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High-throughput targeted proteomics discovery approach and spontaneous reperfusion in ST-segment elevation myocardial infarction.
Shavadia, JS, Granger, CB, Alemayehu, W, Westerhout, CM, Povsic, TJ, Brener, SJ, van Diepen, S, Defilippi, C, Armstrong, PW
American heart journal. 2020;:137-144
Abstract
BACKGROUND Although spontaneous reperfusion (SR) prior to primary percutaneous coronary intervention (pPCI) is associated with improved outcomes, its pathophysiology remains unclear. The objective of the study was to explore associations between SR in ST-segment elevation myocardial infarction (STEMI) using a multimarker cardiovascular proteins strategy METHODS We evaluated STEMI patients from the Assessment of Pexelizumab in Acute Myocardial Infarction trial treated with pPCI within 6 hours from symptom onset. SR was core laboratory-defined as pre-PCI Thrombolysis in Myocardial Infarction flow 2 or 3. Ninety-one cardiovascular disease-related serum biomarkers drawn prior to PCI were analyzed using a high-throughput "targeted discovery" panel. Expression levels for individual biomarkers were compared between patients with/without SR. A hierarchical clustering method of biomarkers identified clusters of biomarkers that differentiated the 2 groups. Associations between individual biomarkers and clusters with SR were further evaluated by multivariable logistic regression. RESULTS Of 683 patients studied, 290 had spontaneous reperfusion; those with compared to without SR were more likely noninferior STEMI and had lower clinical acuity and lower baseline levels of troponin and creatine kinase. SR was associated with a lower occurrence of 90-day composite of death, heart failure, or cardiogenic shock. Fifty-two of 91 individual biomarkers were significantly univariably associated with SR. Forty-five remained significant with adjustment for false discovery rate. Using cluster analysis, 26 biomarkers clusters were identified, explaining 72% of total covariance, and 13 biomarker clusters were significantly associated with SR after multivariable adjustment. SR was associated with higher mean expression levels of proteins in all 13 clusters. The cluster most strongly associated with SR consisted of novel proteins across various distinct, yet interlinked, pathobiological processes (kallikrein-6, matrix extracellular phosphoglycoprotein, matrix mettaloproteinaise-3, and elafin). CONCLUSIONS Spontaneous reperfusion prior to pPCI in STEMI was associated with a lower risk of adverse clinical events. These exploratory data from a targeted discovery proteomics platform identifies novel proteins across diverse, yet complementary, pathobiological axes that show promise in providing mechanistic insights into spontaneous reperfusion in STEMI. CONDENSED ABSTRACT Spontaneous reperfusion has been established with improved STEMI outcomes, yet its pathobiology is unclear and appears to involve diverse physiological processes. Using a 91-biomarker high-throughput proteomics platform, we studied 683 STEMI patients in the APEX AMI trial (290 had core laboratory-adjudicated pre-PCI TIMI 2/3 flow) and identified 52 proteins that univariably associate with spontaneous reperfusion. Cluster analysis identified 26 biomarker clusters (explaining 72% of total variance), 13 of which, after multivariable adjustment, were significantly associated with spontaneous reperfusion. Four proteins (kallikrein-6, matrix extracellular phosphoglycoprotein, matrix mettaloproteinaise-3, and elafin) across diverse, yet complementary, pathways appear to be associated most strongly with spontaneous reperfusion.
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Systemic microvascular dysfunction in microvascular and vasospastic angina.
Ford, TJ, Rocchiccioli, P, Good, R, McEntegart, M, Eteiba, H, Watkins, S, Shaukat, A, Lindsay, M, Robertson, K, Hood, S, et al
European heart journal. 2018;(46):4086-4097
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Abstract
AIMS: Coronary microvascular dysfunction and/or vasospasm are potential causes of ischaemia in patients with no obstructive coronary artery disease (INOCA). We tested the hypothesis that these patients also have functional abnormalities in peripheral small arteries. METHODS AND RESULTS Patients were prospectively enrolled and categorised as having microvascular angina (MVA), vasospastic angina (VSA) or normal control based on invasive coronary artery function tests incorporating probes of endothelial and endothelial-independent function (acetylcholine and adenosine). Gluteal biopsies of subcutaneous fat were performed in 81 subjects (62 years, 69% female, 59 MVA, 11 VSA, and 11 controls). Resistance arteries were dissected enabling study using wire myography. Maximum relaxation to ACh (endothelial function) was reduced in MVA vs. controls [median 77.6 vs. 98.7%; 95% confidence interval (CI) of difference 2.3-38%; P = 0.0047]. Endothelium-independent relaxation [sodium nitroprusside (SNP)] was similar between all groups. The maximum contractile response to endothelin-1 (ET-1) was greater in MVA (median 121%) vs. controls (100%; 95% CI of median difference 4.7-45%, P = 0.015). Response to the thromboxane agonist, U46619, was also greater in MVA (143%) vs. controls (109%; 95% CI of difference 13-57%, P = 0.003). Patients with VSA had similar abnormal patterns of peripheral vascular reactivity including reduced maximum relaxation to ACh (median 79.0% vs. 98.7%; P = 0.03) and increased response to constrictor agonists including ET-1 (median 125% vs. 100%; P = 0.02). In all groups, resistance arteries were ≈50-fold more sensitive to the constrictor effects of ET-1 compared with U46619. CONCLUSIONS Systemic microvascular abnormalities are common in patients with MVA and VSA. These mechanisms may involve ET-1 and were characterized by endothelial dysfunction and enhanced vasoconstriction. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov registration is NCT03193294.
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The REFLO-STEMI trial comparing intracoronary adenosine, sodium nitroprusside and standard therapy for the attenuation of infarct size and microvascular obstruction during primary percutaneous coronary intervention: study protocol for a randomised controlled trial.
Nazir, SA, Khan, JN, Mahmoud, IZ, Greenwood, JP, Blackman, DJ, Kunadian, V, Been, M, Abrams, KR, Wilcox, R, Adgey, AA, et al
Trials. 2014;:371
Abstract
BACKGROUND Microvascular obstruction (MVO) secondary to ischaemic-reperfusion injury is an important but underappreciated determinant of short- and longer-term outcome following percutaneous coronary intervention (PCI) treatment of ST-elevation myocardial infarction (STEMI). Several small studies have demonstrated a reduction in the degree of MVO utilising a variety of vasoactive agents, with adenosine and sodium nitroprusside (SNP) being most evaluated. However, the evidence base remains weak as the trials have had variable endpoints, differing drug doses and delivery. As such, the results regarding benefit are conflicting. METHODS The REperfusion Facilitated by LOcal adjunctive therapy in STEMI (REFLO-STEMI) trial is a multicentre, prospective, randomised, controlled, open label, study with blinded endpoint analysis: Patients presenting within 6 h of onset of STEMI and undergoing planned primary PCI (P-PCI) with TIMI 0/1 flow in the infarct-related artery (IRA) and no significant bystander coronary artery disease on angiography, are randomised into one of three groups: PCI with adjunctive pharmacotherapy (intracoronary adenosine or SNP) or control (standard PCI). All receive Bivalirudin anticoagulation and thrombus aspiration. The primary outcome is infarct size (IS) (determined as a percentage of total left ventricular mass) measured by cardiac magnetic resonance imaging (CMRI) undertaken at 48 to 72 h post P-PCI. Secondary outcome measures include MVO (hypoenhancement within infarct core) on CMRI, angiographic markers of microvascular perfusion and MACE during 1-month follow-up. The study aims to recruit 240 patients (powered at 80% to detect a 5% absolute reduction in IS). DISCUSSION The REFLO-STEMI study has been designed to address the weaknesses of previous trials, which have collectively failed to demonstrate whether adjunctive pharmacotherapy with adenosine and/or SNP can reduce measures of myocardial injury (infarct size and MVO) and improve clinical outcome, despite good basic evidence that they have the potential to attenuate this process. The REFLO-STEMI study will be the most scientifically robust trial to date evaluating whether adjunctive therapy (intracoronary adenosine or SNP following thrombus aspiration) reduces CMRI measured IS and MVO in patients undergoing P-PCI within 6 h of onset of STEMI. TRIAL REGISTRATION Trial registered 20th November 2012: ClinicalTrials.gov Identifier NCT01747174.
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Open-label, randomized, placebo-controlled evaluation of intracoronary adenosine or nitroprusside after thrombus aspiration during primary percutaneous coronary intervention for the prevention of microvascular obstruction in acute myocardial infarction: the REOPEN-AMI study (Intracoronary Nitroprusside Versus Adenosine in Acute Myocardial Infarction).
Niccoli, G, Rigattieri, S, De Vita, MR, Valgimigli, M, Corvo, P, Fabbiocchi, F, Romagnoli, E, De Caterina, AR, La Torre, G, Lo Schiavo, P, et al
JACC. Cardiovascular interventions. 2013;(6):580-9
Abstract
OBJECTIVES This study sought to assess whether intracoronary adenosine or nitroprusside following thrombus aspiration (TA) is superior to TA alone for the prevention of microvascular obstruction (MVO) in ST-segment elevation myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention (PCI). BACKGROUND MVO, due to its multifactorial pathogenesis, still occurs after TA in a sizeable portion of patients. METHODS We performed a placebo-controlled, randomized, open-label, blind-examination, multicenter trial. A total of 240 STEMI patients with Thrombolysis In Myocardial Infarction (TIMI) flow grade 0/1 were randomly allocated 1:1:1 to receive adenosine (n = 80), nitroprusside (n = 80), or saline (n = 80) given distal to the occluded site after TA. The primary endpoint was the incidence of ST-segment resolution (STR) >70% on surface electrocardiogram at 90 min after PCI. Secondary endpoints were angiographic MVO incidence (TIMI flow grade ≤2 or 3 with a myocardial blush grade <2) and major adverse cardiac event (MACE) rate at 30 days as a composite of cardiac death, myocardial infarction, target lesion revascularization, and heart failure requiring hospitalization. RESULTS STR >70% occurred in in 71% of adenosine-treated patients, in 54% of nitroprusside-treated patients, and in 51% of saline-treated patients (p = 0.009 and p = 0.75, respectively, vs. saline). Angiographic MVO occurred in 18% of adenosine-treated patients, in 24% of nitroprusside-treated patients, and in 30% of saline-treated patients (p = 0.06 and p = 0.37, respectively, vs. saline). MACE occurred in 10%, 14%, and 20% of patients, respectively (p = 0.08 and p = 0.29 vs. saline). CONCLUSIONS In STEMI patients treated by PCI and TA, the additional intracoronary administration of adenosine, but not that of nitroprusside, results in a significant improvement of MVO, as assessed by STR.
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Effects of rosuvastatin on coronary flow reserve and metabolic mismatch in patients with heart failure (from the CORONA Study).
van der Harst, P, Slart, RH, Tio, RA, Dunselman, PH, Willemsen, AT, van den Heuvel, AF, Voors, AA, van Veldhuisen, DJ, ,
The American journal of cardiology. 2010;(4):517-21
Abstract
In patients with heart failure (HF), statin treatment might improve myocardial perfusion, but could also have detrimental effects on myocardial metabolism. A predefined substudy of the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) trial sought to determine the effects of statin treatment on myocardial blood flow reserve and cardiac metabolism. Sixteen patients with HF (New York Heart Association class II or III) were randomized to rosuvastatin 10 mg/day (n = 8) or placebo treatment (n = 8). At baseline and after 6 months of treatment, nitrogen-13 ammonia at rest and after dipyridamole stress and 18-fluorodeoxyglucose positron emission tomography were performed. Rosuvastatin treatment significantly lowered total (-36%, p <0.01) and low-density lipoprotein (-47%, p <0.001) cholesterol and C-reactive protein levels (-36%, p <0.05). Myocardial perfusion reserve (ratio) changed from 1.64 +/- 0.90 to 1.30 +/- 0.37 in placebo-treated and from 1.51 +/- 0.18 to 1.55 +/- 0.34 in rosuvastatin-treated patients (p = NS). Metabolic mismatch changed from 4.25 +/- 2.37% to 4.38 +/- 3.81% in placebo-treated and from 5.13 +/- 2.75% to 3.50 +/- 2.73% in rosuvastatin-treated patients (p = NS). In conclusion, changes regarding myocardial perfusion and metabolic mismatch after 6 months of rosuvastatin treatment in patients with HF did not suggest any beneficial or adverse effects in this pilot study, although due to the small numbers of patients small effects might have been missed.
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Relation between leucocyte count, myonecrosis, myocardial perfusion, and outcomes following primary angioplasty.
Prasad, A, Stone, GW, Stuckey, TD, Costantini, CO, Mehran, R, Garcia, E, Tcheng, JE, Cox, DA, Grines, CL, Lansky, AJ, et al
The American journal of cardiology. 2007;(8):1067-71
Abstract
We examined whether leukocytosis is a negative prognostic factor in patients who underwent primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI), and, if so, determined whether it is associated with impaired myocardial perfusion. Previous studies have identified leukocytosis as a predictor of mortality in AMI. Whether this association holds in patients how have undergone primary PCI using contemporary pharmacotherapy and correlates with impaired myocardial perfusion is unknown. Clinical outcomes and reperfusion success, using Thrombolysis In Myocardial Infarction (TIMI) flow and myocardial blush grades, were examined according to tertiles of baseline leukocyte count in 1,268 patients who underwent primary PCI for AMI in the CADILLAC trial. Patients with higher leukocyte count were younger and more likely to be current smokers. Preprocedure TIMI grade 0 flow was more frequent in patients with higher leukocyte counts, but postprocedural TIMI grade 3 flow rates were equally high (>94%) in all 3 groups. Myocardial blush grade 2/3 was achieved at similar rates after PCI in patients with low, intermediate, and high baseline leukocyte counts (52.0% vs 51.5% vs 50.1%, p = 0.8). Higher baseline leukocyte counts were associated with greater myonecrosis (p <0.0001) and increased mortality at 1 year (2.7% vs 4.6% vs 5.4%, respectively, p = 0.047). By multivariate analysis, baseline leukocyte count (in increments of 1,000, hazard ratio 1.07, 95% confidence interval 1.02 to 1.10, p = 0.005) and peak creatine phosphokinase (hazard ratio 1.22, 95% confidence interval 1.14 to 1.29, p <0.001) were independent predictors of 1-year mortality. In conclusion, baseline leukocytosis is an independent correlate of larger infarct and increased mortality after primary PCI in AMI, an effect not explained by decreased myocardial perfusion.
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Effectiveness and safety of the Proxis system in demonstrating retrograde coronary blood flow during proximal occlusion and in capturing embolic material.
Sievert, H, Wahr, DW, Schuler, G, Schofer, JJ, Sutsch, G, Pavliska, J, Skowasch, M
The American journal of cardiology. 2004;(9):1134-9
Abstract
The Feasibility And Safety Trial for its embolic protection device during transluminal intervention in coronary vessels: a European Registry (FASTER) was designed to demonstrate that (1) the Proxis embolic protection system can control anterograde flow and reverse blood flow in native coronary arteries and saphenous vein grafts; and (2) this system can capture embolic debris. Percutaneous coronary intervention on stenotic coronary lesions revolutionized treatment of coronary disease, but is associated with the risk of major adverse cardiac events. This prospective, nonrandomized, multicenter clinical feasibility and safety study enrolled 40 patients with 51 lesions at 4 centers who underwent treatment of stenotic lesions with proximal emboli protection (Proxis system). Proxis was successfully used 95% of the time, and embolic debris was qualitatively identified in all cases. Major adverse cardiac events occurred in 2 patients (5.0%): 1 late in-stent thrombosis resulting in death and 1 non-Q-wave infarction when a lesion was crossed before deployment of the Proxis system. Mean vessel occlusion time was 4.3 +/- 2.4 minutes. Native flow reversal was sufficient in 31 patients, with a mean aspirate volume of 11.8 +/- 6.5 ml. When the infusion catheter was used to augment reflow, mean occlusion time was 4.6 minutes. In conclusion, this trial is the first to demonstrate that retrograde blood flow can be achieved during proximal occlusion and that the Proxis system can be used safely during intervention of saphenous vein grafts and native coronary arterial lesions to capture embolic material.