## Background

Deceleration time (DT) of early mitral inflow (E) is a marker of diastolic left ventricular (LV) chamber stiffness that is routinely measured during the quantitation of LV diastolic function with Doppler echocardiography. Shortened DT after myocardial infarction predicts worse cardiovascular outcome. Recent studies have shown that indexing DT to peak E-wave velocity (pE) augments its prognostic power in a population with a high prevalence of coronary risk factors and in patients with hypertension during antihypertensive treatment. However, in ambulatory subjects with stable coronary artery disease (CAD), it is not known whether DT predicts cardiovascular events and whether DT/pE improves its prognostic power.

## Methods

The ability of DT and DT/pE to predict heart failure (HF) hospitalizations and other major adverse cardiovascular events (MACEs) was studied prospectively in 926 ambulatory patients with stable CAD enrolled in the Heart and Soul Study. Unadjusted and multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for HF and other MACEs.

## Results

During a mean of 6.3 ± 2.0 years, there were 124 hospitalizations for HF and 198 other MACEs. Relative to participants with mitral E/A ratios in the normal range (0.75 < E/A < 1.5; *n *= 604), those with E/A ratios ≥ 1.5 ( *n *= 107) had an increased risk for HF (HR, 2.54; 95% CI, 1.52–4.25, *P *< .001) but not for other MACEs (HR, 1.00; 95% CI, 0.60–1.68; *P *= 1.00), while those with E/A ratios ≤ 0.75 ( *n *= 215) were not at increased risk for either outcome. Among patients with normal E/A ratios, lower DT/pE predicted HF (HR, 0.47; 95% CI, 0.23–0.97, *P *= .04 per point increase in ln{msec/[cm/sec]}), while DT alone did not. However, in this group with normal E/A ratios, neither DT/pE nor DT alone was predictive of other MACEs. In patients with E/A ratios ≤ 0.75 ( *n *= 215) and those with E/A ratios ≥ 1.5 ( *n *= 107), neither DT nor DT/pE predicted either end point.

## Conclusions

In ambulatory patients with stable CAD, restrictive filling (E/A ratio ≥ 1.5) is a powerful predictor of HF. Among those with normal mitral E/A ratios (0.75–1.5), only DT/pE predicts HF, while neither DT nor DT/pE predicts other MACEs. This suggests that mitral E/A ratio has significant prognostic value in patients with CAD, and in those with normal mitral E/A ratios, the normalization of DT to pE augments its prognostic power.

Deceleration time (DT) of early mitral filling velocity (E) is routinely measured as part of the echocardiographic evaluation of left ventricular (LV) diastolic function ( Figure 1 ). Extremes of DT are associated with poor outcomes. Shortened DT in middle-aged and older adults, a marker of increased LV chamber stiffness, predicts cardiovascular (CV) events in patients with symptomatic or asymptomatic LV systolic dysfunction and in survivors of myocardial infarction (MI). Longer DT, a marker of impaired LV relaxation, predicts CV outcomes after non–ST-segment elevation MI. To date, the prognostic value of DT in ambulatory patients with stable coronary artery disease (CAD) remains unexplored.

Because peak E-wave velocity (pE) is determined by left atrial (LA) pressure at the end of ventricular systole, the LA-LV pressure gradient immediately thereafter, and the intensity of early diastolic LV suction, and because DT is measured from pE and is positively related to it, variations in loading conditions that increase or lower pE may confound the relationship of DT with the underlying rate of early diastolic LV relaxation ( Figure 1 ). Therefore, we hypothesized in two previously published studies that normalization of DT to pE would augment its prognostic value. In a population with high prevalence of hypertension and of diabetes but without prevalent CAD, we found that DT/pE significantly predicted CV outcomes, whereas DT alone did not. We confirmed this finding in a cohort of patients with treated hypertension, also free of prevalent CAD. However, it is not known whether normalization of DT to pE improves its prognostic capacity in patients with known CAD. Because both DT and pE are routinely measured by echocardiography, it would be useful to determine whether this simple ratio of these two variables would be a better predictor of adverse CV outcomes.

In this study, conducted in a cohort of ambulatory patients with known stable CAD, we tested the hypotheses that DT is a significant predictor of heart failure (HF) hospitalization and other major adverse CV events (MACEs) and that normalization of DT to pE augments its prognostic value.

## Methods

The Heart and Soul Study is a prospective cohort study of psychosocial factors and health outcomes in 1,024 patients with coronary disease. Methods and objectives have been described previously. Criteria for enrollment were (1) history of MI, (2) angiographic evidence of ≥50% diameter stenosis in ≥1 coronary vessel, (3) evidence of exercise-induced ischemia on treadmill electrocardiography or stress nuclear perfusion imaging, or (4) history of coronary revascularization. Patients were excluded if they deemed themselves unable to walk 1 block, were within 6 months of acute coronary syndromes, or planned to move out of the local area within 3 years. Nine hundred twenty-six patients in sinus rhythm with complete echocardiographic assessments of mitral E-wave and A-wave velocities and E-wave DT and without mitral stenosis were included in this analysis.

All subjects gave informed consent under protocols approved by the University of California, San Francisco, committee on human research, the research and development committee of the San Francisco Veterans Affairs Medical Center, the medical human subjects committee of Stanford University, the human subjects committee at the Veterans Affairs Palo Alto Health Care System, and the data governance board of the Community Health Network of San Francisco.

## Echocardiography

Complete resting two-dimensional echocardiography and Doppler ultrasound examinations included standard two-dimensional parasternal short-axis, apical two-chamber and four-chamber, and subcostal views using an Acuson Sequoia Ultrasound System (Siemens Medical Solutions USA, Inc., Mountain View, CA). LV end-diastolic and end-systolic volumes were estimated using the modified biplane methods of discs. LV ejection fraction was calculated as (LV end-diastolic volume − LV end-systolic volume)/LV end-systolic volume. LV mass was estimated using the truncated ellipsoid method and indexed to body surface area. LA volume was calculated using the biplane method of discs. Mitral inflow velocities (E and A) were obtained in the apical four-chamber view using pulse-wave Doppler, with the sample volume placed between the mitral leaflet tips. Mitral E-wave DT was measured from the peak of the E-wave velocity ( Figure 1 ). We divided mitral E/A ratios into three clinically relevant categories on the basis of prior studies: (1) impaired relaxation = E/A ≤ 0.75, (2) normal = 0.75 < E/A < 1.5, and (3) restrictive filling = E/A ≥ 1.5. All echocardiograms were reviewed by one cardiologist (N.B.S.).

## Clinical Outcomes

We conducted annual telephone interviews with participants or their proxies to assess emergency room visits, hospitalizations, or death. Medical records, death certificates, and coroner’s reports were reviewed by two independent and blinded adjudicators. If the adjudicators agreed on the outcome classification, their classification was binding. If they disagreed, a third blinded adjudicator reviewed the event and determined the outcome classification. Adjudication of CV events, including HF hospitalizations, MIs, strokes, and transient ischemic attacks, has been discussed extensively elsewhere. The two outcomes studied in this report are HF hospitalizations and other MACEs (CV death, nonfatal MI, stroke, or transient ischemic attack).

## Statistical Analysis

Baseline characteristics are reported as mean ± SD for continuous variables and as proportions for categorical variables. Differences between two groups were determined using unpaired *t *tests for continuous variables and χ ^{2 }tests for categorical variables. Differences among more than two groups were assessed using analysis of variance with the Scheffé post hoc test. Histograms demonstrated that both DT and DT/pE had positively skewed distributions. Therefore, they were both transformed using the natural logarithmic function before further analyses. Given the U-shaped relationship between DT and CV outcomes, we hypothesized that the magnitude and direction of the effect of the prognostic value of DT would vary with the mitral E/A ratio. To determine the interaction between DT and DT/pE on the one hand and mitral E/A ratio on the other, we constructed Cox proportional-hazards models with DT or DT/pE, E/A ratio, and an interaction term (DT × E/A or DT/pE × E/A) as predictor variables and HF hospitalization and other MACEs as outcome variables. Because both interaction terms (DT × E/A and DT/pE × E/A) were significant predictors of outcomes, subsequent analyses were stratified by clinically relevant categories of mitral E/A ratio (≤0.75, 0.75–1.5, and ≥1.5). Cox proportional-hazards models, stratified by mitral E/A ratio, were used to evaluate the unadjusted and adjusted relationships of DT and DT/pE with time to HF hospitalization and other MACEs. To further explore mitral E/A ratio as a predictor, Cox proportional-hazards models were constructed to evaluate the unadjusted and adjusted relationships between mitral E/A ratio as a categorical variable (≤0.75, 0.75–1.5, and ≥1.5) and HF hospitalizations and other MACEs. C-statistics, representing the area under the curve obtained using receiver operating characteristic curve analysis, were used to compare the performance characteristics of various echocardiographic parameters in predicting HF hospitalization and other MACEs. All analyses were performed using SPSS version 12.0 (SPSS, Inc., Chicago, IL).

## Statistical Analysis

Baseline characteristics are reported as mean ± SD for continuous variables and as proportions for categorical variables. Differences between two groups were determined using unpaired *t *tests for continuous variables and χ ^{2 }tests for categorical variables. Differences among more than two groups were assessed using analysis of variance with the Scheffé post hoc test. Histograms demonstrated that both DT and DT/pE had positively skewed distributions. Therefore, they were both transformed using the natural logarithmic function before further analyses. Given the U-shaped relationship between DT and CV outcomes, we hypothesized that the magnitude and direction of the effect of the prognostic value of DT would vary with the mitral E/A ratio. To determine the interaction between DT and DT/pE on the one hand and mitral E/A ratio on the other, we constructed Cox proportional-hazards models with DT or DT/pE, E/A ratio, and an interaction term (DT × E/A or DT/pE × E/A) as predictor variables and HF hospitalization and other MACEs as outcome variables. Because both interaction terms (DT × E/A and DT/pE × E/A) were significant predictors of outcomes, subsequent analyses were stratified by clinically relevant categories of mitral E/A ratio (≤0.75, 0.75–1.5, and ≥1.5). Cox proportional-hazards models, stratified by mitral E/A ratio, were used to evaluate the unadjusted and adjusted relationships of DT and DT/pE with time to HF hospitalization and other MACEs. To further explore mitral E/A ratio as a predictor, Cox proportional-hazards models were constructed to evaluate the unadjusted and adjusted relationships between mitral E/A ratio as a categorical variable (≤0.75, 0.75–1.5, and ≥1.5) and HF hospitalizations and other MACEs. C-statistics, representing the area under the curve obtained using receiver operating characteristic curve analysis, were used to compare the performance characteristics of various echocardiographic parameters in predicting HF hospitalization and other MACEs. All analyses were performed using SPSS version 12.0 (SPSS, Inc., Chicago, IL).

## Results

## Patient Characteristics of the Study Population

The study population was middle-aged to elderly (mean age, 66 ± 11 years) and predominantly male (81%) and white (59%). There was a high prevalence of hypertension (70%) and moderate prevalence of diabetes (26%) and of current smoking (20%); 17% of the study population had histories of HF hospitalization, and 54% had a histories of MI. Moreover, 35% had undergone prior coronary bypass and 39% had undergone percutaneous coronary intervention. No or trace mitral regurgitation (MR) was present in 757 participants (82%), mild MR in 162 participants (17%), and moderate MR in seven participants (1%); no patient had severe MR.

## Patient and Echocardiographic Characteristics by Mitral Inflow Categories

Most participants (65%) had normal mitral inflow patterns (0.75 < E/A < 1.5), while a substantial proportion had impaired relaxation (E/A ≤ 0.75; 23%) or restrictive inflow (E/A ≥ 1.5; 12%) ( Table 1 ). Participants with impaired relaxation were older and more likely to have histories of MI and to take β-blockers compared with those with normal inflow. More participants with restrictive inflow had histories of coronary revascularization (both coronary bypass and angioplasty) and were taking renin-angiotensin inhibitors compared with those with normal inflow.

Variable | E/A ≤ 0.75 ( n = 215) |
0.75 < E/A < 1.5 ( n = 604) |
E/A ≥ 1.5 ( n = 107) |
P ^{∗ } |
---|---|---|---|---|

Age (y) | 72 ± 9 ^{† } |
65 ± 10 | 63 ± 12 | <.001 |

Men | 170 (79%) | 496 (82%) | 86 (80%) | .60 |

Body mass index (kg/m ^{2 }) |
28 ± 5 | 28 ± 5 | 28 ± 6 | .40 |

White | 128 (60%) | 361 (60%) | 59 (56%) | .42 |

Hypertension | 146 (68%) | 432 (72%) | 73 (69%) | .52 |

Diabetes | 51 (24%) | 161 (27%) | 28 (26%) | .69 |

MI | 128 (60%) ^{‡ } |
309 (52%) | 61 (58%) | .08 |

HF | 41 (19%) | 88 (15%) | 27 (26%) ^{‡ } |
.02 |

Coronary bypass | 71 (33%) | 206 (34%) | 50 (47%) ^{‡ } |
.02 |

Coronary angioplasty | 75 (35%) | 239 (40%) | 48 (45%) | .18 |

Current smoking | 37 (17%) | 131 (22%) | 18 (17%) | .25 |

Low-density lipoprotein (mg/dL) | 107 ± 35 | 104 ± 32 | 101 ± 28 | .20 |

High-density lipoprotein (mg/dL) | 46 ± 14 | 45 ± 14 | 46 ± 16 | .41 |

Log C-reactive protein (mg/dL) | 0.36 ± 0.58 | 0.27 ± 0.57 | 0.30 ± 0.60 | .12 |

Serum creatinine (mg/dL) | 1.23 ± 0.83 ^{‡ } |
1.10 ± 0.61 | 1.21 ± 0.65 | .04 |

LV ejection fraction (%) | 60 ± 11 ^{‡ } |
63 ± 9 | 60 ± 11 ^{‡ } |
<.001 |

LV mass index (kg/m ^{2 }) |
104 ± 30 ^{‡ } |
97 ± 36 | 102 ± 30 | .02 |

LA volume index (mL/m ^{2 }) |
30 ± 9 ^{‡ } |
32 ± 10 | 38 ± 14 ^{† } |
<.001 |

E-wave velocity (cm/sec) | 63 ± 17 ^{† } |
78 ± 20 | 91 ± 22 ^{† } |
<.001 |

A-wave velocity (cm/sec) | 99 ± 23 ^{† } |
76 ± 22 | 49 ± 13 ^{† } |
<.001 |

Mitral DT (msec) | 276 ± 73 ^{† } |
238 ± 56 | 207 ± 52 ^{† } |
<.001 |

Mitral DT/pE (msec/[cm/sec]) | 4.85 ± 2.32 ^{† } |
3.30 ± 1.38 | 2.47 ± 1.08 ^{† } |
<.001 |

Aspirin use | 177 (82%) | 482 (80%) | 78 (73%) | .14 |

β-blocker use | 94 (44%) ^{† } |
381 (63%) | 66 (62%) | <.001 |

Renin-angiotensin inhibitor use | 109 (51%) | 295 (49%) | 64 (60%) ^{‡ } |
.11 |

Statin use | 140 (65%) | 396 (66%) | 64 (60%) | .52 |