Study Population
We prospectively enrolled 198 patients who were referred to the Nuclear Cardiology Center at the Sheba Medical Center, Tel Hashomer, Israel, for a clinically-indicated exercise stress MPI study. Exclusion criteria included patients with: unstable angina, decompensated heart failure, systolic blood pressure > 200 mmHg or diastolic blood pressure > 110 mmHg, uncontrolled arrhythmias, severe aortic stenosis, acute pulmonary embolism, acute myocarditis or pericarditis, acute aortic dissection, intra- and extra-cardiac shunts, hemodialysis and those aged < 18 or > 80 years of age. The study was approved by the hospital’s Institutional Review Board and all patients provided informed consent.
Exercise Stress Protocol And Image Acquisition Sequence
Beta blockers and calcium-channel antagonists were terminated at least 24 hours before testing, and nitrates at least 6 hours before testing. During the pre-imaging stress-lab evaluation and procedures, standard 12 leads for ECG monitoring and leads for image gating were applied, and a venous catheter was inserted into an antecubital vein. The imaging room was equipped with an ECG monitor, emergency cart and oxygen source.
A "stress-first-rest-second" protocol was used, as previously described [12–21]. Briefly, after obtaining baseline heart rate, blood pressure, and a 12 lead ECG, a symptom-limited treadmill-exercise (Bruce protocol) was performed. At peak exercise, an IV bolus of 6–11 mCi 99mTc-sestamibi, according to a body mass index-related dose schedule, was injected. The first imaging was started at least 20 minutes after the IV tracer injection. The patient was placed in the supine position of the cadmium-zinc-telluride-SPECT camera (Discovery NM 530c, General Electric Healthcare, Israel). The detector was positioned to include the entire heart image, as well as to isolate the heart from extra-cardiac activity. Acquisitions utilized a 20% energy window centered around the 140 KeV peak of 99mTc-sestamibi, and a16-bin ECG-gating was performed using a 50% acceptance window. Subsequently, the patient was placed in a prone position and imaging was repeated. After at least 1.5 hours, the patient returned to the lab for rest injection and acquisition using 16–31 mCi of 99mTc-sestamibi, according to a body mass index-related dose schedule. Images were reoriented into short-axis and vertical and horizontal long-axis slices using standard software (QPS/QGS, Cedars-Sinai Medical Center, Los Angeles, CA, USA). All image contours were reviewed by experienced technologists and nuclear cardiologists on a case-by-case basis and were individually adjusted if necessary [12–21].
Automated Quantification Of Perfusion
The QPS software computed the total perfusion deficit score by integrating the hypo-perfusion severities below normal limits in polar map coordinates [14]. Normal limit thresholds were defined as 3.0 mean absolute deviations (approximately equivalent to 2.5 standard deviations) for each polar map sample. Ischemic total perfusion deficit was calculated as an absolute difference between stress and rest total perfusion deficit [15, 16, 18], and was expressed as a percentage.
The Non-invasive Cardiac System
The NICaS calculates the stroke volume by measuring impedance cardiography in a tetra-polar mode, derived from electrodes placed on one wrist and the contra-lateral ankle [7, 8]. During transmission of an electrical current through the body, resistivity to its conduction (bio-impedance) is measured.The resistivity of blood and plasma is the lowest in the body, 150 and 63ohm/cm, respectively, while resistivity of cardiac muscle, lungs and fat is 750, 1275 and 2,500 ohm/cm, respectively.Thus, when an alternating current of 32.5 kHz, 1.4 mA is delivered through the two electrodes, it is primarily distributed via the extracellular fluid and the blood, and the changes in body resistivity are therefore related to the dynamic changes of the blood and plasma volume. Therefore, the measured bio-impedance and its fluctuations over time are proportional to the stroke volume. Consequently, each systolic increase in the aortic blood volume is associated with a proportional increase in the measurable conductance of the whole body. In addition, a standard three-lead ECG connection is made for measuring the pulse rate. Patient age, gender, weight, height, hematocrit and electrolytes are entered into the NICaS when the monitoring is started and are used for the stroke volume calculation. Cardiac output is calculated by multiplying stroke volume by the heart rate.
Measurements are adjusted to the body surface area to yield stroke index (SI) and cardiac index (CI). Mean arterial pressure (MAP), calculated from standard blood pressure measurements, together with SI and CI allows the calculation of stroke work index (SWI = MAP*SI/7500.8 J/m2), cardiac power index (CPI = MAP*CI/451 W/m2) and total peripheral index (TPRI = MAP/CI*80 Dyn*Sec/cm5*m2).
This simple to operate, non-invasive technique has been validated in several studies as a reliable estimation of resting CO, compared with traditional, invasive techniques in different settings including healthy subjects, patients with heart failure and ischemia [7–11]. Evaluation of impedance was performed both before and immediately after exercise. The differences between rest and stress hemodynamic parameters were compared with the severity and extent of myocardial ischemia by MPI.
Statistics
Statistical analyses were performed using SPSS software (version 2b, IBM Corporation). All baseline variables are described as mean ± SD. Rest, stress and changes of hemodynamic parameters are described as mean and 95% confidence interval. A one-way ANOVA was used to compare differences for continuous variables. A chi-square test was used to compare differences across subgroups for categorical variables. A 2-tailed p < 0.05 as a cut-off was considered statistically significant. Receiver operator characteristic (ROC) curve was used to calculate sensitivity and specificity.