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 for this study have been previously described.11
Administrative databases were used to identify and enroll outpatients with documented coronary disease from two Department of Veterans Affairs (VA) Medical Centers (San Francisco and Palo Alto, California), one university-based medical center (University of California, San Francisco), and nine public health clinics in the Community Health Network of San Francisco, California. Criteria for enrollment were: 1) history of myocardial infarction (MI), 2) angiographic evidence of at least 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) history of coronary revascularization, or 5) prior diagnosis of coronary disease by an internist or cardiologist. Participants were excluded if they had a history of MI in the prior 6 months, deemed themselves unable to walk one block, or were planning to move out of the local area within three years. The study protocol was approved by the institutional review boards 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, CA). 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 blinded to clinical and laboratory information, evaluated, confirmed and, when needed, corrected each measurement. LV end-systolic and end-diastolic volumes were obtained by planimetry using the biplane method of discs as described.12
The LVEF was calculated as (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.13
Patterns of LV diastolic dysfunction were based on 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 velocity time integral. Based on previously published criteria,14
normal LV diastolic pattern was defined as E/A ratio of 0.75 to 1.5 and systolic dominant pulmonary venous flow. Impaired relaxation pattern (mild LV diastolic dysfunction) was defined as E/A ratio ≤ 0.75 and systolic dominant pulmonary venous flow. Pseudonormal pattern (moderate LV diastolic dysfunction) was defined as E/A ratio of 0.75 to 1.5 and with diastolic dominant pulmonary venous flow. Restrictive filling pattern (severe LV diastolic dysfunction) was defined as an E/A of 1.5 or greater and with diastolic dominant pulmonary venous flow.15
Our group has previously shown that there is no statistically significant difference between patients with normal LV diastolic pattern and impaired relaxation pattern with regards to all-cause mortality, heart disease death, hospitalization for HF, and hospitalization for MI in our cohort.15
Thus these two 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 and thus groups with either a pseudonormal or restrictive filling pattern were combined to form the study group considered to have diastolic dysfunction. Of the 1024 participants enrolled, diastolic function could only be determined in 911 because of either non-sinus rhythm, LV pacing, heart rate > 100 beats/min, severe mitral disease, or technical reasons.
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 and questioning participants or their proxies regarding any emergency room visits or hospitalizations. Medical records, death certificates, and coroner's reports were retrieved. Participants were censored at point of HF admission, lost to follow-up, or death. Two blinded adjudicators reviewed each event and, if there was agreement, the outcome classification was binding. If there was disagreement, a third blinded adjudicator reviewed the event and determined the outcome classification.
All-cause mortality was determined using review of death certificates. Hospitalization for HF was defined for a clinical syndrome with a minimum one-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 decreased cardiac index, increased pulmonary capillary wedge pressure, decreasing oxygen saturation, and end-organ hypoperfusion, if available, were included in 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 (PHQ-9). Weekly angina was assessed using the Seattle Angina Questionnaire. Study personnel recorded all current medications and measured height, weight, and blood pressure. Medication use was recorded by having subjects bring medication bottles to the baseline interview and categorize the medications 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 performed, and we used stress echocardiography to identify inducible ischemia, defined as the presence of cardiac wall motion abnormality at peak exercise that was not present at rest.
Differences in participant characteristics based on beta 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 beta blocker use with cardiovascular outcomes in patients with and without diastolic dysfunction. To determine the independent effects of beta 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:16
age, sex, smoking, history of MI, diabetes, serum creatinine. Given the strong association of self-reported history of HF and LV systolic dysfunction (EF < 45%) with both beta blocker use and HF hospitalization, we further adjusted for these variables. For these analyses, we report hazard ratios (HRs) with 95% confidence intervals (CIs). Analyses were performed using Statistical Analysis Software (version 9, SAS Institute Inc., Cary, North Carolina).