Jacob Lønborg

Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction.

AIMS Exenatide, a glucagon-like-peptide-1 analogue, increases myocardial salvage in experimental settings with coronary occlusion and subsequent reperfusion. We evaluated the cardioprotective effect of exenatide at the time of reperfusion in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). METHODS AND RESULTS A total of 172 patients with STEMI and Thrombolysis in Myocardial Infarction flow 0/1 were randomly assigned to exenatide or placebo (saline) intravenously. Study treatment was commenced 15 min before intervention and maintained for 6 h after the procedure. The primary endpoint was salvage index calculated from myocardial area at risk (AAR), measured in the acute phase, and final infarct size measured 90 ± 21 days after pPCI by cardiac magnetic resonance (CMR). In 105 patients evaluated with CMR, a significantly larger salvage index was found in the exenatide group than in the placebo group (0.71 ± 0.13 vs. 0.62 ± 0.16; P= 0.003). Infarct size in relation to AAR was also smaller in the exenatide group (0.30 ± 0.15 vs. 0.39 ± 0.15; P= 0.003). In a regression analysis, there was a significant correlation between the infarct size and the AAR for both treatment groups and an analysis of covariance showed that datapoints in the exenatide group lay significantly lower than for the placebo group (P= 0.011). There was a trend towards smaller absolute infarct size in the exenatide group (13 ± 9 vs. 17 ± 14 g; P= 0.11). No difference was observed in left ventricular function or 30-day clinical events. No adverse effects of exenatide were observed. CONCLUSION In patients with STEMI undergoing pPCI, administration of exenatide at the time of reperfusion increases myocardial salvage.

Exenatide Reduces Final Infarct Size in Patients With ST-Segment–Elevation Myocardial Infarction and Short-Duration of Ischemia

Background— Exenatide has been demonstrated to be cardioprotective as an adjunct to primary percutaneous coronary intervention in patients with ST-segment–elevation myocardial infarction (STEMI). The aim of the post hoc analysis study was to evaluate the effect of exenatide in relation to system delay, defined as time from first medical contact to first balloon. Methods and Results— Patients with STEMI and Thrombolysis In Myocardial Infarction flow 0/1 were randomly assigned to intravenous exenatide or placebo continuous infusion. Study treatment was commenced 15 minutes before intervention and maintained for 6 hours after the procedure. The patients were stratified according to median system delay (132 minutes). Final infarct size and myocardial area at risk were measured by cardiovascular magnetic resonance. Among patients with a system delay ⩽132 minutes (n=74), treatment with exenatide resulted in a smaller infarct size (9 grams [interquartile range (IQR), 4–13] versus 13 grams [IQR, 8–24], P=0.008, corresponding to 8% [IQR, 4–12] versus 11% [IQR, 7–17] of the left ventricle, P=0.015). In a regression analysis adjusting for myocardial area at risk the data points of the exenatide group lay significantly lower than for the placebo group (P=0.006). In the patients with system delay >132 minutes (n=74) no difference was observed in infarct size expressed as grams (P=0.49) or percentage (P=0.46). There was significant interaction between system delay (less than or equal to median versus greater than median) and treatment allocation in terms of infarct size (P=0.018). Conclusions— In this post hoc analysis, exenatide treatment was associated with a 30% decrease in final infarct size in patients with short system delay, whereas no cardioprotective effect in patients with long system delay was seen. However, this finding must be confirmed in larger studies. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00835848.

Final infarct size measured by cardiovascular magnetic resonance in patients with ST elevation myocardial infarction predicts long-term clinical outcome: an observational study

AIMS Tailored heart failure treatment and risk assessment in patients following ST-segment elevation myocardial infarction (STEMI) is mainly based on the assessment of the left ventricular (LV) ejection fraction (EF). Assessment of the final infarct size in addition to the LVEF may improve the prognostic evaluation. To evaluate the prognostic importance of the final infarct size measured by cardiovascular magnetic resonance (CMR) in patients with STEMI. METHODS AND RESULTS In an observational study the final infarct size was measured by late gadolinium enhancement CMR 3 months after initial admission in 309 patients with STEMI. The clinical endpoint was a composite of all-cause mortality and admission for heart failure. During the follow-up period of median 807 days (IQR: 669-1117) 35 events (5 non-cardiac deaths, 3 cardiac deaths, and 27 admissions for heart failure) were recorded. Patients with a final infarct size ≥ median had significantly higher event rates than patients with a final infarct size <median (17 vs. 6%; Log rank P = 0.002). In a multivariable Cox regression analysis, including age, peak troponin T, LVEF, LV volume index, and heart rate, the final infarct size remained significantly associated with the occurrence of subsequent events (adjusted hazard ratio 1.13 per 1% increase (95% CI: 1.05-1.21; P = 0.001). The overall Wald χ(2) value of a model including known risk factors was 47.3, which increased to 57.9 when the final infarct size was added (P = 0.001 for the difference). CONCLUSION Assessment of the final infarct size by CMR 3 months after a STEMI provides strong independent prognostic information incremental to known risk factors including the LVEF, and may help to improve the risk stratification of STEMI patients.

Left atrial volume and function in patients following ST elevation myocardial infarction and the association with clinical outcome: a cardiovascular magnetic resonance study

AIMS The left atrium (LA) transfers blood to the left ventricle in a complex manner. LA function is characterized by passive emptying (LA passive fraction), active emptying (LA ejection fraction), and total emptying (LA fractional change). Despite this complexity, the clinical relevance of the LA is based almost exclusively on LA maximal volume (LAmax), which may not glean the full prognostic potential. Cardiovascular magnetic resonance (CMR) is considered the most accurate method for studying LA function and size. The aim of the present study was to evaluate the prognostic importance of LA function in patients following ST elevation myocardial infarction (STEMI). METHODS AND RESULTS In 199 patients, a CMR scan was performed within 1-3 days after STEMI to measure LAmax and minimal volume (LAmin) and LA function. The incidence of death, re-infarction, stroke, and admission for heart failure [major adverse cardiac event (MACE)] were registered during the follow-up period [2.3 years (inter-quartile range: 2.0-2.5)]. A total of 40 patients (20%) met the clinical endpoint of MACE during follow-up. In a Cox regression analysis adjusting for known risk factors, LA fractional change remained independently associated with MACE [adjusted hazard ratio: 0.66 (95% confidence interval: 0.46-0.95)]. LAmax, LAmin, or LA passive fraction was not independently associated with MACE. Furthermore, LA fractional change provided incremental prognostic value to LAmax and other known predictors (Wald χ(2) 31.0 vs. 39.9, P= 0.016). CONCLUSION In STEMI patients, impaired LA fractional change is independently associated with outcome and provide incremental prognostic information to established predictors including LAmax.

Impact of system delay on infarct size, myocardial salvage index, and left ventricular function in patients with ST-segment elevation myocardial infarction.

BACKGROUND The association between reperfusion delay and myocardial damage has previously been assessed by evaluation of the duration from symptom onset to invasive treatment, but results have been conflicting. System delay defined as the duration from first medical contact to first balloon dilatation is less prone to bias and is also modifiable. The purpose was to evaluate the impact of system delay on myocardial salvage index (MSI) and infarct size in patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention (PCI). METHODS In patients with ST-elevation myocardial infarction, MSI and final infarct size were assessed using cardiovascular magnetic resonance. Myocardial area at risk was measured within 1 to 7 days, and final infarct size was measured 90 ± 21 days after intervention. Patients were grouped according to system delay (0 to 120, 121 to 180, and >180 minutes). RESULTS In 219 patients, shorter system delay was associated with a smaller infarct size (8% [interquartile range 4-12%], 10% [6-16%], and 13% [8-17%]; P < .001) and larger MSI (0.77 [interquartile range 0.66-0.86], 0.72 [0.59-0.80], and 0.68 [0.64-0.72]; P = .005) for a system delay of up to 120, 121 to 180, and >180 minutes, respectively. A short system delay as a continuous variable independently predicted a smaller infarct size (r = 0.30, P < .001) and larger MSI (r = -0.25, P < .001) in multivariable linear regression analyses. Finally, shorter system delay (0-120 minutes) was associated with improved function (P = .019) and volumes of left ventricle (P = .022). CONCLUSIONS A shorter system delay resulted in smaller infarct size, larger MSI, and improved LV function in patients treated with primary PCI. Thus, this study confirms that minimizing system delay is crucial for primary PCI-related benefits.

ST-Segment resolution and clinical outcome with ischemic postconditioning and comparison to magnetic resonance

BACKGROUND Ischemic postconditioning (IPost) during primary percutaneous coronary intervention (PPCI) is suggested to reduce myocardial damage. However, the association with ST-segment resolution (STR) and clinical outcome is not determined. The primary aim of this study was to evaluate the association of IPost with STR and clinical outcome. Secondly, we sought to determine the relationship between STR and cardiac magnetic resonance (CMR) parameters in these patients. METHODS One hundred eighteen patients referred for PPCI were randomly assigned to either conventional PPCI or PPCI with IPost. In a single electrocardiographic lead, STR was determined. Treatment modalities were compared as regards STR, ST-segment elevation, and the number of patients achieving complete-STR (≥70%), incomplete-STR (30%-70%), and no-STR (<30%). Patients were evaluated for clinical outcome after 15 months. Furthermore, patients with and without complete-STR were compared as regards CMR parameters. RESULTS There was a tendency toward a better outcome with IPost for the number of patients achieving complete-STR (55% vs 63%; P=.09), ST-segment elevation (1.41 vs 1.12 mm; P=.07), and New York Heart Association class (P=.06). No difference in other cardiac events was observed. Furthermore, data determine that patients with complete-STR have smaller infarct size (12.9% vs 21.1%; P<.01) and a better ejection fraction (55.7% vs 47.7%; P<.01). CONCLUSIONS Patients treated with IPost are suggested to have improved STR and New York Heart Association classification. Infarct size and the functional CMR parameters were better in the patients with complete-STR; as to this, single-lead STR remains an important predictor for successful treatment in patients treated with IPost.

Deferred stent implantation in patients with ST-segment elevation myocardial infarction: a pilot study

AIMS Disturbance in the flow of an infarct-related artery due to embolisation of thrombus and plaque material occurs frequently during primary percutaneous coronary intervention (PCI) and is associated with impaired prognosis. The aim of the present study was to minimise the risk of embolisation during PCI in patients with ST-segment elevation myocardial infarction (STEMI). METHODS AND RESULTS Of 124 consecutive patients with STEMI, thrombectomy and/or balloon dilatation was performed in 110 (89%). Stent implantation was deferred in 113 (91%) patients who then comprised the study group. In 38% of the patients stent implantation was deemed unnecessary at the second examination because of <30% residual stenosis and no visible thrombus, and all lesions re-examined three months later were patent. Major adverse cardiac events occurred in two patients during eight months of follow-up (one cardiac death, one case of reinfarction with target lesion revascularisation). In five patients no PCI was performed at all. Myocardial salvage determined by cardiac magnetic resonance in a subset of patients was relatively high. CONCLUSIONS Deferred stent implantation is safe in the majority of patients with STEMI. Although the concept has to be evaluated in a randomised trial, the strategy may prove beneficial for many patients referred for primary PCI.

Impact of Acute Hyperglycemia on Myocardial Infarct Size, Area at Risk, and Salvage in Patients With STEMI and the Association With Exenatide Treatment: Results From a Randomized Study

Hyperglycemia upon hospital admission in patients with ST-segment elevation myocardial infarction (STEMI) occurs frequently and is associated with adverse outcomes. It is, however, unsettled as to whether an elevated blood glucose level is the cause or consequence of increased myocardial damage. In addition, whether the cardioprotective effect of exenatide, a glucose-lowering drug, is dependent on hyperglycemia remains unknown. The objectives of this substudy were to evaluate the association between hyperglycemia and infarct size, myocardial salvage, and area at risk, and to assess the interaction between exenatide and hyperglycemia. A total of 210 STEMI patients were randomized to receive intravenous exenatide or placebo before percutaneous coronary intervention. Hyperglycemia was associated with larger area at risk and infarct size compared with patients with normoglycemia, but the salvage index and infarct size adjusting for area at risk did not differ between the groups. Treatment with exenatide resulted in increased salvage index both among patients with normoglycemia and hyperglycemia. Thus, we conclude that the association between hyperglycemia upon hospital admission and infarct size in STEMI patients is a consequence of a larger myocardial area at risk but not of a reduction in myocardial salvage. Also, cardioprotection by exenatide treatment is independent of glucose levels at hospital admission. Thus, hyperglycemia does not influence the effect of the reperfusion treatment but rather represents a surrogate marker for the severity of risk and injury to the myocardium.

Influence of pre-infarction angina, collateral flow, and pre-procedural TIMI flow on myocardial salvage index by cardiac magnetic resonance in patients with ST-segment elevation myocardial infarction

BACKGROUND In patients with ST-segment elevation myocardial infarction (STEMI) pre-infarction angina, pre-procedural TIMI flow and collateral flow to the myocardium supplied by the infarct related artery are suggested to be cardioprotective. We evaluated the effect of these factors on myocardial salvage index (MSI) and infarct size adjusting for area at risk in patients with STEMI treated with primary percutaneous coronary intervention. METHODS AND RESULTS Cardiac magnetic resonance (CMR) was used to measure myocardial area at risk within 1-7 days and final infarct size 90 ± 21 days after the STEMI in 200 patients. MSI was calculated as (area-at-risk infarct size) / area-at-risk. Patients with pre-infarction angina had a median MSI of 0.80 (IQR 0.67 to 0.86) versus 0.72 (0.61 to 0.80) in those without pre-infarction angina, P = 0.004). In a regression analysis of the infarct size plotted against the area-at-risk there was a strong trend that the line for the pre-infarction angina group was below the one for the non-angina group (P = 0.05). Patients with pre-procedural TIMI flow 0/1, 2 and 3 had a median MSI of (0.69 (IQR 0.59 to 0.76), 0.78 (0.68 to 0.86) and 0.85 (0.77 to 0.91), respectively (P<0.001). Collateral flow did not change MSI (P = 0.45) nor area-at-risk (P = 0.40) and no significant difference in infarct size adjusted for area at risk (P = 0.25) was observed. CONCLUSIONS Pre-infarction angina increases MSI in patients with STEMI supporting the theory that pre-infarction angina leads to ischemic preconditioning. As opposed to the presence of angiographically visible collateral flow to the infarct area pre-procedural TIMI flow is strongly associated with MSI.

Targeting reperfusion injury in the era of primary percutaneous coronary intervention: hope or hype?

Introduction of reperfusion therapy by primary percutaneous coronary intervention (PCI) has resulted in improved outcomes for patients presenting with ST-segment elevation myocardial infarction. Despite the obvious advantages of primary PCI, acute restoration of blood flow paradoxically also jeopardises the myocardium in the first minutes of reperfusion—a phenomenon known as reperfusion injury. Prevention of reperfusion injury may help to improve outcome following primary PCI. This review focuses on the clinical evidence of potential therapeutic cardioprotective methods as adjuvant to primary PCI. Despite overall disappointing, there exists some promising strategies, including ischaemic postconditioning, remote ischaemic conditioning, pharmacological conditioning with focus on adenosine, cyclosporine A, glucose–insulin–potassium, exenatide, atrial natriuretic peptide and metoprolol and cooling. But hitherto no large randomised study has demonstrated any effect on outcome, and ongoing studies that address this issue are underway. Moreover, this review will discuss important clinical predictors associated with reperfusion injury during primary PCI that may interfere with a potential protective effect (pre-PCI thrombolysis in myocardial infarction flow, preinfarction angina, collateral flow, duration of ischaemia and hyperglycaemia). This paper will also provide a short overview of the technical issues related to surrogate endpoints in phase II trials. Based upon these discussions, the paper will provide factors that should be taken into account when designing future clinical studies.