative T wave ≥ 1 mm in amplitude in two or more contiguous leads. The frontal QRS-T angle was calculated as the smallest angle between the frontal plane QRS and T-wave axes (QRS-T angle = |QRS axis − T-wave axis|; if |QRS-T angle| > 180°, the complementary angle [i.e., 180° − QRS-T angle] was used).

Echocardiography

All study participants underwent comprehensive two-dimensional echocardiography with Doppler and Doppler tissue imaging. All standard echocardiographic views were obtained using commercially available ultrasound systems with harmonic imaging (iE33 or 7500, Philips Medical Systems, Andover, MA; or Vivid 7, GE Healthcare). Cardiac structure and function (including LV systolic and diastolic function and RV size and function) were quantified as recommended by the American Society of Echocardiography.

LV end-diastolic and end-systolic volumes, and left atrial volume, were measured in the apical four-chamber and two-chamber views using the biplane method of disks. LV ejection fraction was calculated as (LV end-diastolic volume − LV end-systolic volume)/LV end-diastolic volume. LV mass index was calculated using the linear method, as outlined in American Society of Echocardiography guidelines.

LV diastolic function was graded according to published criteria using mitral inflow characteristics and tissue Doppler e′ velocities. Tissue Doppler e′ and s′ velocities were measured at the septal and lateral aspects of the mitral annulus and were averaged. Sample volume size and placement were optimized for all pulse-wave Doppler and tissue Doppler measurements. All Doppler and tissue Doppler measurements were averaged over three beats (five beats for patients in atrial fibrillation).

Right heart parameters were measured on echocardiography according to published guidelines. Specifically, we measured RV basal diameter, RV length, RV end-diastolic area, RV end-systolic area, RV wall thickness, and right atrial area. Tricuspid annular plane systolic excursion (TAPSE) was also calculated. Last, pulmonary artery systolic pressure was measured using the peak tricuspid regurgitation velocity (to estimate peak tricuspid regurgitation gradient) and adding that to the estimated right atrial pressure, which was based on size and collapsibility of the inferior vena cava.

All cardiac structural measurements, including right heart parameters, were indexed to body surface area. All echocardiographic measurements were made blinded to all other data by an experienced research sonographer using ProSolv 4.0 echocardiographic analysis software (ProSolv CardioVascular, Indianapolis, IN) and verified by an experienced investigator with expertise in echocardiography.