Background
Increasing diastolic dysfunction (DD) grade is associated with increased heart failure (HF). Patients with preserved ejection fractions and grade 1 DD may have left atrial dilatation, e′ < 8 cm/sec, increased left ventricular (LV) mass, or variable E/e′ ratios. The aim of this study was to test the hypothesis that LV hypertrophy or E/e′ ratio > 8 may be associated with a greater incidence of HF.
Methods
Two hundred twelve patients with grade 1 DD and ejection fractions > 50% were retrospectively studied. Group 1 comprised 108 patients with E/A ratios < 0.8, without LV hypertrophy, e′ < 8 cm/sec, and E/e′ ratios < 8. Group 2 comprised 104 patients with LV hypertrophy or E/e′ ratios > 8. Patients with incident HF and valvular or coronary disease were excluded. Using two-dimensional Doppler echocardiography, LV and left atrial volumes and transmitral spectral and tissue Doppler were analyzed. Medical records were examined for laboratory data, HF admissions, and all-cause mortality from 2004 to 2012.
Results
Despite similar ejection fractions, patients in group 2 had greater LV and left atrial volumes, LV mass index values, and E/e′ ratios ( P < .01 for all). HF incidence was greater in group 2 (30 vs 4, P < .001). Combined HF or all-cause mortality was greater in group 2 (46 vs 14, P < .001). Multivariate analysis revealed that HF was associated with E/e′ ratio ( P < .0001), systolic blood pressure ( P = .0123), and LV mass index ( P = .042). Combined HF or all-cause mortality was associated with E/e′ ratio ( P < .0001), LV mass index ( P = .009), and lower calcium channel blocker use ( P = .0011).
Conclusions
HF alone or HF and all-cause mortality were increased in patients with grade 1 DD in the presence of LV hypertrophy or elevated LV filling pressures.
Highlights
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Grade 1 DD comprises a heterogeneous group of patients.
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Group 1 had no LV hypertrophy or E/e′ ratio > 8, while group 2 may have either or both.
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HF occurred in 29% versus 4% over 8 years in group 2 versus group 1.
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HF and all-cause mortality occurred in 44% versus 14% over 8 years in group 2 versus group 1.
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Predictors of HF include E/e′ ratio, systolic blood pressure, and LV mass index.
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Predictors of HF and all-cause mortality include E/e ratio, reduced calcium channel blocker use, and LV mass index.
The American Society of Echocardiography, in its guidelines for the evaluation and interpretation of diastolic function, divided diastolic dysfunction (DD) into three grades: impaired relaxation (grade 1), pseudonormal (grade 2), and restrictive (grade 3). Increasing grades of DD have been associated with increased incidence of heart failure (HF) and adverse cardiovascular events including death in patients with preserved and those with reduced left ventricular (LV) ejection fractions (LVEFs). However, not all patients neatly fit into one of the three grades or in a normal grade. For patients with preserved LVEFs and grade 1 DD, left atrial volume index tends to be >34 mL/m 2 , average peak rapid mitral annular velocity to be <8 cm/sec, E/A ratio to be <0.8, deceleration time to be >200 msec, and the average E/e′ ratio to be <8. There may be patients with clear Doppler evidence of impaired relaxation but with lesser degrees of left atrial dilation or values in the upper normal range. Furthermore, patients may fit into grade 1 with E/A ratios < 0.8 and deceleration times > 200 msec but have values of average E/e′ ratio > 8. Furthermore, if the left atrial volume index is >34 mL/m 2 , this might suggest elevated LV filling pressures, but does this indicate an adverse prognosis for patients with E/e′ ratios < 8? Finally, the presence of LV hypertrophy associated with grade 1 DD may confer a worse long-term prognosis.
We hypothesized that a subgroup of patients with preserved LVEFs and grade 1 DD in the absence of LV hypertrophy or E/e′ ratio > 8 will have a lower incidence of adverse cardiac events, specifically HF. To test this hypothesis, we retrospectively reviewed a cohort of patients with grade 1 DD who underwent Doppler echocardiography from January to July 2004 and followed them through December 2012.
Methods
Patients
We conducted a single-center retrospective review of all patients who demonstrated evidence of grade 1 DD as defined by the American Society of Echocardiography criteria from January to July 2004 and were followed through December 2012, with an average follow-up duration of 105 ± 2 months. The study was approved (with expedited review) by the institutional review board of the University of Florida–Jacksonville College of Medicine. There were 259 patients with LVEFs > 50% and grade 1 DD without evidence of additional valvular heart disease, HF at the time of echocardiography, coronary artery disease, or cardiomyopathy. Indications for echocardiography were dyspnea (88 patients), chest pain (76 patients), palpitations (50 patients), abnormal results on electrocardiography (35 patients), and heart murmurs (10 patients). We were able to identify 212 patients with adequate Doppler echocardiograms allowing the determination of LV size, thickness, and function, left atrial volume, assessment of diastolic indices with transmitral Doppler and tissue Doppler, and tissue Doppler assessment of longitudinal strain who were in sinus rhythm without intraventricular conduction delays. Patients with more than minimal mitral annular calcification were not included. Patients were divided into group 1 (108 patients) with E/A ratios < 0.8, deceleration times > 200 msec, and averages of septal and lateral mitral annular e′ < 8 cm/sec. Patients who also had increased LV wall thickness by evidence of posterior or septal wall thickness ≥ 12 mm (LV hypertrophy) or E/e′ ratios ≥ 8 were included in group 2 (104 patients) because increased LV mass index and increased E/e′ ratio are associated with a greater incidence of adverse cardiovascular events. Thirty-one patients without evidence of cardiac disease on the basis of history, physical examination, and echocardiography were selected from a larger group of patients with normal results on echocardiography during this time period and were age- and sex-matched to the grade 1 DD groups as a control comparison group. Patients with well-controlled hypertension without LV hypertrophy were included in the comparison control group.
For each patient selected for inclusion, the medical records were examined for the patient’s age, sex, height, weight, body surface area, body mass index, laboratory results, and medications at the time echocardiography was performed. Patients were deemed to have hypertension if their blood pressure exceeded 140/90 mm Hg or they were taking antihypertensive medications. Patients were deemed to have diabetes mellitus if their fasting blood glucose was >126 mg%, their postprandial glucose was >200 mg%, or they were taking antidiabetic medications. Patients were deemed to have hyperlipidemia if their total cholesterol (>200 mg/dL) or fasting triglycerides (>150 mg/dL) were elevated or they were taking medications to reduce cholesterol or triglycerides. QRS duration was obtained from 12-lead electrocardiography. During follow-up, the development of HF was determined from the inpatient and outpatient medical records using the Framingham criteria. All-cause mortality was determined from medical records and by querying the Social Security Death Index.
Echocardiography
All cine images and Doppler tracings were previously acquired using three cardiac cycles, and the average of the three cycles was used for all calculations. Two-dimensional Doppler echocardiography including M-mode, spectral, and color flow Doppler and tissue Doppler were obtained in all patients using either a Vivid 7 (GE Medical Systems, Milwaukee, WI) or an iE33 echocardiograph (Philips Medical Systems, Andover, MA). Systolic blood pressure, diastolic blood pressure, and pulse pressure were also recorded at the time of echocardiography. From the M-mode tracings of the left atrium, we measured left atrial dimension in midsystole using the leading edge–to–leading edge technique. Using two-dimensional echocardiography, the LV outflow tract was measured from the parasternal long-axis view during peak systole. End-diastolic dimension, end-systolic dimension, and septal and inferolateral wall thickness at end-diastole were measured using the American Society of Echocardiography standards. Relative wall thickness was calculated as the ratio of twice the posterior wall thickness in end-diastole and end-diastolic dimension. LV end-diastolic and end-systolic volumes were measured using the apical biplane Simpson rule and indexed to body surface area. LV mass index was calculated using the American Society of Echocardiography formula and indexed to body surface area :
LV mass = 0.8 × { 1.04 [ ( LV internal dimension in diastole + posterior wall thickness in diastole + septal wall thickness in diastole ) 3 − ( LV internal dimension in diastole ) 3 ] } + 0.6 g.
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