Impact of completeness of revascularization by coronary intervention on exercise capacity early after acute ST-elevation myocardial infarction

The study protocol was conform to the ethical guidelines of the 1975 Declaration of Helsinki, and was approved by the Human Research Committee of the Peking University Third Hospital (Beijing, China), which waived the requirement for informed consent.

We selected our study population from a database, which contained 1600 patients admitted to the Peking University Third Hospital, China, between September 2007 and December 2011 for an acute STEMI. Inclusion criteria were: 1) acute STEMI; 2) successful primary PCI using drug-eluting stents; and 3) CPET performed within 7–30 days of STEMI onset. The clinical criteria used for STEMI diagnosis at the time of admission were: 1) chest pain persisting ≥30 minutes; 2) ST-segment elevation of at least 0.1 mV in ≥2 contiguous electrocardiographic leads; and/or 3) increased levels of cardiac biomarkers (creatine kinase-MB, troponin-I, or troponin-T). Exclusion criteria were: 1) cardiogenic shock at presentation (systolic blood pressure ≤ 90 mmHg); 2) pulmonary edema on admission; 3) previous MI; 4) pulmonary disease comorbidity (such as chronic obstructive pulmonary disease); or 5) previous revascularization procedure (PCI or coronary artery bypass grafting, CABG). After application of these criteria, 326 patients were available for analysis. Patients were included if their whole dataset was available.

Included patients were classified into 3 groups: a single-vessel disease (SVD) group (n = 118), a MVD with CR group (n = 112), and a MVD with IR group (n = 96). Demographic data, comorbidities, STEMI characteristics, angiography findings, revascularization procedure, echocardiography data, and CPET results were evaluated.

In all patients, diagnostic coronary angiography followed by PCI of the IRA was performed immediately after admission, using standard techniques. PCI of the IRA was based on angiography-guided decisions. The goal of PCI was to restore thrombolysis in myocardial infarction (TIMI) grade 3 flow with residual stenosis <30%. Achievement of this goal was defined as a successful procedure. Delayed PCI of the non-IRA was performed during the subsequent days of the index hospitalization. After primary PCI, all patients received 100 mg of aspirin daily (indefinitely) and 75 mg of clopidogrel daily (for one year), as well as β-blockers (BB), angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), and statins, if these agents were not contraindicated.

The coronary arteries were classified based on anatomical criteria. The following vessels were considered as major coronary arteries: left main, left anterior descending, circumflex, and right coronary arteries. Diagonal, obtuse marginal, and intermediate branches were considered to be major branches. Lesions at a bifurcation were analyzed as if they were two diseased arteries. MVD was defined as the presence of ≥50% stenosis of ≥2 major epicardial coronary arteries or their major branches, as assessed during initial coronary angiography. The coronary artery disease (CAD) severity in MVD patients was assessed according to a modified Gensini’s stenosis scoring system [14]. This score is computed by assigning a severity score to each coronary stenosis based on the degree of luminal narrowing and its topographic importance. Reduction in lumen diameter was evaluated and assigned a score of 1, 2, 4, 8, 16 and 32 for 25%, 50%, 75%, 90%, 99% and complete occlusion, respectively. A multiplier was also assigned to the value of each affected segment based on the functional significance of the myocardial area supplied by that segment: 5 for the left main coronary artery; 2.5 for the proximal segment of the left anterior descending artery; 2.5 for the proximal segment of the circumflex artery; 1.0 for the right coronary artery, the distal segment of the left anterior descending artery, the posterolateral artery and the obtuse marginal artery; and 0.5 for all other segments.

CR was defined as the absence of total occlusion, with no residual stenosis of >70% found in any major coronary artery or major branch, at discharge, based on visual assessment [15, 16]. To validate the visual assessment, quantitative coronary angiography (QCA) was performed in 254 lesions and compared with visual assessment; there was no significant difference between the two methods (P = 0.41, data not shown).

Current guidelines recommend CPET during hospitalization or early after discharge [17‐19]. CPET was performed in our patients with the primary aim of prognosis assessment, and to determine exercise intensity based on VO_2max and oxygen uptake at anaerobic threshold (VO_2AT). After a familiarization test, a symptom-limited CPET was performed within 7–30 days of STEMI, in a single-exercise laboratory. We used a modified Bruce treadmill protocol with continuous monitoring of 12 standard echocardiographic leads. Analysis of ventilatory expired gas was performed using a metabolic system (MAX-II, Physio-Dyne Instrument Corp., USA). The following endpoints were used for termination of the test: 1) achieving 85% of the predicted maximum heart rate for age; 2) respiratory exchange ratio (RER) ≥1.1; 3) presence of chest pain, dyspnea, dizziness, palpitations, leg pain or fatigue; 4) fall in systolic blood pressure of 10 mmHg accompanied by symptoms of lightheadedness; 5) excessive systemic blood pressure increase to ≥230/130 mmHg; 6) sustained ventricular tachycardia or frequent runs of non-sustained ventricular tachycardia; or 7) horizontal or downsloping ST depression ≥0.2 mV. Test results were interpreted by two experienced evaluators who were blinded to: 1) patients’ names; 2) other studies results; 3) patients’ clinical history; and 4) physical findings.

An ischemic ST deviation was defined as ST depression, measured 0.08 s from the J point, of 0.1 mV or more, and followed by more significant ischemia until the end of the test. The definition of VO_2peak was the highest O₂ consumption during any stage of maximal exercise that could be sustained for 30 s. The VO_2AT was measured by the V-slope method [20]. The oxygen pulse was defined as the oxygen consumption per heart beat, and is related directly to the stroke volume according to the Fick formula: oxygen pulse = stroke volume x (arterial - venous) oxygen.

Statistical analysis was performed using SPSS 20.0 for Mac (SPSS Inc., USA). Continuous parameters are expressed as mean ± standard deviation (SD) unless otherwise specified; categorical variables are presented as numbers and proportions. For continuous variables, comparisons between groups were made using one-way analysis of variance (ANOVA), with a Fisher’s LSD post-hoc test. Categorical variables were compared using the Chi-square test. Relationships between CPET parameters, angiography findings, subject demographic features, STEMI characteristics, and cardiovascular risk factors were assessed using regression analyses. A p-value <0.05 was indicative of statistical significance.

Clinical characteristics of the participants are summarized in Table 1. The majority of patients were male (89.0%), mean age was 55.6 ± 11.2 years, 48.8% of patients had anterior wall MI, and the proportion of Killip Class I on admission was 97.2%. There were no significant differences between the three groups in any characteristic, with the exception of hypertension: hypertension was more common in both the CR and IR groups than in the SVD group (p < 0.05), but did not differ between the CR and IR groups.

Comparison of these data between the IR and CR groups revealed that patients with IR had a higher prevalence of three-vessel disease (57.3 vs. 31.3%, p < 0.001), and were managed using fewer stents (1.6 ± 0.7 vs. 2.1 ± 0.8, p < 0.001) than patients with CR, including the stents from an eventual second PCI in the CR group (Table 1). Extent of baseline stenosis of the non-infarct-related lesions was similar between the CR and IR groups (CR: 83.3% ± 11.7% vs. IR: 81.0% ± 10.8%, p = 0.12). There was no difference in Gensini’s score between the two groups (CR = 63.2 ± 37.0 vs. IR = 65.2 ± 36.5, P = 0.814).

Results of stress electrocardiography and CPET are shown in Table 2. Ischemic ST deviation occurred in 7.1% of patients, with a peak heart rate of 129.6 ± 18.0 bpm. No significant differences were observed between the CR and IR groups with respect to any of the variables assessed (proportion of patients with ischemic ST deviation, peak heart rate, VO_2peak, VO_2AT and peak oxygen pulse). There were also no significant differences between the MVD groups (IR or CR) and the SVD group with regard to the proportion of patients with ischemic ST deviation, peak heart rate, VO_2peak and VO_2AT. However, there was a trend for VO_2peak and VO_2AT to be lower in patients with MVD than in those with SVD (Table 2). The peak oxygen pulse was significantly different between the SVD and IR groups (p = 0.005), although no significant differences were observed between the CR group and either the SVD or IR groups.

Stepwise multiple regression analysis was performed to further evaluate the relationship between exercise capacity and the revascularization status of patients with MVD (i.e., those with either CR or IR). In particular, we were interested in determining whether CR, as compared with IR, was a predictor of exercise capacity. The variables selected for the multivariate analysis included age, gender, BMI, hypertension, hyperlipidemia, diabetes mellitus, smoking, anterior wall MI, Killip class I, peak CK value, LVEDD, LVEF, and SVD, CR and IR. After adjustment for age, gender, body mass index (BMI), cardiovascular risk factors, MI characteristics and echocardiography parameters, CR was not found to be an independent predictor of VO_2peak (OR = −0.123, 95% confidence interval [CI] -2.986 to 0.232, p = 0.093), VO_2AT (OR = 0.002, 95% CI −1.735 to 1.773, p = 0.983), or peak oxygen pulse (OR = −0.102, 95% CI −1.435 to 0.105, p = 0.090). However, as detailed in Table 3, gender, age and LVEF were predictors of VO_2peak, gender and anterior infarction were negatively correlated with VO_2AT, and gender, age, BMI and LVEF were associated with peak oxygen pulse.

This study is not without limitations. First, this was a retrospective observational study, rather than a prospective study such as a randomized controlled trial. As a result, we cannot exclude the possibility of a selection bias. Indeed, it is possible that CR was attempted and encouraged in patients in whom it seemed more feasible or more clinically relevant. It is also possible that baseline differences in exercise performance may have existed prior to PCI, and that exercise performance before MI may have been an important determinant of exercise performance shortly after PCI, especially in a non-randomized study, with a small numbers of patients medicated with multiple drugs. Since MI is unpredictable, we could not directly measure pre-MI exercise performance, and would have to rely on indirect measures such as questionnaires, which was not possible in the present study due to its retrospective nature. Second, the amount of ischemia damage was not directly assessed (e.g. using magnetic resonance imaging, MRI), but was measured using Troponin I, which is nevertheless considered gold standard. Third, 97% of our sample had a Killip class 1, indicating that these patients were a low risk population. Achieving a complete CR might show more benefits in higher risk patients. Fourth, the treatment strategy was based on angiography evidences, and not on ischemia evidences. Finally, the choice of endpoints might affect the conclusion. In the present study, we used quantitative endpoints. However, studies using clinical and qualitative endpoints might provide inconsistent results [22]. An appropriately prospectively designed randomized controlled trial, with a larger cohort of participants and with clear measurements of ischemia (such as MRI), would allow for a more detailed assessment of the relative merits of CR and IR in patients with MVD.