The Comorbidity of Peripheral Arterial Disease Attenuates Complications During Primary Percutaneous Coronary Intervention in ST-Elevation Myocardial Infarction

ABSTRACT: Background: In animal studies, chronic skeletal muscle ischemia induces myocardial remote ischemic preconditioning (RIPC). We hypothesized that a history of peripheral arterial disease (PAD) might attenuate complications during primary percutaneous coronary intervention (PCI) in patents with acute ST-elevation myocardial infarction (STEMI). Methods: Seventy-five STEMI patients (40 with PAD and 35 without PAD) were retrospectively studied. PAD was defined as ankle brachial index <0.9, or brachial ankle pulse wave velocity >1,800 cm/s. MI size and acute complications during PCI were compared. For patients without post-stenting coronary flow worsening, the difference between post-stenting and pre-stenting fluoroscopic frame count (∆FFC) was also compared. Results: Mean age was 68±12 years and 60 patients were males. Apart from greater age and more cases with hypertension in the PAD group, basic clinical and PCI data were similar. PAD patients had lower complications during PCI (20 vs 8, P=.001), lower peak CK-total (3,590±2,657 vs 2,035±1,353 IU/L, P=.003), and lower peak CK-MB (298±192 vs 185±129 IU/L, P=.021). For the 53 patients without coronary flow worsening, PAD patients had lower ∆FFC (-2.26±8.5, SE=1.94 vs -4.28±1.19, SE=2.20 frames, P=.035). Conclusion: Our observation study suggests that PAD attenuates complications during PCI and infarct size in patients with STEMI, probably by PAD-induced RIPC.  

VASCULAR DISEASE MANAGEMENT 2013:10(8):E142-E151

Key words: myocardial infarction, peripheral vascular disease, percutaneous coronary intervention, reperfusion injury

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One of the concerns in the acute setting of ST-elevation myocardial infarction (STEMI) is cardiac ischemia/reperfusion injury (IRI).¹ Recently, ischemic preconditioning (IPC) was shown to attenuate IRI if brief ischemic insult followed by reperfusion was introduced before the development of index myocardial ischemia.^2,3 It is also found that myocardial infarction (MI) size can be reduced if a brief period of ischemia was applied to a distant organ before myocardial ischemia, an extension of IPC that was called remote ischemic preconditioning (RIPC).⁴ Myocardial RIPC was found to occur after ischemia in a variety of remote tissues^4,5 of which skeletal muscles attracted most interest, being accessible and manipulated without great clinical risk, and myocardial RIPC was shown to decrease MI size in animal studies.^6,7 

Chronic skeletal muscle ischemia represents an exaggerated model of RIPC, which induces the formation of local collateral circulation.^8,9 Animal studies have shown that chronic limb ischemia also induces coronary collateral circulation that was associated with smaller MI^10,11 less inducible ventricular arrhythmia,¹² and better coronary flow after MI.¹¹

Peripheral arterial disease (PAD) is found in approximately 60% of patients with coronary artery disease (CAD).¹³ PAD increases the long-term risk among patients with CAD and predicts worse outcomes of acute coronary syndrome.¹⁴

Recent studies found that the presence of PAD, indicated by low ABI^15-17 or high brachial ankle pulse wave velocity (baPWV) values,^18-20 might lead to the elevation of the circulating levels of some anti-inflammatory, vasodilator, or angiogenesis-inducing substances, raising questions about whether PAD-induced chronic skeletal muscle ischemia could be a source of RIPC.

Accordingly, the purpose of our study was to test the hypothesis that patients presenting with STEMI associated with the comorbidity of PAD, suggested by abnormal ABI or baPWV values, have less complications during primary PCI.

Method

We retrospectively reviewed our hospital database for patients who underwent primary PCI because of acute STEMI between April 2005 and December 2011. The study protocol was approved by the Institutional Review Board on Biochemichal Research at Kobe University Hospital, Kobe, Japan. Clinical, demographic, laboratory, and echocardiographic data, in addition to PCI reports and fluoroscopic runs, were reviewed from our local network server.

STEMI diagnosis was made if patients had ST elevation of 1 mm or more in 2 or more contagious leads associated with reciprocal ST-segment depression together with abnormally increasing cardiac enzymes.²¹ Patients were included if they had been tested for the presence of PAD by ABI and baPWV prior to STEMI-related admission or during their hospital stay.

Defining peripheral arterial disease

ABI and baPWV were measured using an automatic oscillometric device (Form PWV/ABI, BP-203RPE II, Omron Colin Co., Ltd.) as previously described.^22,23 In our study, PAD was defined as ABI <0.9²⁴ or baPWV>1,800 cm/s²⁵ on either or both limbs.

STEMI-related complications on presentation

Patients were classified to have complications on presentation if they presented with cardiopulmonary arrest (CPA), cardiogenic shock, or their occurrence before restoration of the culprit vessel flow (door-to-balloon window).

Acute PCI-related complications

Acute complications during PCI were defined as occurrence of any of the following: new intraprocedural hypotension, intraprocedural worsening of ST-segment elevation, any form of reperfusion arrhythmia occurring after restoration of the flow to the infarct area, or intraprocedural worsening of the coronary flow in the culprit vessel after stent implantation. 

Intraprocedural worsening of ST elevation was defined as ≥1 mm worsening of ST-segment elevation during PCI compared to admission ECG or any intraprocedural re-elevation of the ST-segment after PCI-induced partial or complete ST-segment resolution.

Assessment of intraprocedural coronary flow

Coronary flow was studied visually using thrombolysis in myocardial infarction (TIMI) flow class after each step of PCI; namely, initial wiring of the culprit lesion, thrombus aspiration, pre-stenting balloon dilatations, stent deployment, and post-stenting balloon dilatations. Patients were considered to have coronary flow worsening if TIMI flow class decreased by ≥1 grade after stenting compared to an initially restored flow.

Coronary flow in patients without intraprocedural flow worsening

Coronary flow was further assessed by counting the fluoroscopic frames spanning the start and end of contrast injection as an indirect measure of coronary flow velocity (fluoroscopic frame count; FFC). It is worth noting that the frame rate of the fluoroscopic runs of all patients were the same (15 frames/second). FFC was counted in two preselected fluoroscopic runs; the first was the pre-stenting fluoroscopic run with the best TIMI flow (FFC_pre) and the second was the fluoroscopic run taken just after stent deployment (FFC_final). Frame counts were calculated from the frame at which contrast first encounters the ostium of the culprit vessel until the first frame where contrast reaches its most distal branch. Finally, ∆FFC was calculated as the difference between FFC_final and FFC_pre.

Infarct size assessment

Creatine kinase total (CK-total) and MB fraction (CK-MB) levels were measured serially every 6 hours. Values on presentation, 6 hours after presentation, and peak values were obtained to study the difference in serial changes between patients with or without PAD.

Infarct sizes were determined using peak CK-total and CK-MB. ∆CK-total and ∆CK-MB were measured as differences between peak values of CK-total and CK-MB and their values on presentation.

Statistical analysis

Categorical variables were represented as numbers and percentages and were compared using a χ² test or Fisher exact test if the number of subjects in any cell was <5. Continuous variables were represented as mean ± standard deviation, were tested for normality using the Shapiro-Wilk test, and were compared using Student t test for independent variables if the variable followed a normal distribution, or Mann-Whitney U test if it did not follow a normal distribution. One-way ANOVA was used to examine the effect of PAD on serial enzyme measurements. Data were considered statistically significant if the P value was <.05. Comparisons were performed using SPSS software (Statistical Product and Services Solutions, version 16.0, SPSS Inc.).

Results

Between April 2005 and December 2011, data from 380 patients with acute MI were available of whom 198 patients were STEMI. ABI and baPWV were available for 75 cases and accordingly they comprised the study group.

Classifying patients according to ABI and baPWV

Thirty-five patients had no PAD, and 40 patients were the study group with PAD. Among patients with PAD, 18 had ABI <0.9 (0.68±0.154) and 22 patients were classified as having PAD because of baPWV >1,800 cm/s (2,103±501 cm/s)

Basic clinical data

Table 1 summarizes basic admission and PCI data for both groups. Overall, the mean age was 67.64±11.98 years and 60 (80%) patients were males. Apart from significantly older patients and more patients with hypertension in the PAD group, there was no significant difference between both groups regarding sex, BMI, coronary risk factors, peak C-reactive protein, or ejection fraction on presentation. On pre-PCI coronary catheterization, both groups had no significant differences regarding number of diseased vessels, culprit lesion location, the proximity of culprit lesion, or lesion class according to the AHA classification (Table 1).

Acute STEMI-related complications

Complicated presentation related to STEMI, namely CPA, arrhythmia, or cardiogenic shock, occurred in 17 patients overall (8 without PAD and 9 with PAD) The occurrence of each complication or the occurrence of any of them was not different between groups (Table 2).

Reperfusion-related complications

Overall, 28 patients had one or more complications during PCI, a finding that occurred significantly less in patients with PAD (20 vs 8 patients, P=.004). PCI complications that occurred less in patients with PAD were new hypotension, reperfusion arrhythmia, and the development of post-stenting TIMI-flow worsening. Although fewer cases had worsening of ST elevation during PCI, this was not statistically significant (Table 2).

Comparisons of intraprocedural TIMI flow 

Figure 1 shows TIMI flow class before and after stenting for both study groups. The initially restored flow was TIMI class III in 60 patients (27 without PAD and 33 with PAD), TIMI class II in 13 patients (6 without PAD and 7 with PAD), and TIMI class I in 2 patients without PAD.

Intraprocedural TIMI-flow worsening occurred in 22 patients, and there was significantly different complication between groups; patients with PAD showed significantly fewer cases (16 vs 6 patients, P=.004, Table 2). After intracoronary nicorandil, 14 of these cases finished the procedure with TIMI class III flow, 3 cases finished the procedure with TIMI class II flow, and 4 finished with TIMI class I flow.

Composite of all acute complications

The composite of any acute complication (on presentation or during PCI) was significantly lower in patients with PAD (27 vs 11 patients, OR=0.172, 95% CI 0.064-0.466, and P<.0001) (Table 2).

Infarction size

CK-total and CK-MB serial measurements were available in 68 patients (32 without PAD and 36 with PAD), and 66 patients (31 without PAD and 35 with PAD), respectively. By Mann-Whitney U test, CK-total and CK-MB values on presentation were similar between groups. CK-total, and not CK-MB, became significantly lower in patients with PAD at 6 hours and was even more significantly lower, in addition to significantly lower CK-MB, when peak values were compared (Table 3). Moreover, patients with PAD showed significantly lower ∆CK-total and ∆CK-MB.

One-way ANOVA (Figure 2) suggested that the serial increase of CK-total was significantly lower in patients with PAD (P=.018), while there was a strong trend towards a lower serial increase in CK-MB (P=.069). Post-hoc analysis with Turkey test revealed that both enzymes were not significantly different on presentation and 6 hours after presentation in case of CK-total (P=1.00 and .17, respectively), and in the case of CK-MB (P=1.000 and 0.766, respectively). However, peak levels of CK-total and CK-MB were significantly lower in patients with PAD (P=.002 and .02, respectively). 

Comparisons for patients with low CK-total on presentation

It is expected that time from onset of pain to hospital presentation might bias the results concerning cardiac enzymes. Because data concerning the time to presentation was not available in this study, all comparisons regarding cardiac enzymes were redone in patients who presented to the hospital with low CK-total levels (<150 IU/L). 

Such comparisons confirmed the previously mentioned overall findings (Table 4), when we found that CK-total and CK-MB were similar at presentation; CK-total was significantly lower in patients with PAD at 6 hours and at peak levels, CK-MB was similar at 6 hours but peak levels were significantly lower in PAD patients, and both ∆CK-total and ∆CK-MB were significantly lower in patients with PAD.

Patients without intra-procedural flow worsening

For the 53 patients without post-stenting TIMI-flow worsening, there was no difference between both groups regarding fluoroscopic frame count at flow restoration (FFC_pre). Interestingly, fluoroscopic frame count after stenting (FFC_final) and the difference between FFC_pre and FFC_final (∆FFC) was significantly higher in patients without PAD (Table 5). 

Similar to the previous comparisons, cases with PAD in this subset of patients had a trend toward lower peak CK-total, and despite CK-MB levels were relatively lower in PAD patients, it lost the statistical significance. However, in this subset of patients, ∆CK-total and ∆CK-MB continued to be lower in patients with PAD (Table 5).

Discussion

This observational study suggests that patients with STEMI associated with PAD have less acute complications on presentation or during PCI, smaller infarct size indicated by cardiac enzymes, and better coronary flow, indicated by less flow complications during PCI and by better fluoroscopic frame run after stenting. 

Skeletal muscle ischemia in different types of PAD

In our study, PAD-induced skeletal muscle ischemia seemed to contribute to the better short-term outcomes of STEMI in patients with PAD. The presence of PAD is reportedly a cause of skeletal muscle ischemia that result in claudication and decreased muscle mass. PAD can be occlusive or non occlusive. 

Occlusive PAD is characterized by arterial stenosis because of atherosclerotic plaques that develop chronically, leading eventually to a decrease in the cross-sectional arterial lumen area and thus decreasing blood supply to the skeletal muscles. Occlusive PAD can be diagnosed noninvasively by a low resting or exercise ABI. 

Nonocclusive PAD, on the other hand, is characterized by increased stiffness or calcification of the arterial wall which was also reported to cause claudication and skeletal muscle ischemia^26-28 and can be identified noninvasively by abnormally high ABI or baPWV. Especially baPWV is considered a well known measure of arterial stiffness and reportedly predicts poor exercise tolerance and low VO_2max that seems related to potential PAD^25,29-31 and might be related to skeletal muscle ischemia.³² In our study, we included both types of PAD by studying patients who had ABI <0.9 as a marker of occlusive PAD, and baPWV >1,800 cm/s as markers of nonocclusive PAD.

PAD and coronary heart disease

The findings of this study go against the common consensus that PAD complicating coronary heart disease is a marker of poor prognosis and complications both after PCI and carotid artery bypass grafting. However, a recent study showed that in patients undergoing coronary artery bypass grafting surgery, the coexistence of PAD was a predictor of poor prognosis only in the long term and not in the short term after surgery. The authors, however, did not describe the mechanism of such observation.³³ 

In a comment to that study, Ozeke et al, hypothesized that the mechanism behind this was the possibility of myocardial RIPC in patients with PAD.³⁴ Thus, the findings of our study do not change the common belief of the long-term poor outcomes of patients with PAD if they suffer of coronary heart disease, but, shows that patients with PAD might have a paradoxical advantage during the acute stage of MI and during PCI, probably because the myocardium might be preconditioned chronically by the previously developed PAD. 

Effects of chronic limb ischemia in animal studies

RIPC was mostly tested based on the transient ischemia model. However, recently, animal studies have shown that chronic skeletal muscle ischemia induced coronary angiogenesis that cause myocardial preconditioning resulting in smaller infarcts, less inducible ventricular tachycardia and better coronary flow after AMI.^10-12 

In our study, better ∆FFC and significantly lower cardiac enzymes noticed in patients with PAD, together with the significantly lower composite of all acute complications, seem to agree with these findings, however in humans.

Possible mechanisms

Several mechanisms have been proposed to explain the phenomenon of RIPC, such as suppression of inflammatory genes,⁴ modulation of ATP-sensitive K⁺ channels,⁵ nuclear factor κB p105, nitric oxide synthase,³⁵ or free-radicals pathways.³⁶ RIPC was also found to stimulate neovascularization in the ischemic myocardium by upregulation of vascular endothelial growth factor gene expression that lead to limitation of infract size.³⁷ Despite its promise in animal studies, the clinical benefit of RIPC in human studies remains controversial.^38,39

It has been reported that patients with PAD and ABI <0.9 have an increased level of vascular endothelial growth factor angiopietin-2 and hypoxia-inducible growth factor-1 alpha leading to angiogenesis.^15-17 Patients with high carotid-femoral PWV showed strong positive correlation with genetic expression of angiopoietin-1 and angiopoietin-2 which are also angiogenic.¹⁸ Moreover, increased baPWV was reported to be associated with increased levels of nitric oxide synthase²⁰ and the anti-inflammatory acute phase reactant complement-1 inhibitor.¹⁹

Because all previously mentioned substances are circulating, it is reasonable to deduce that such tissue-protective or angiogenic substances might have an effect on the myocardium as well as cause RIPC. Accordingly, mechanisms related to RIPC seem to extend in chronic PAD of different causes explaining the better coronary flow and smaller MI in patients with PAD in our study.

Study Limitations

Unfortunately, this study suffered critical limitations: first, this is a retrospective analysis of a small number of patients. Second, because of being a retrospective study, and because ABI and baPWV are not routinely measured for patients with STEMI in our hospital, STEMI patients who did not have ABI/baPWV measured were excluded from the study. However, some of the patients excluded might have actually had PAD and thus excluding them might have biased the results of the study. Thus, for the aforementioned two reasons, a future prospective analysis using larger patient groups is recommended to verify the study findings. Third, our study included two different types of PAD, and although both types were shown in literature to cause skeletal muscle ischemia and claudication, future studies showed prospectively test our findings on each type of PAD separately. Fourth, TIMI-frame count (TFC) was introduced recently as an objective automated measure of coronary flow velocities. The TFC was not used in our study, again, because of being a retrospective analysis. Instead, we used the fluoroscopic frame count. However, fluoroscopic frame count used in our study can be affected by the speed of contrast injection and target vessel length. Because comparisons were made according to the differences in FFC_pre and FFC_final, we feel that these limitations have minimally affected our results, because they were measured in the same vessel and injections were always done by the same operator. Finally, substances suggested to be responsible for RIPC were not measured in our study. Further studies should take these measurements into concern.

Conclusion

In this observational study it is suggested that the comorbidity of PAD attenuates acute complications of primary PCI in patients with STEMI, probably because of RIPC that might occur in association with or as a contribution to better coronary collateral circulation.

Editor’s Note: Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest related to the content of this manuscript.

Manuscript received March 20, 2013; provisional acceptance given April 8, 2013; final version accepted May 6, 2013.

Address for correspondence: Toshiro Shinke, MD, PhD, Kobe University Graduate School of Medicine, Department of Cardiovascular Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 6500017, Japan. Email: shinke@med.kobe-u.ac.jp

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