Usefulness of Stress Myocardial Perfusion Imaging and Baseline Clinical Factors to Predict Cardiovascular Events in Patients with Peripheral Artery Disease

Research Article

J Cardiovasc Disord. 2015;2(1): 1011.

Usefulness of Stress Myocardial Perfusion Imaging and Baseline Clinical Factors to Predict Cardiovascular Events in Patients with Peripheral Artery Disease

Furuhashi T, Moroi M*, Minakawa M, Masai H, Kunimasa T, Fukuda H and Sugi K

Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, Japan

*Corresponding author: Moroi M, Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, 2-17-6 Ohashi, Meguro-ku, Tokyo 153- 8515, Japan

Received: March 19, 2015; Accepted: April 27, 2015; Published: April 28, 2015


Introduction: Peripheral Artery Disease (PAD) is a well-established risk factor for poor cardiovascular prognosis. Stress Myocardial Perfusion Imaging (MPI) is a widely used diagnostic and prognostic tool for Coronary Artery Disease (CAD). Normal stress MPI generally correlates with excellent cardiovascular prognosis. We assessed the usefulness of stress MPI and baseline clinical factors as independent predictors of cardiovascular events in patients with PAD and suspected or known CAD.

Methods: Stress MPI was performed in 97 PAD patients. The mean followup period was 30 months. PAD was defined as an ankle-brachial index of <0.9 or a history of revascularisation for PAD. Advanced Chronic Kidney Disease (CKD) was defined as Stage IV to V CKD or CKD requiring haemodialysis. Cardiovascular events included cardiac death, nonfatal myocardial infarction and Braunwald class III unstable angina requiring hospitalisation.

Results: Cardiovascular events were observed in 28 patients (29%). Multivariate Cox regression analysis revealed that advanced CKD (hazard ratio = 4.03; P < 0.001); left ventricular ejection fraction (hazard ratio = 0.96; P = 0.008); and, summed stress scores on stress MPI (hazard ratio = 1.15; P = 0.013) were independent and significant predictors of cardiovascular events.

Conclusion: In PAD patients, advanced CKD, impaired left ventricular systolic function and abnormal summed stress scores on stress MPI can be significant and independent predictors of cardiovascular events. In patients who have these risk factors, aggressive management strategies (strengthened suboptimal therapies and careful observation) should be implemented as early as possible.

Keywords: Chronic Kidney Disease; Coronary Artery Disease; Myocardial Perfusion Defect; Prognosis


ABI: Ankle-Brachial Index; CAD: Coronary Artery Disease; CKD: Chronic Kidney Disease; eGFR: Estimated Glomerular Filtration Rate; LVEF: Left Ventricular Ejection Fraction; MI: Myocardial Infarction; MPI: Myocardial Perfusion Imaging; PAD: Peripheral Artery Disease; QGS: Quantitative Gated SPECT; SSS: Summed Stress Score; SRS: Summed Rest Score; SDS: Summed Difference Score; SPECT: Single-Photon Emission Computed Tomography


PAD is well established as a risk factor for cardiovascular disease, and previous angiographic studies have shown that 33–55% of patients with asymptomatic PAD have significant coronary stenosis [1-6]. CKD is also a major cardiovascular risk factor [7-10], and poor cardiovascular prognosis is characteristic of CKD patients treated with haemodialysis. Previous studies have established the usefulness of stress MPI to diagnose CAD and to assess cardiovascular prognosis [11-19]. Normal stress MPI results correlate with excellent cardiovascular prognosis, as evidenced by the annual cardiovascular event rate of <1% [20]. On the other hand, in CKD patients treated with haemodialysis, normal stress MPI results are not necessarily associated with good cardiovascular prognosis; of haemodialysis patients with normal stress MRI results, 4–9% per year experience cardiovascular events, with poor prognosis [21,22]. Here, we assess the usefulness of baseline clinical factors and stress MPI to predict cardiovascular events in patients with PAD and suspected or known CAD.


Patients and study protocol

This was a retrospective study of patients who had undergone stress MPI. In total, 1015 consecutive patients with a suspected or confirmed history of CAD underwent thallium-201 stress MPI between 2008 and 2010. The following patients were excluded: 154 with no prognostic data following stress MPI; 760 with no evidence of PAD; and 4 with significant ischaemia (SDS of =2 on stress MPI) who achieved revascularization within 2 months of subsequent percutaneous coronary intervention [14]. In total, 97 patients with PAD were included in the study. PAD was defined on the basis of a previous medical history of angioplasty of peripheral arteries or an ABI of <0.9 [1-3].

The study protocol was approved by the Committee on Human Investigation of the Toho University Ohashi Medical Center (approval No. 12-62), and the study was conducted in accordance with the ethical standards of the 1964 Declaration of Helsinki (as revised in Tokyo in 2004) and subsequent revisions. All included patients provided informed consent.

Information on the history of PAD was obtained from clinical records or patient interviews. In addition, data on age, sex, medication usage, past medical history and other coronary risk factors were routinely collected during stress MPI. The following were considered possible cardiovascular risk factors: cigarette smoking (current and past), history of hypertension, diabetes, hyperlipidaemia, or CKD; or a history of CAD in a first-degree relative (aged <55 years for men and <65 years for women). Hypertension was defined as systolic blood pressure >140 mmHg, diastolic blood pressure >90 mmHg or current treatment with antihypertensive medications. Diabetes was defined as fasting blood glucose >126 mg/dL, glycosylated haemoglobin >6.5% (based on the National Glycohemoglobin Standardization Program definition) or current treatment with insulin or oral anti-diabetic medications. Hyperlipidaemia was defined as the presence of hypercholesterolaemia (total cholesterol >220 mg/dL), hypertriglyceridaemia (serum triglyceride >150 mg/dL) or current lipid-lowering therapy. CKD was defined according to the National Kidney Foundation criteria [23] as an eGFR of < 60 mL/min/1.73 m² or persistent proteinuria for at least 3 months. Advanced CKD was defined as confirmed (2 consecutive measurements =3 months apart) eGFR = 30 mL/min/1.73 m² (Stage IV to V of CKD) and haemodialysis for =1 month. The LVEF was measured by motionmode echocardiography within 1 month of stress MPI.

Stress MPI

Exercise or pharmacological stress tests were performed. Cardiac medications and caffeine ingestion were stopped for 1 day before the examination. All exercise tests were performed using a treadmill; no patient underwent ergometer exercise stress testing. The treadmill exercise test (Bruce protocol) was considered adequate if patients achieved 85% of the maximum predicted heart rate or developed chest pain. Patients with limited exercise capacity (who failed to achieve 85% of the predicted heart rate during the treadmill test) underwent a pharmacological stress test using intravenous adenosine infusion. Adenosine and thallium-201 were administered in different arms. An automated infusion pump was used to deliver intravenous adenosine (0.120 mg/kg/min) over 6 min. Thallium-201 (111 MBq; Fujifilm RI Pharma Co., Ltd., Tokyo, Japan) was injected into a peripheral vein either 1 min before cessation of the treadmill stress test or 3 min after initiation of adenosine infusion.

All myocardial perfusion SPECT data were acquired using a 3-headed gamma camera (MS-3; Siemens, Chicago, IL, USA) equipped with a low-energy cardiofocal collimator and a computer interface (ICON; Siemens, Chicago, IL, USA). Stress SPECT was performed 10 after stress testing, and resting SPECT was performed 4 after MPI. In total, 90 projections were obtained for 20 s each in 4/360° intervals and stored on 64 × 64 matrices. A 15% symmetrical energy window centred on the 70 keV peak was used. Tomographic reconstruction was performed by the standard filtered back-projection technique using a Butterworth filter with a cut-off frequency of 0.5 cycles/pixel, and an order of 5. No correction was made for attenuation or scatter.

SPECT images were reoriented along the short horizontal and vertical long axes for analysis. SPECT data analysis was performed on the basis of agreement between at least two experienced nuclear medicine physicians (T.F. and M.M). Defects were classified as reversible (including partially reversible) or fixed (irreversible). SPECT images were assessed to determine the presence, location and severity of any perfusion defect. Observers assessed SPECT images visually and did not use software applications. The left ventricle was divided into 17 segments, each of which was assigned a score using a 5-point scoring system (0 = normal, 1 = mildly reduced, 2 = moderately reduced, 3 = severely reduced and 4 = uptake absent). The following scores were calculated: the Summed Score at Stress (SSS) which showed myocardial ischaemia and MI; the summed score at rest Summed Rest Score (SRS) which showed MI and prolonged myocardial ischaemia [24] and the difference between the Stress and rest Scores (SDS), which showed myocardial ischaemia. As demonstrated in previous studies, based on an excellent cardiovascular prognosis, an SSS of <4 was considered to be normal [12,25,26].

Endpoints and follow-up

Follow-up commenced after the assessment of clinical information and stress MPI. Cardiovascular events considered as endpoints were cardiac death, nonfatal MI and Braunwald class III unstable angina requiring hospitalisation. Cardiac deaths included sudden death, fatal MI and death due to heart failure or death due to arrhythmia. Sudden death was defined as witnessed cardiac arrest, death within 1 h of onset of acute symptoms or unexpected death in people who had been considered well for the previous 24 h. Braunwald class III unstable angina was defined as acute angina at rest within 48 h of onset. Patients were regularly followed up for a mean duration of 31 ± 21 months (range, 1–65 months).

Statistical analysis

Continuous variables are presented as mean ± standard deviation, and categorical variables are presented as observed number of patients (percentage). To compare patient characteristics between groups, the Mann–Whitney U test was used for continuous variables, and Fisher’s exact test was used for categorical variables. Cox regression hazard analysis was used to assess the possible risk factors. Kaplan–Meier event-free curves were generated, and the risks of endpoints were compared between patient groups using logrank tests. Statistical analyses were performed using SPSS statistical software (SPSS Incorporated, Chicago, Illinois, USA). A P value <0.05 was considered statistically significant.

Results and Discussion

Patient characteristics

Table 1 summarizes patient characteristics and compares the results of patients who developed cardiovascular events with those of patients who did not. The frequency of advanced CKD, a familial history of CAD and a history of CAD were significantly higher in patients who developed cardiovascular events. Patients who developed cardiovascular events had lower LVEFs on echocardiography. Regarding stress MPI results, SSS and SRS were significantly higher in patients who developed cardiovascular events.