Heart failure (HF) is a common public health problem, and many new cases are now recognized to occur in patients with preserved left ventricular ejection fraction. β Blockers improve the outcomes of patients with known left ventricular systolic dysfunction, but whether β blockers provide similar protection among patients with left ventricular diastolic dysfunction is unclear. We studied the association between use of β blockers and subsequent hospitalization for HF in patients with diastolic dysfunction and stable coronary heart disease. We evaluated medication use and performed echocardiography at baseline in a prospective cohort of 911 outpatients with known coronary heart disease from the Heart and Soul Study. Hospitalizations for HF were assessed by blinded review of the medical records during an average follow-up of 5.2 years. Of the 911 participants, 118 (13%) had diastolic dysfunction, of whom 2 were lost to follow-up. Of the 116 remaining patients, 19 (25%) of the 77 using β blockers were hospitalized for HF compared to 16 (41%) of the 39 not using β blockers (age-adjusted hazard ratio 0.51, 95% confidence interval 0.26 to 1.00; p = 0.05). This association remained after additional adjustment for gender, smoking, history of myocardial infarction, diabetes, and creatinine (hazard ratio 0.46, 95% confidence interval 0.23 to 0.93; p = 0.03). The results were similar after excluding 31 participants with a history of self-reported HF (hazard ratio 0.33, 95% confidence interval 0.13 to 0.86; p = 0.02) and 24 participants with concurrent systolic dysfunction (hazard ratio 0.36, 95% confidence interval 0.14 to 0.89; p = 0.03). In conclusion, the use of β blockers is associated with a decreased risk of hospitalization for HF in patients with diastolic dysfunction and stable coronary heart disease.
Heart failure (HF) is a common and significant public health problem. Diastolic HF, or HF with preserved left ventricular (LV) ejection fraction (EF), has become a well-recognized subset of HF. β Blockers are a commonly prescribed class of medications that are known to improve the outcomes of patients with LV systolic dysfunction. However, questions have been raised regarding the relative benefits of β blockers in patients with hypertension, and β blockers remain of uncertain benefit in patients with LV diastolic dysfunction. Furthermore, a paucity of data is available regarding how β blockade affects the long-term outcomes of this patient population. The Heart and Soul study represents a large cohort of patients with stable coronary heart disease (CHD) who are commonly prescribed β blockers. We studied the association between the use of β blockers and subsequent hospitalization for HF in patients with diastolic dysfunction and stable CHD.
Methods
The Heart and Soul Study is a prospective cohort study designed to determine how psychological factors influence cardiovascular outcomes in patients with CHD. The enrollment process and methods have been previously described. Administrative databases were used to identify and enroll outpatients with documented coronary disease from 2 Department of Veterans Affairs Medical Centers (San Francisco and Palo Alto, California), 1 university-based medical center (University of California, San Francisco, California), and 9 public health clinics in the Community Health Network of San Francisco, California. The criteria for enrollment were (1) a history of myocardial infarction, (2) angiographic evidence of ≥50% stenosis by area in at least one coronary vessel, (3) evidence of exercise-induced ischemia by treadmill electrocardiogram or stress nuclear perfusion imaging, (4) a history of coronary revascularization, or (5) a previous diagnosis of coronary disease by an internist or cardiologist. Participants were excluded if they had experienced myocardial infarction in the previous 6 months, deemed themselves unable to walk one block, or were planning to move out of the local area within 3 years. The study protocol was approved by the institutional review board at each participating site, and all patients provided written informed consent.
Two-dimensional echocardiography was performed on all patients using an Acuson Sequoia ultrasound system with harmonic imaging and a 3.5-MHz transducer (Siemens Medical Solutions, Mountain View, California). Standard 2-dimensional parasternal short-axis and apical 2- and 4-chamber views during quiet respiration or held expiration were obtained. Two highly experienced sonographers made all sonographic measurements, and a single cardiologist reader (N.B.S.), who was unaware of the clinical and laboratory information, evaluated, confirmed, and, when needed, corrected each measurement. The LV end-systolic and end-diastolic volumes were obtained by planimetry using the biplane method of disks, as previously described. The LVEF was calculated as follows: (end-diastolic volume − end-systolic volume) / end-diastolic volume. Using the standard apical 4-chamber view, spectral Doppler signals of mitral inflow and pulmonary vein flow were obtained according to the guidelines of the American Society of Echocardiography. Patterns of LV diastolic dysfunction were determined by mitral inflow E/A ratios of peak velocities at early rapid filling (E) and late filling due to atrial contraction (A) and systolic or LV diastolic dominant pulmonary venous flow using the velocity time integral. According to previously published criteria, a normal LV diastolic pattern was defined as an E/A ratio of 0.75 to 1.5 and systolic dominant pulmonary venous flow. An impaired relaxation pattern (mild LV diastolic dysfunction) was defined as an E/A ratio of ≤0.75 and systolic dominant pulmonary venous flow. A pseudonormal pattern (moderate LV diastolic dysfunction) was defined as an E/A ratio of 0.75 to 1.5, with diastolic dominant pulmonary venous flow. A restrictive filling pattern (severe LV diastolic dysfunction) was defined as an E/A of ≥1.5 and diastolic dominant pulmonary venous flow.
Our group has previously shown that no statistically significant difference is present between patients with normal LV diastolic pattern and impaired relaxation pattern with regard to all-cause mortality, heart disease death, hospitalization for HF, and hospitalization for myocardial infarction in our cohort. Thus, these 2 groups were combined to form the comparison group considered to have no clinically significant diastolic dysfunction. Less than 5% of the study population had restrictive filling; thus, the groups with either a pseudonormal or a restrictive filling pattern were combined to form the study group considered to have diastolic dysfunction. Of the 1,024 participants enrolled, diastolic function could only be determined in 911 because of a nonsinus rhythm, LV pacing, heart rate >100 beats/min, severe mitral disease, or technical reasons.
The outcomes evaluated included all-cause mortality and incident hospitalization for HF. A combined outcome of death and hospitalization for HF was included for analysis. We conducted annual follow-up using telephone interviews to question participants or their proxies regarding any emergency room visits or hospitalizations. The medical records, death certificates, and coroner’s reports were retrieved. Participants were censored at the point of HF admission, if lost to follow-up, or death. Two blinded adjudicators reviewed each event and, if agreement was present, the outcome classification was binding. If disagreement occurred, a third, blinded adjudicator reviewed the event and determined the outcome classification.
All-cause mortality was determined by reviewing death certificates. Hospitalization for HF was defined as a clinical syndrome with a minimum 1-night hospital stay and involving at least 2 of the following: paroxysmal nocturnal dyspnea, orthopnea, elevated jugular venous pressure, pulmonary rales, a third heart sound, cardiomegaly on chest radiography, or pulmonary edema on chest radiography. These clinical signs and symptoms must have represented a clear change from the normal clinical state of the patient and must have been accompanied by either failing cardiac output, as determined by peripheral hypoperfusion (in the absence of other causes such as sepsis or dehydration), or peripheral or pulmonary edema treated with intravenous diuretics, inotropes, or vasodilators. Supportive documentation of a decreased cardiac index, an increased pulmonary capillary wedge pressure, decreasing oxygen saturation, and end organ hypoperfusion, if available, were included in the adjudication.
Each participant completed a detailed questionnaire that included age, gender, race, medical history, level of physical activity, current smoking, and level of alcohol consumption. We measured depressive symptoms in participants using the 9-item Patient Health Questionnaire. Weekly angina was assessed using the Seattle Angina Questionnaire. Study personnel recorded all current medications and measured participants’ height, weight, and blood pressure. Medication use was recorded by having the subjects bring their medication bottles to the baseline interview. The medications were categorized according to Epocrates Rx (San Mateo, CA). Glucose, serum creatinine, log C-reactive protein, total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were measured from fasting serum samples. A symptom-limited graded exercise treadmill test was also performed.
Differences in participant characteristics stratified by β-blocker use were determined using analysis of variance for continuous variables and chi-square tests for dichotomous variables. We used Cox proportional hazard models to evaluate the independent association of β-blocker use with cardiovascular outcomes in patients with and without diastolic dysfunction. To determine the independent effects of β-blocker use on cardiac outcomes, we adjusted these models for the following covariates selected, a priori, on the basis of inspection of directed acyclic graphs : age, gender, smoking, history of myocardial infarction, diabetes, serum creatinine. Given the strong association of self-reported history of HF and LV systolic dysfunction (EF <45%) with both β-blocker use and HF hospitalization, we further adjusted for these variables. For these analyses, we report the hazard ratios (HRs) with the 95% confidence intervals (CIs). The analyses were performed using Statistical Analysis Systems, version 9 (SAS Institute, Cary, North Carolina).
Results
From September 2000 to December 2002, 1,024 participants were enrolled. Of the 909 remaining after diastolic function was measured and excluding the 2 participants lost to follow-up, 534 (59%) were taking β blockers and 375 (41%) were not. The baseline demographics and patient characteristics are reported in Table 1 .
| Characteristic | β-Blocker Use (n = 534) | No β-Blocker Use (n = 375) | p Value |
|---|---|---|---|
| Age (years) | 67 ± 11 | 67 ± 11 | 0.77 |
| Men | 449 (84%) | 297 (79%) | 0.05 |
| Race or ethnic group | 0.55 | ||
| White | 317 (59%) | 227 (61%) | |
| Black | 84 (16%) | 65 (17%) | |
| Hispanic | 46 (9%) | 34 (9%) | |
| Asian | 66 (12%) | 41 (11%) | |
| Other | 21 (4%) | 8 (2%) | |
| Body mass index (kg/m 2 ) | 29 ± 5 | 28 ± 5 | 0.12 |
| Current smoking | 95 (18%) | 85 (23%) | 0.08 |
| Regular alcohol consumption | 136 (26%) | 127 (34%) | 0.006 |
| Diabetes | 156 (29%) | 83 (22%) | 0.02 |
| Myocardial infarction | 316 (60%) | 173 (46%) | <0.0001 |
| Heart failure | 106 (20%) | 44 (12%) | 0.001 |
| Depression (Patient Health Questionnaire score ≥10) | 106 (20%) | 67 (18%) | 0.45 |
| Stroke | 74 (14%) | 58 (16%) | 0.49 |
| Weekly angina | 109 (20%) | 60 (16%) | 0.10 |
| Systolic blood pressure (mm Hg) | 134 ± 23 | 131 ± 19 | 0.04 |
| Diastolic blood pressure (mm Hg) | 75 ± 11 | 74 ± 11 | 0.86 |
| Heart rate (beats/minute) | 64 ± 11 | 73 ± 12 | <0.0001 |
| Left ventricular ejection fraction | 62% ± 9% | 62% ± 10% | 0.44 |
| Fasting plasma glucose (mg/dl) | 121 ± 43 | 118 ± 45 | 0.28 |
| Serum creatinine (mg/dl) | 1.2 ± 0.7 | 1.1 ± 0.5 | 0.01 |
| Log C-reactive protein | 0.66 ± 1.29 | 0.73 ± 1.33 | 0.47 |
| Total cholesterol (mg/dl) | 173 ± 38 | 186 ± 47 | <0.0001 |
| Triglycerides (mg/dl) | 150 ± 130 | 131 ± 116 | 0.02 |
| High-density lipoprotien cholesterol (mg/dl) | 44 ± 13 | 49 ± 14 | <0.0001 |
| Low-density lipoprotien cholesterol (mg/dl) | 100 ± 31 | 111 ± 38 | <0.0001 |
The outcomes stratified by β-blocker use and the presence or absence of LV diastolic dysfunction are reported in Table 2 . The mean follow-up was 5.2 years. Of the 909 study participants, 116 (13%) had echocardiographic evidence of diastolic dysfunction (pseudonormal or restrictive filling pattern) at baseline. Of these patients, 77 (66%) were taking β blockers and 39 (34%) were not. Of the 116 patients with diastolic dysfunction, 19 (25%) of the 77 using β blockers were hospitalized for HF compared to 16 (41%) of the 39 not using β blockers (p = 0.07). Likewise, trends were seen in favor of β-blocker use in patients with diastolic dysfunction for all-cause mortality (31% [24 of 77] vs 44% [17 of 39]; p = 0.19) and the combined outcome of HF hospitalization or death (40% [31 of 77] vs 54% [21 of 39]; p = 0.16). No appreciable differences were seen in the outcomes for the patients without diastolic dysfunction.
| Outcome | No Diastolic Dysfunction | Diastolic Dysfunction | ||||
|---|---|---|---|---|---|---|
| β-Blocker Use (n = 457) | No β-Blocker Use (n = 336) | p Value | β-Blocker Use (n = 77) | No β-Blocker Use (n = 39) | p Value | |
| Heart failure hospitalization | ||||||
| Patients | 48 (11%) | 26 (8%) | 0.20 | 19 (25%) | 16 (41%) | 0.07 |
| Age-adjusted hazard ratio (95% CI) | 1.36 (0.84–2.19) | 0.21 | 0.51 (0.26–1.00) | 0.05 | ||
| Multivariate-adjusted hazard ratio (95% CI) | 1.07 (0.66–1.75) | 0.78 | 0.46 (0.23–0.93) | 0.03 | ||
| All-cause mortality | ||||||
| Patients | 103 (23%) | 67 (20%) | 0.19 | 24 (31%) | 17 (44%) | 0.19 |
| Age-adjusted hazard ratio (95% CI) | 1.05 (0.77–1.43) | 0.74 | 0.68 (0.36–1.28) | 0.23 | ||
| Multivariate-adjusted hazard ratio (95% CI) | 0.93 (0.67–1.28) | 0.64 | 0.63 (0.33–1.23) | 0.18 | ||
| Heart failure hospitalization or death | ||||||
| Patients | 122 (27%) | 74 (22%) | 0.16 | 31 (40%) | 21 (54%) | 0.16 |
| Age-adjusted hazard ratio (95% CI) | 1.19 (0.89–1.58) | 0.25 | 0.59 (0.34–1.03) | 0.06 | ||
| Multivariate-adjusted hazard ratio (95% CI) | 1.03 (0.76–1.39) | 0.85 | 0.48 (0.27–0.88) | 0.02 | ||
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