Myocardial endothelin-1 release and indices of inflammation during angioplasty for acute myocardial infarction and stable coronary artery disease☆

Article Outline

• Abstract
• Methods
  • Study population and patient selection
  • Angioplasty and insertion of CS catheter
  • Collection and processing of blood
  • Plasma ET-1 measurement
  • Assessment of plasma cytokine and C-reactive protein levels
  • Assessment of left ventricular wall motion
  • Statistics
• Results
  • Patient demographics and angioplasty procedure
  • Plasma ET-1 in AMI and stable angina
  • Cardiac ET-1 release and LV function
  • Inflammatory cytokines and C-reactive protein in AMI and stable angina
• Discussion
• References
• Copyright

Abstract 

Background

Elevations in endothelin-1 (ET-1) and inflammatory cytokines may impair myocardial reperfusion through the induction of microvascular constriction or obstruction; however, the generation of these factors close to the site of lesion rupture is unknown.

Methods and results

Coronary sinus (CS) and aortic blood was sampled during angioplasty for acute myocardial infarction (AMI) or stable angina to assess the local release of ET-1, interleukin-1β, interleukin-6, tumor necrosis factor-α and C-reactive protein following atherosclerotic plaque rupture. Transthoracic echocardiography documented left ventricular function in AMI. ET-1 levels were higher in CS than in aortic blood in AMI (3.0 ± 0.3 pmol/L vs 2.6 ± 0.3 pmol/L, P = .04), but not in stable angina (1.7 ± 0.2 pmol/L vs 1.5 ± 0.3 pmol/L, P = NS). CS ET-1 levels were also higher in AMI than in stable angina (3.0 ± 0.3 pmol/L vs 1.7 ± 0.2 pmol/L, P = .002), and correlated with left ventricular dysfunction (R² = 0.51, P = .02). In contrast, C-reactive protein levels were higher in CS than in aortic blood only in stable angina (2.3 ± 0.4 mg/L vs 1.8 ± 0.3 mg/L, P = .01). Similarly, CS tumor necrosis factor-α was higher in stable angina than in AMI (6.0 ± 1.4 pg/mL vs 2.5 ± 0.9 pg/mL, P = .02).

Conclusions

Local myocardial release of ET-1 is highest in AMI, where it relates to the extent of myocardial dysfunction. Although local inflammation is a component of stable coronary artery disease, it does not appear acutely enhanced in AMI.

The rapid and successful restoration of perfusion to the affected myocardium is critical to the treatment of acute myocardial infarction (AMI). Strategies that restore patency to the infarct-related artery such as thrombolysis¹ and percutaneous coronary intervention (PCI)² improve survival in AMI. However in many instances, flow in the infarct-related artery is poor despite the successful restoration of patency, a phenomenon known as “no-reflow.”³ The no-reflow phenomenon is detectable in as many as 40% of AMI patients,⁴ and is associated with poor recovery of myocardial function⁵ and a higher incidence of left ventricular (LV) failure.⁶ Although its underlying mechanism is not known, we have recently demonstrated that atherosclerotic plaque rupture induces distal microvascular constriction, which is a major determinant of reduced arterial flow.⁷

A number of locally generated factors could mediate such a vasoconstrictor response. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide that has been identified in atherosclerotic plaque.⁸ In addition, patients with AMI and elevated systemic levels of ET-1 have a poorer prognosis,⁹ possibly a consequence of impaired microvascular reperfusion.¹⁰ The recognition that inflammation is an important component of the atherosclerotic process has also revealed an association between adverse outcomes following AMI and elevated inflammatory markers such as C-reactive protein,¹¹ tumor necrosis factor-α,¹², interleukin-1β, and interleukin-6.¹¹ Acute inflammation may impair microvascular flow either through tumor necrosis factor-α–mediated distal microvascular constriction¹³ or by promoting leucocyte adhesion and plugging of microvessels, resulting in capillary stasis.¹⁴

Prior studies investigating ET-1 generation and initiation of the inflammatory process following AMI all utilized peripheral blood for their analyses. Therefore, the contribution of local myocardial release of ET-1 and inflammatory mediators, as well as their implications for microvascular flow, have not been elucidated. In this prospective study we assessed the heart's contribution to the local release of ET-1 as well as indices of inflammation in the context of atherosclerotic plaque rupture occurring in AMI patients treated with emergency percutaneous coronary intervention (PCI), or a consequence of PCI for stable angina. By simultaneous sampling of coronary sinus (CS) and aortic blood, we identified a gradient of these potentially vasoactive factors across the coronary circulation. Transthoracic echocardiography performed acutely assessed the relationship between locally generated vasomotor factors and impairment of LV wall motion.

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Methods 

Study population and patient selection 

Twenty-one patients with either AMI (n = 10) or stable angina (n = 11) were included in our study. All subjects were enrolled through the Alfred Hospital Heart Centre, Melbourne, Australia. Informed consent was obtained from the patient before enrollment and the study was carried out with the approval of the Alfred Hospital Ethics Committee.

Patients with AMI were defined by symptoms of chest pain for >30 minutes in association with electrocardiographic changes consistent with AMI.² Only those undergoing acute PCI were enrolled. We included patients in our chronic stable angina group if they had angiographically severe coronary stenoses and stable symptoms, with no history of AMI or unstable angina in the previous month.

Angioplasty and insertion of CS catheter 

All PCI patients received aspirin (150 mg/d) and heparin IV (minimum of 6000 IU) before commencing angioplasty. Clopidogrel was commenced following completion of the procedure as an oral loading dose of 300 mg followed by a maintenance dose of 75 mg/d. Abciximab (Eli Lilly/Centocor, Indianapolis, Ind), was administered to all AMI patients during angioplasty, as an intravenous bolus (0.25 mg/kg) followed by continuous infusion (0.125 μg/kg per min for 12 h). The angioplasty procedure involved balloon catheter dilation of the artery followed by deployment of an intracoronary stent in all patients with AMI and stable angina.

The CS was cannulated before commencing the angioplasty procedure in the patients with stable angina. Because the insertion of the CS catheter significantly delays the treatment of AMI, the CS catheter was placed immediately following successful restoration of angiographic patency in AMI patients. In all patients, either a 7F CS catheter (Webster CCS 7/8U, 90A, Webster Laboratories, Baldwin Park, Calif) or a 6F Judkins Left 5 catheter (Cordis, Miami Lakes, Fla) was inserted via the left antecubital or right femoral veins, respectively.

Collection and processing of blood 

In stable angina patients, aortic and CS blood was sampled simultaneously prior to the commencement of PCI and then again on completion of the procedure. In AMI patients, CS and aortic blood was sampled on completion of PCI. All blood samples were placed immediately on ice, then plasma was separated by spinning at 5000 rpm for 10 minutes. Aliquots were placed into 1-mL Eppendorf tubes (Eppendorf AG, Hamburg, Germany) and then frozen at −80°C. In addition, peripheral blood creatinine kinase was measured serially in AMI patients and on the day following PCI in elective angioplasty patients. Periprocedural infarction in elective patients was defined by a 3-fold increase of creatinine kinase.¹⁵

Plasma ET-1 measurement 

Plasma ET-1 levels were measured by in-house radioimmunoassay following extraction based on methods previously described for atrial natriuretic peptide¹⁶ with the exception of the preincubation step, which was for 3 hours at room temperature. Plasma samples (2 mL) were extracted on SepPak C18 cartridges (Waters, Milford, Mass) as previously described.¹⁷ The extracts underwent assay using antisera raised to human ET-1 (Peninsula Laboratories, Belmont, Calif) with human ET-1 as standard (Peninsula Laboratories). The cross-reactivity provided by the manufacturer of the ET-1 antisera to ET-2, ET-3, and big-ET was 7%, 7%, and 17%, respectively. Plasma extracts diluted in parallel to the standard curve, suggesting immunologic identity. Detection limit of the assay was 1.1 pmol/L. Intra- and interassay coefficients of variation were 5.9% and 7.8%, respectively. Recovery of ET-1 spiked into plasma was 69%.

Assessment of plasma cytokine and C-reactive protein levels 

Plasma interleukin-1β, interleukin-6, and tumor necrosis factor-α levels were measured using commercial immunometric assay kits obtained from Immulite (Diagnostic Products, Los Angeles, Calif). The limits of detection for interleukin-1β, interleukin-6, and tumor necrosis factor-α were 1.5 pg/mL, 5 pg/mL, and 1.7 pg/mL, respectively. All 3 immunometric assays were performed with high and low controls tested repeatedly during the assay process as described by the manufacturer. C-reactive protein levels were assessed by high-sensitivity immunoturbidimetric assay performed on a 917 Hitachi Automated Analyser (Roche, Basel, Switzerland).

Assessment of left ventricular wall motion 

All AMI patients underwent transthoracic echocardiography within 24 hours of the AMI. The left ventricle (LV) was divided into 16 segments as previously described,¹⁸ and a numerical score from 1 to 6 was allocated to each segment. The LV wall motion score for each patient equalled the sum of the 16 segmental scores. The number of affected LV segments was defined as the number of segments with a wall motion score ≥2.

Statistics 

All continuous data are expressed as mean ± 1 standard error. Comparisons between independent groups utilizes the Mann-Whitney test, while comparisons between related means utilizes the Wilcoxon signed ranks test. To ascertain the strength of association, the Spearman rank order correlation coefficient is calculated. Comparisons of proportions between groups are made with Fisher's exact test. In all cases, P < .05 is considered significant.

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Results 

Patient demographics and angioplasty procedure 

There was an antecedent history of symptomatic ischemic heart disease in 5 of the 10 AMI patients and in all patients in the stable angina group (P < .05, Fisher's exact test). There was also a higher incidence of β-blocker usage in the stable angina group (11 of 11 stable angina subjects vs 3 of 10 AMI subjects, P = .001). Otherwise, there were no significant differences in patient demographics between the stable angina and AMI groups (Table I). The mean time to reperfusion from the onset of symptoms in the AMI group was 3.2 ± 0.5 hours (upper limit 6.4 hours). All AMI and stable angina patients underwent PCI and stenting without complication, with Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 and no residual dissection or significant stenosis (>30%). The mean procedural heparin dose was lower in the AMI group, presumably due to concurrent abciximab administration in this group (Table II). The maximum balloon inflation pressure was higher in the elective PCI group (16.4 ± 0.9 vs 13.4 ± 0.5, P = .02), suggesting a higher fibrous component in these lesions. There was 1 small periprocedural infarction in the elective PCI group, with an asymptomatic creatinine kinase elevation of 830 U/L. This patient had an otherwise uncomplicated clinical course and did not require repeat angiography. The mean creatinine kinase peak in AMI patients was 1709 ± 380 U/L.

Table I. Patient demographics

Table II. Angiographic and procedural data

Plasma ET-1 in AMI and stable angina 

CS ET-1 plasma levels following infarct PCI were higher than aortic plasma levels (3.0 ± 0.3 pmol/L vs 2.6 ± 0.3 pmol/L, P < .05; Figure 1, A) and were also elevated compared with stable angina patients pre-PCI (3.0 ± 0.3 pmol/L vs 1.7 ± 0.2 pmol/L, P < .01) and post-PCI (3.0 ± 0.3 pmol/L vs 2.3 ± 0.2 pmol/L, P < .05; Figure 1, B). Before PCI in patients with stable angina, the CS and aortic plasma ET-1 levels were similar (1.7 ± 0.2 pmol/L vs 1.5 ± 0.3 pmol/L, P = NS). After elective PCI, CS plasma ET-1 levels were increased (1.7 ± 0.2 pmol/L pre-PTCA vs 2.3 ± 0.2 pmol/L post-PTCA, P < .05; Figure 2).

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• Figure 1. 

  Plasma ET-1 levels in AMI and stable angina. In AMI patients, CS plasma ET-1 levels were higher than the levels in aortic plasma (A), and also higher than the CS levels of patients with stable angina both pre- and post-PCI (B). *P < .05. †P < .01.

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• Figure 2. 

  Differences in CS plasma ET-1 levels of stable angina patients pre- and post-PTCA, demonstrating elevated CS ET-1 levels following angioplasty. *P < .01.

Cardiac ET-1 release and LV function 

Because ET-1 may exacerbate myocardial ischemia,¹⁹ we assessed LV wall motion acutely in all AMI patients in relationship to CS plasma ET-1. In AMI patients, the level of CS ET-1 correlated with the overall LV wall motion score (R² = 0.51, P = .02; Figure 3). In addition, CS plasma ET-1 also correlated with the number of affected LV segments (R² = 0.53, P = .01). The presence of preinfarction angina in AMI patients had no effect on CS or aortic ET-1 levels (P = NS for both comparisons, data not shown).

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• Figure 3. 

  CS ET-1 levels and left ventricular function in AMI patients. CS ET-1 levels correlated significantly with the echocardiographic left ventricular wall motion score. *P < .05.

Inflammatory cytokines and C-reactive protein in AMI and stable angina 

In stable angina patients, CS C-reactive protein levels were significantly higher than aortic levels (2.3 ± 0.4 mg/L vs 1.8 ± 0.3 mg/L, P = .01). However, patients with AMI exhibited no such difference between the CS and aortic C-reactive protein levels (1.8 ± 0.04 mg/L vs 1.7 ± 0.4 mg/L, P = NS). Interestingly, plasma CS tumor necrosis factor-α levels in stable angina patients were higher than in AMI patients (6.0 ± 1.4 pg/mL vs 2.5 ± 0.9 pg/mL, P = .02; Figure 4). There was a trend towards higher CS tumor necrosis factor-α levels in AMI patients with preinfarction angina (4.1 ± 1.3 pg/mL for preinfarction angina vs 0.9 ± 0.9 pg/mL without preinfarction angina, P = .07), but not for C-reactive protein (1.2 ± 0.1 mg/L vs 2.3 ± 0.7 mg/L, P = NS). In all patients, the levels of interleukin-1β and interleukin-6 from both CS and aortic blood were either undetectable or below the normal range. In AMI patients, there was no correlation between the LV wall motion score and either CS tumor necrosis factor-α or CS C-reactive protein (R² < 0.1, P = NS for both comparisons).

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• Figure 4. 

  Comparison of CS tumour necrosis factor-α (TNF-α) levels of patients with stable angina compared with AMI patients. *P = .02.

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Discussion 

An understanding of locally released vasomotor and inflammatory mediators is a prerequisite to the development of future therapies to improve myocardial salvage in AMI. In our study, the elevated plasma levels of ET-1 in the CS of AMI patients compared to levels in aortic blood indicate a cardiac source of ET-1, released upon atherosclerotic plaque rupture. The correlation between CS ET-1 plasma levels and the extent of myocardial infarction assessed by echocardiography implicate the local release of ET-1 during AMI as an important negative prognostic factor; neither CS C-reactive protein nor tumor necrosis factor-α levels correlated with the severity of myocardial infarction.

ET-1 is a potent vasoconstrictor peptide synthesized in vascular endothelial and smooth muscle cells of the coronary²⁰ and peripheral arterial circulation,²¹ exerting both autocrine and paracrine effects.²² Elevated peripheral levels of ET-1 observed following myocardial infarction²³ have been suggested to exacerbate myocardial ischaemia,¹⁹ in view of high levels of ET-1 in atherosclerotic plaque.⁸ Two receptor subtypes (ET-A and ET-B) mediate the vasomotor effects of ET-1,²² with the ET-A receptor being the major mediator of constriction.²⁴ Exogenous ET-1 induces both macro- and microvascular constriction of coronary²⁵ and peripheral arteries,²⁶ and in coronary artery disease locally produced/released ET-1 is a major contributor to resting coronary tone.²⁷ Cardiac ischaemia increases the production of ET-1,²⁸ which upon release causes microvascular constriction to further impair microvascular reperfusion. Pharmacologic blockade of the ET-A receptor in animal models of myocardial infarction improves myocardial reperfusion,²⁹ supporting a pathophysiological vasoconstrictor role for locally released ET-1.

Previous studies in atherosclerotic subjects have demonstrated elevations of the inflammatory markers tumor necrosis factor-α, interleukin-1β and C-reactive protein, with higher levels associated with an adverse prognosis.¹¹, ¹² Elevated C-reactive protein levels have also been associated with complex atherosclerotic plaque morphology³⁰ typical of the culprit lesions that possess flow-limiting stenoses.³¹ However, because only peripheral blood samples were utilized in assessing these cytokines, it has not been possible to differentiate a local cardiac source of inflammatory cytokines from a generalized systemic response in the atherosclerotic process. In our study, C-reactive protein levels of patients with stable angina were higher in CS than in aortic blood, supporting the assertion that local inflammation is a factor driving the atherosclerotic process.

Our data confirm the heart as an important source of ET-1 in AMI, while also providing evidence of local inflammation in subjects with stable coronary atherosclerosis. We did not, however, find differences in either C-reactive protein or tumor necrosis factor-α between CS and aortic blood in AMI patients. Furthermore, the levels of CS tumor necrosis factor-α were actually lower in AMI patients than in those with stable angina. As abciximab does not interfere with the radioimmunoassay used to measure plasma tumor necrosis factor-α (Taylor, unpublished), a number of factors may have contributed to this finding. The administration of abciximab to all AMI patients in our study may have blunted the tumor necrosis factor-α increase because this drug can suppress its myocardial release by cross-reacting with leukocyte integrin receptors.³² Also, the sympathetic nervous system inhibits myocardial production of tumor necrosis factor-α via activation of β-adrenergic receptors.³³ The combination of a relatively high sympathetic drive in AMI patients,³⁴ coupled with a significantly lower usage of β-blocker drugs in this patient group prior to the angioplasty procedure, could also contribute to a reduction in tumor necrosis factor-α release. Although clopidogrel therapy inhibits C-reactive protein release, the administration of this drug to all patients would rule this out as a likely confounder in our study.³⁵

Release kinetics of inflammatory mediators must also be considered, because C-reactive protein and tumor necrosis factor-α are typically maximally elevated days after AMI,³⁶ with no measurable increase of tumor necrosis factor-α within 9 hours of AMI in peripheral blood despite the early release of interleukin-1β and interleukin-6.³⁷ Recent evidence suggests a role for these cytokines in stimulating the production of C-reactive protein from coronary artery smooth muscle cells.³⁸ Finally, the inflammatory response may be dependent more on the duration of the atherosclerotic process and the extent of the atherosclerotic burden than on the actual clinical mode of presentation. A high proportion of patients presenting with AMI in our study had no antecedent history of symptomatic ischemic heart disease, suggesting that they may represent a group of patients at a relatively early stage of atherosclerotic development. In contrast, atherosclerotic lesions that are flow-limiting are more advanced in their histologic composition than unstable atheroma,³¹ which may be reflected by a greater degree of chronic inflammation. Our observed trend towards lower CS tumor necrosis factor-α levels in AMI patients without preinfarction angina would support this hypothesis.

Microvascular reperfusion in AMI is an essential component of current treatment strategies. The emergence of ET-1 as a potent lesion-derived vasoconstrictor peptide, together with the recognition of atherosclerosis as an inflammatory disease, suggests key roles for released ET-1 and inflammatory cytokines in limiting successful myocardial reperfusion following AMI. Our finding of a close relationship between the extent of left ventricular dysfunction after AMI and local ET-1 release implicates this peptide in the reduction of myocardial perfusion in AMI.

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