The Heart and Soul Study is a prospective cohort study investigating the influence of psychosocial factors on cardiovascular events in outpatients with stable coronary artery disease. The enrollment process for the Heart and Soul Study has been previously described.4
Eligible participants had ≥1 of the following: (1) history of myocardial infarction, (2) angiographic evidence of ≥50% diameter stenosis in ≥1 coronary artery, (3) evidence of exercise-induced ischemia by treadmill electrocardiogram or stress nuclear perfusion imaging, or (4) history of coronary revascularization. Subjects were excluded if they deemed themselves unable to walk 1 block or if they were planning to move out of the local area within 3 years.
The study protocol was approved by the following institutional review boards: the University of California San Francisco committee on human research, the research and development committee at the San Francisco Veterans Affairs Medical Center, the medical human subjects committee at 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. All participants provided written informed consent.
Between September 2000 and December 2002, a total of 1,024 participants enrolled in the study. Of these, we were unable to determine the TRV/VTIRVOT in 223 participants due to absence of an adequate tricuspid regurgitation envelope and/or suboptimal alignment with the RVOT Doppler signal. Six participants were lost to follow-up, leaving a total of 795 for outcome analysis.
A complete 2-dimensional echocardiogram at rest using an Acuson Sequoia ultrasound system (Siemens Medical Solutions, Mountain View, California) with a 3.5-MHz transducer and Doppler ultrasound examination was performed in all patients. Standard 2-dimensional parasternal short-axis and apical 2- and 4-chamber views during inspiration were obtained. The peak TRV for the present study was the highest measurement obtainable by Doppler imaging among the parasternal, apical, and subcostal views. Pulmonary artery systolic pressure was estimated using the modified Bernoulli equation (ΔP = 4v2
). Right atrial pressure was estimated by ultrasonic inspection of the inferior vena cava as previously described5
and was added to the tricuspid regurgitation gradient to determine pulmonary artery systolic pressure. VTIRVOT
was obtained by placing a pulse-wave Doppler sample volume in the proximal RVOT at the level of the pulmonic valve, in the parasternal short-axis view, and tracing the outer boundaries of the spectral Doppler signal to obtain VTIRVOT
. The sample volume was placed such that the closing but not the opening click of the pulmonic valve was visualized, and the opening valve Doppler signal was equal to or greater than the closing signal. This measurement was repeated up to 3 times if possible and the average value was recorded. TRV/VTIRVOT
was then calculated (). End-diastolic pulmonary regurgitation gradient was determined as previously described.6
Left ventricular ejection fraction was calculated as (end-diastolic volume − end-systolic volume)/end-diastolic volume. Diastolic dysfunction was defined as the presence of ≥1 of the following: impaired relaxation, defined as a ratio of peak mitral early diastolic to atrial contraction velocity (E/A) of ≤0.75 with systolic dominant pulmonary vein flow; pseudonormal, defined as 0.75 < E/A <1.5 with diastolic dominant pulmonary vein flow; restrictive filling, defined as an E/A ≥1.5 with diastolic dominant pulmonary vein flow. A single technician made all sonographic measurements, and a single experienced cardiologist reader, who was blinded to clinical and laboratory data, evaluated each echocardiogram.
Figure 1 Noninvasive estimation of PVR by TRV/VTIRVOT (TRV 2.4 m/s, VTIRVOT 0.21 m, TRV/VTIRVOT 2.4 m/s ÷ 0.21 m = 11 s−1). CW = continuous wave doppler; HR = heart rate; Min Grad = minimum gradient; Pk Grad = peak gradient; PV Vmax = maximum velocity. (more ...)
Baseline demographics, self-reported age, gender, ethnicity, medical history, and smoking status were determined by questionnaire. Participants were weighed and measured without shoes, and body mass index was calculated. All participants were instructed to bring their medication bottles to the study appointment where study personnel recorded all current medications.
We conducted annual telephone interviews with participants or their proxies regarding recent emergency room visits, hospitalizations, or death. Medical records, death certificates, and coroner reports were reviewed by 2 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. All-cause mortality was determined by review of death certificates. Death was considered due to cardiovascular causes if the death certificate listed acute myocardial infarction, congestive heart failure, or arrhythmia as the primary cause of death. Sudden death, defined as death occurring unexpectedly within 1 hour of the onset of symptoms, was also considered cardiovascular. Hospitalization for heart failure was defined as a minimum 1-night hospital stay for a clinical syndrome comprising ≥2 of the following: paroxysmal nocturnal dyspnea, orthopnea, increased jugular venous pressure, pulmonary rales, third heart sound, and cardiomegaly or pulmonary edema on chest x-ray. These clinical signs and symptoms must have represented a clear change from the baseline clinical status of the participant and must have been accompanied by failing cardiac output as determined by peripheral hypoperfusion (in the absence of other causes such as sepsis or dehydration) or peripheral or pulmonary edema requiring intravenous diuretics, inotropes, or vasodilators. Cardiovascular events were defined as the composite of cardiovascular death, nonfatal myocardial infarction, or stroke. Nonfatal myocardial infarction was defined as hospitalization for acute myocardial infarction as defined by American Heart Association diagnostic criteria.
We included 795 participants with completed outcome adjudications in the analyses. Because age-, gender-, and race-specific normal ranges for TRV/VTIRVOT have not been established, we categorized TRV/VTIRVOT into quartile groups. Differences in baseline characteristics were compared with the use of analysis of variance for continuous variables and chi-square test for dichotomous variables. We used multivariate logistic regression analysis to calculate hazard ratios (HRs) for quartiles of TRV/VTIRVOT as the primary predictor variable. We report HRs with 95% confidence intervals. Predefined end points were all-cause mortality, cardiovascular death, heart failure hospitalization, and the combined end point (composite of cardiovascular death, nonfatal myocardial infarction, and stroke). To determine the independent association between TRV/VTIRVOT and outcomes, we adjusted for known clinical risk factors (age, gender, smoking status, hypertension, diabetes, body mass index, history of myocardial infarction, history of congestive heart failure, history of chronic obstructive pulmonary disease) and echocardiographic risk factors (left ventricular ejection fraction, pulmonary artery systolic pressure, and end-diastolic pulmonary regurgitation gradient). Statistical analysis was performed using SAS 9.1 (SAS Institute, Cary, North Carolina).