Impact on cardiovascular outcome of coronary revascularization-induced changes in ischemic perfusion defect and myocardial flow reserve

This retrospective study included 120 consecutive patients with suspected or known CAD who underwent stress-rest ⁸²Rb PET/CT at baseline (MPI-1) and at follow-up (MPI-2), after clinically driven coronary revascularization (percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG)). The clinical indication for revascularization was performed by referring physician based on angina symptoms, evaluation of stress-induced ischemia, viability testing when available, and invasive coronary angiography. Patients were referred for MPI after revascularization if they were symptomatic. Asymptomatic patients were referred due to incomplete or suboptimal revascularization or as part of risk stratification [12]. The mean interval time between revascularization and MPI-2 was 15 ± 9 months. No cardiac events occurred between coronary revascularization and MPI-2. From the initial cohort of 120 patients, those with previous CABG, left ventricular ejection fraction < 40%, or clinical diagnosis of heart failure before MPI-1 were excluded, leaving a final cohort of 102 patients. As part of the baseline examination, clinical teams collected information on traditional cardiovascular risk factors (including age, sex, body mass index, diabetes, dyslipidemia, smoking, hypertension, and family history of CAD). Patients were classified as having diabetes if they were receiving treatment with oral hypoglycemic drugs or insulin. Hypertension was defined as a blood pressure ≥ 140/90 mm Hg or the use of anti-hypertensive medication [13]. Hypercholesterolemia was defined as total cholesterol level ≥ 6.2 mmol/L or treatment with cholesterol lowering medication. A positive family history of CAD was defined by the presence of disease in first-degree relatives younger than 55 years in men or 65 years in women. Angina symptoms were defined in the presence of typical angina, atypical angina, or non-anginal chest pain [3]. The review committee of our institution approved the study, and all patients gave informed consent (Ethics Committee, University Federico II, protocol number 110/17).

As a routine preparation for ⁸²Rb cardiac PET/CT, patients were asked to discontinue taking nitrates for 6 h, calcium channel blockers and caffeine-containing beverages for 24 h, and beta-blockers for 48 h before their appointment. Scans were acquired using a Biograph mCT 64-slice scanner (Siemens Healthcare). For both rest and stress images, 1110 MBq of ⁸²Rb was injected intravenously, and a 6-min list-mode PET study was acquired. Pharmacologic stress was then administered using adenosine (140 μg × kg⁻¹ × min⁻¹ for 4.5 min). Both rest and stress dynamic images were reconstructed into 26 time frames (12 × 5 s, 6 × 10 s, 4 × 20 s, and 4 × 40 s; total, 6 min) using the vendor standard ordered subset expectation maximization 3D reconstruction (2 iterations, 24 subsets) with 6.5-mm Gaussian post-processing filter. The images were corrected for attenuation using the low-dose CT. Hemodynamic parameters and 12-lead ECG were recorded at baseline and throughout the infusion of adenosine. Trans-axial PET perfusion images were automatically reoriented into short-axis and vertical and horizontal long-axis slices. Regional myocardial perfusion was visually assessed, using standardized segmentation of 17 myocardial regions [14]. Total perfusion defect (TPD) reflecting a combination of both severity and extent of myocardial defect was calculated using automated software (Cedars-Sinai Medical Center, Los Angeles, CA) [15]. The ischemic TPD (ITPD) was defined as stress TPD − rest TPD and expressed as % of left ventricle. A change of ≥ 5% was used as the criterion for a significant serial change in ITPD in an individual patient [16]. The variations in perfusion pattern between MPI-1 and MPI-2 were categorized as improvement when there was a decrease in ITPD value ≥ 5%; no change; and worsening with an increase of ≥ 5% in ITPD.

Absolute MBF (in ml/min/g) was computed from the dynamic rest and stress imaging series with commercially available software (FlowQuant, University of Ottawa Heart Institute) [17]. MFR was defined as the ratio of hyperemic to baseline MBF and was considered reduced when < 2 [18]. Variations in quantitative pattern were categorized as improvement with recovery of MFR form reduced values to normal values after revascularization; no change; and worsening with change in MFR from normal values to reduced values after revascularization.

Patient follow-up was prospectively obtained by the use of a questionnaire that was assessed by a phone call to all patients and general practitioners or cardiologists and by review of hospital or physicians’ records by individuals blinded to the patient’s test results. For the purpose of the present investigation, we performed a landmark analysis starting follow-up from MPI-2 [19]. The outcome was a composite endpoint of cardiovascular events including cardiac death, nonfatal myocardial infarction, repeated revascularization, and heart failure, whichever came first. The cause of death was confirmed by review of death certificate, hospital chart, or physician’s records. Death was considered of cardiac origin if the primary cause was defined as acute myocardial infarction, congestive heart failure, valvular heart disease, sudden cardiac death, or cardiac interventional/ surgical procedure related. Myocardial infarction was defined when > 2 of the following 3 criteria were met: chest pain or equivalent symptom complex, positive cardiac biomarkers, or typical electrocardiographic changes [20]. The date of the last examination or consultation was used to determine the length of follow-up.

Continuous data are expressed as mean ± standard deviation and categorical data as percentage. A student two-sample t-test and chi-square test were used to compare the differences in continuous and categorical variables, respectively. A P < 0.05 (two-sided) was considered statistically significant. Annualized event rates (AER), expressed as % person-years, were calculated as the cumulative number of events divided by person-time. This latter is an estimate of the actual time at risk that all persons contribute to the study, i.e., the sum of each individual follow-up period. Hazard ratios with 95% confidence intervals (CI) were calculated by univariable Cox regression analysis. The incremental prognostic value of clinical data and imaging findings considering variables in hierarchical order was assessed by the likelihood ratio χ². Event-free survival curves were obtained by the Kaplan–Meier method and compared with the log-rank test. Statistical analysis was performed with Stata 12 software (StataCorp, College Station, TX, USA).

At Cox univariable analysis both ITPD and MFR worsening resulted as predictors of events (Table 4). The AER of patients with or without ITPD and MFR worsening is reported in Fig. 2. As showed, patients with ITPD worsening showed a better outcome in the presence of improved or no change MFR compared to patients with both ITPD and MFR worsening (P < 0.001). Patients with improvement or no change of ITPD showed a worst outcome in the presence of MFR worsening (P < 0.05). The worst outcome was observed in patients with ITPD and MFR worsening (log-rank 32.9, P for trend < 0.001) (Fig. 3). At incremental analysis (Fig. 4), the addition of ITPD worsening to a model including only clinical data increased the global χ² from 4.26 to 24.92 (P < 0.001). The addition of MFR worsening to a model including clinical data and ITPD further increased the χ² to 35.06 (P < 0.05).