[Uncommon tumor-associated deep vein thrombosis]. / Eine nicht alltägliche tumorassoziierte Thrombose.

Here, we report on a patient with deep vein thrombosis of the right leg, in whom diagnostic work-up revealed a previously unknown chondrosarcoma of the tibia. Physical examination revealed a firm, nondisplaceable mass on the dorsal side of the right knee that appeared as a cystic formation on ultrasound. X­ray, computed tomography, and magnetic resonance imaging were consistent with chondrosarcoma, which had likely provoked the thrombosis by local compression or paraneoplastic mechanisms. After resection of the tumor, anticoagulation was continued. In a review of all findings, a final diagnosis of highly differentiated chondrosarcoma with thrombosis of the popliteal vein was made.

Plasma Concentrations of Myeloid-Derived Growth Factor in Healthy Individuals and Patients with Acute Myocardial Infarction as Assessed by Multiple Reaction Monitoring-Mass Spectrometry.

Myeloid-derived growth factor (MYDGF in humans, Mydgf in mice) is a secreted protein with previously unknown biological functions. In a recent study, Mydgf was shown to mediate cardiac repair after acute myocardial infarction (MI) in mice. Lack of a sensitive assay to measure MYDGF in the circulation has hampered its further investigation. Here, we developed a liquid chromatography/multiple reaction monitoring-mass spectrometry MYDGF assay, employing SDS-PAGE-based protein fractionation to deplete high-abundant proteins and a stable isotope-labeled synthetic standard peptide for quantification. The assay had a lower limit of quantification of 0.8 ng/mL and a linear range up to 190 ng/mL. Within-run and total imprecision ranged from 8 to 17% and 11 to 20%, respectively. MYDGF plasma concentrations were not affected by either storage at room temperature for 4 h or up to three freeze-thaw cycles. Apparently healthy adults presented with a median (range) MYDGF concentration of 3.3 (1.3-6.7) ng/mL ( n = 120). MYDGF concentrations were elevated 2.7-fold ( P < 0.001) in patients with acute MI ( n = 101) and were associated with inflammatory biomarkers, renal dysfunction, and long-term cardiovascular mortality. The new assay and the favorable preanalytic characteristics of the analyte will facilitate studies into the pathophysiology of MYDGF and its potential use as a biomarker or protein therapeutic in patients with acute MI or other disease states.

Fibroblast activation protein alpha expression identifies activated fibroblasts after myocardial infarction.

INTRODUCTION: Fibroblast activation protein α (FAP) is a membrane-bound serine protease expressed by activated fibroblasts during wound healing in the skin. Expression of FAP after myocardial infarction (MI) and potential effects on cardiac wound healing are largely unknown. METHODS: MI was induced in rats and FAP expression was analyzed at 3, 7 and 28 days post-MI by microarray, Western blot and immunohistochemistry. In human hearts after MI, a FAP(+) fibroblast population was identified, and characterized by immunohistochemistry for prolyl-4-hydroxylase ß, α-smooth muscle actin, Thy-1 and vimentin. Signaling pathways leading to FAP expression were studied in human cardiac fibroblasts by Western blot and ELISA using TGFß1, TGF-beta type I-receptor (TGFbR1)-inhibitor SB431542 or the MAPK-inhibitor U0126 as well as siRNA targeting SMAD2 and SMAD3. Finally, fibroblasts were assayed for FAP-dependent migration (modified Boyden-chamber), proliferation (BrdU-assay) and gelatinolytic activity by gelatin zymography. RESULTS: In rats, FAP expression was increased after MI especially in the peri-infarct area peaking at 7 days post-MI. Co-localization analysis identified the majority of FAP(+) cells as activated proto-myofibroblasts and myofibroblasts. Concordantly, FAP(+) fibroblasts were abundant in ischemic tissue of human hearts after MI, but not in healthy control hearts. In vitro, FAP was induced by TGFß1 via the canonical SMAD2/SMAD3 pathway. Depletion of FAP in fibroblasts reduced migratory capacity, while proliferation was not affected. Gelatin zymography revealed gelatinase activity by fibroblast-derived FAP. CONCLUSION: In this study, we show for the first time the expression of FAP in activated fibroblasts after MI and its activation by TGFß1. Effects of FAP on fibroblast migration and gelatinolytic activity indicate a potential role in cardiac wound healing and remodeling.

Molecular Imaging of Myocardial Fibroblast Activation in Patients with Advanced Aortic Stenosis Before Transcatheter Aortic Valve Replacement: A Pilot Study.

Using multimodal imaging, we investigated the extent and functional correlates of myocardial fibroblast activation in patients with aortic stenosis (AS) scheduled for transcatheter aortic valve replacement (TAVR). AS may cause myocardial fibrosis, which is associated with disease progression and may limit response to TAVR. Novel radiopharmaceuticals identify upregulation of fibroblast activation protein (FAP) as a cellular substrate of cardiac profibrotic activity. Methods: Twenty-three AS patients underwent 68Ga-FAP inhibitor 46 (68Ga-FAPI) PET, cardiac MRI, and echocardiography within 1-3 d before TAVR. Imaging parameters were correlated and then were integrated with clinical and blood biomarkers. Control cohorts of subjects without a history of cardiac disease and with (n = 5) and without (n = 9) arterial hypertension were compared with matched AS subgroups. Results: Myocardial FAP volume varied significantly among AS subjects (range, 1.54-138 cm3, mean ± SD, 42.2 ± 35.6 cm3) and was significantly higher than in controls with (7.42 ± 8.56 cm3, P = 0.007) and without (2.90 ± 6.67 cm3; P < 0.001) hypertension. FAP volume correlated with N-terminal prohormone of brain natriuretic peptide (r = 0.58, P = 0.005), left ventricular ejection fraction (r = -0.58, P = 0.02), mass (r = 0.47, P = 0.03), and global longitudinal strain (r = 0.55, P = 0.01) but not with cardiac MRI T1 (spin-lattice relaxation time) and extracellular volume (P = not statistically significant). In-hospital improvement in left ventricular ejection fraction after TAVR correlated with pre-TAVR FAP volume (r = 0.440, P = 0.035), N-terminal prohormone of brain natriuretic peptide, and strain but not with other imaging parameters. Conclusion: FAP-targeted PET identifies varying degrees of left ventricular fibroblast activation in TAVR candidates with advanced AS. 68Ga-FAPI signal does not match other imaging parameters, generating the hypothesis that it may become useful as a tool for personalized selection of optimal TAVR candidates.

Circulating fibroblast activation protein α is reduced in acute ischemic stroke.

Background: Fibroblast activation protein α (FAP), a membrane glycoprotein with dipeptidyl-peptidase and collagenase properties, is expressed in atherosclerotic plaques and remodeling of the extracellular matrix based on fibrosis. Fibrosis is a main contributor of atrial cardiomyopathies. In acute MI, circulating FAP is associated with outcome. Here, we investigated the correlation of circulating FAP to echocardiographic parameters of atrial remodeling and neurological impairment in acute ischemic stroke. Methods: Circulating FAP plasma concentrations were determined by ELISA in 47 patients with acute stroke and 22 control patients without stroke. Echocardiography was performed in all participants. Laboratory analysis, National Institutes of Health Stroke Scale (NIHSS) scoring and prolonged Holter-ECG-monitoring were performed in all stroke patients. Results: Patients with acute stroke had lower circulating FAP concentrations than the control cohort (92 ± 24 vs. 106 ± 22 ng/mL, P < 0.001). There was no difference between the circulating FAP concentration comparing stroke due to atrial fibrillation, embolic stroke of undetermined source (ESUS) or atherosclerotic origin. Septal atrial conduction time (sPA-TDI) and left atrial (LA) volume index to tissue Doppler velocity (LAVI/a') representing echocardiographic parameters of LA remodeling did not correlate with FAP concentrations (sPA-TDI: r = 0.123, p = 0.31; LAVI/a': r = 0.183, p = 0.132). Stroke severity as assessed by NIHSS inversely correlated with circulating FAP (r = -0.318, p = 0.04). FAP concentration had a fair accuracy for identifying stroke in the receiver operating characteristic (ROC) analysis (AUC = 0.710, 95% CI: 0.577-0.843). A FAP concentration of 101 ng/mL discriminated between presence and absence of stroke with a sensitivity of 72% and a specificity of 77%. Lower circulating FAP concentration was associated with cardio-cerebro-vascular events within 12 months after admission. Conclusions: Our study is the first to associate FAP with echocardiographic parameters of LA-remodeling and function. FAP did not correlate with sPA-TDI and LAVI/a'. However, FAP was associated with stroke, neurological impairment, and cardio-cerebral events within 12 months. Therefore, FAP might enable individualized risk stratification in ischemic stroke.

Cardiac Fibroblast Activation in Patients Early After Acute Myocardial Infarction: Integration with MR Tissue Characterization and Subsequent Functional Outcome.

After acute myocardial infarction (AMI), fibroblast activation protein (FAP) upregulation exceeds the infarct region. We sought further insights into the physiologic relevance by correlating FAP-targeted PET with tissue characteristics from cardiac MRI (CMR) and functional outcome. Methods: Thirty-five patients underwent CMR, perfusion SPECT, and 68Ga-FAP inhibitor (FAPI)-46 PET/CT within 11 d after AMI. Infarct size was determined from SPECT by comparison to a reference database. For PET, regional SUVs and isocontour volumes of interest determined the extent of cardiac FAP upregulation (FAP volume). CMR yielded functional parameters, area of injury (late gadolinium enhancement [LGE]) and T1/T2 mapping. Follow-up was available from echocardiography or CMR after 139.5 d (interquartile range, 80.5-188.25 d) (n = 14). Results: The area of FAP upregulation was significantly larger than the SPECT perfusion defect size (58% ± 15% vs. 23% ± 17%, P < 0.001) and infarct area by LGE (28% ± 11%, P < 0.001). FAP volume significantly correlated with CMR parameters at baseline (all P < 0.001): infarct area (r = 0.58), left ventricle (LV) mass (r = 0.69), end-systolic volume (r = 0.62), and end-diastolic volume (r = 0.57). Segmental analysis revealed FAP upregulation in 308 of 496 myocardial segments (62%). Significant LGE was found in only 56% of FAP-positive segments, elevated T1 in 74%, and elevated T2 in 68%. Fourteen percent (44/308) of FAP-positive segments exhibited neither prolonged T1 or T2 nor significant LGE. Of note, FAP volume correlated only weakly with simultaneously measured LV ejection fraction at baseline (r = -0.32, P = 0.07), whereas there was a significant inverse correlation with LV ejection fraction obtained at later follow-up (r = -0.58, P = 0.007). Conclusion: Early after AMI and reperfusion therapy, activation of fibroblasts markedly exceeds the hypoperfused infarct region and involves noninfarcted myocardium. The 68Ga-FAPI PET signal does not match regional myocardial tissue characteristics as defined by CMR but is predictive of the evolution of ventricular dysfunction. FAP-targeted imaging may provide a novel biomarker of LV remodeling that is complementary to existing techniques.

Formation of large coronary arteries by cardiac progenitor cells.

Coronary artery disease is the most common cause of cardiac failure in the Western world, and to date there is no alternative to bypass surgery for severe coronary atherosclerosis. We report that c-kit-positive cardiac progenitor cells (CPCs) activated with insulin-like growth factor 1 and hepatocyte growth factor before their injection in proximity of the site of occlusion of the left coronary artery in rats, engrafted within the host myocardium forming temporary niches. Subsequently, CPCs divided and differentiated into endothelial cells and smooth muscle cells and, to a lesser extent, into cardiomyocytes. The acquisition of vascular lineages appeared to be mediated by the up-regulation of hypoxia-inducible factor 1alpha, which promoted the synthesis and secretion of stromal-derived factor 1 from hypoxic coronary vessels. Stromal-derived factor 1 was critical in the conversion of CPCs to the vascular fate. CPCs formed conductive and intermediate-sized coronary arteries together with resistance arterioles and capillaries. The new vessels were connected with the primary coronary circulation, and this increase in vascularization more than doubled myocardial blood flow in the infarcted myocardium. This beneficial effect, together with myocardial regeneration attenuated postinfarction dilated myopathy, reduced infarct size and improved function. In conclusion, locally delivered activated CPCs generate de novo coronary vasculature and may be implemented clinically for restoration of blood supply to the ischemic myocardium.

Genetic ablation of fibroblast activation protein alpha attenuates left ventricular dilation after myocardial infarction.

INTRODUCTION: Regulating excessive activation of fibroblasts may be a promising target to optimize extracellular matrix deposition and myocardial stiffness. Fibroblast activation protein alpha (FAP) is upregulated in activated fibroblasts after myocardial infarction (MI), and alters fibroblast migration in vitro. We hypothesized that FAP depletion may have a protective effect on left ventricular (LV) remodeling after MI. MATERIALS AND METHODS: We used the model of chronic MI in homozygous FAP deficient mice (FAP-KO, n = 51) and wild type mice (WT, n = 55) to analyze wound healing by monocyte and myofibroblast infiltration. Heart function and remodeling was studied by echocardiography, morphometric analyses including capillary density and myocyte size, collagen content and in vivo cell-proliferation. In non-operated healthy mice up to 6 months of age, morphometric analyses and collagen content was assessed (WT n = 10, FAP-KO n = 19). RESULTS: Healthy FAP-deficient mice did not show changes in LV structure or differences in collagen content or cardiac morphology. Infarct size, survival and cardiac function were not different between FAP-KO and wildtype mice. FAP-KO animals showed less LV-dilation and a thicker scar, accompanied by a trend towards lower collagen content. Wound healing, assessed by infiltration with inflammatory cells and myofibroblasts were not different between groups. CONCLUSION: We show that genetic ablation of FAP does not impair cardiac wound healing, and attenuates LV dilation after MI in mice. FAP seems dispensable for normal cardiac function and homeostasis.

Molecular imaging of fibroblast activation protein after myocardial infarction using the novel radiotracer [68Ga]MHLL1.

Background: Myocardial infarction (MI) evokes an organized remodeling process characterized by the activation and transdifferentiation of quiescent cardiac fibroblasts to generate a stable collagen rich scar. Early fibroblast activation may be amenable to targeted therapy, but is challenging to identify in vivo. We aimed to non-invasively image active fibrosis by targeting the fibroblast activation protein (FAP) expressed by activated (myo)fibroblasts, using a novel positron emission tomography (PET) radioligand [68Ga]MHLL1 after acute MI. Methods: One-step chemical synthesis and manual as well as module-based radiolabeling yielded [68Ga]MHLL1. Binding characteristics were evaluated in murine and human FAP-transfected cells, and stability tested in human serum. Biodistribution in healthy animals was interrogated by dynamic PET imaging, and metabolites were measured in blood and urine. The temporal pattern of FAP expression was determined by serial PET imaging at 7 d and 21 d after coronary artery ligation in mice as percent injected dose per gram (%ID/g). PET measurements were validated by ex vivo autoradiography and immunostaining for FAP and inflammatory macrophages. Results: [68Ga]MHLL1 displayed specific uptake in murine and human FAP-positive cells (p = 0.0208). In healthy mice the tracer exhibited favorable imaging characteristics, with low blood pool retention and dominantly renal clearance. At 7 d after coronary artery ligation, [68Ga]MHLL1 uptake was elevated in the infarct relative to the non-infarcted remote myocardium (1.3 ± 0.3 vs. 1.0 ± 0.2 %ID/g, p < 0.001) which persisted to 21 d after MI (1.3 ± 0.4 vs. 1.1 ± 0.4 %ID/g, p = 0.013). Excess unlabeled compound blocked tracer accumulation in both infarct and non-infarct remote myocardium regions (p < 0.001). Autoradiography and histology confirmed the regional uptake of [68Ga]MHLL1 in the infarct and especially border zone regions, as identified by Masson trichrome collagen staining. Immunostaining further delineated persistent FAP expression at 7 d and 21 d post-MI in the border zone, consistent with tracer distribution in vivo. Conclusion: The simplified synthesis of [68Ga]MHLL1 bears promise for non-invasive characterization of fibroblast activation protein early in remodeling after MI.

Activation of cardiac progenitor cells reverses the failing heart senescent phenotype and prolongs lifespan.

Heart failure is the leading cause of death in the elderly, but whether this is the result of a primary aging myopathy dictated by depletion of the cardiac progenitor cell (CPC) pool is unknown. Similarly, whether current lifespan reflects the ineluctable genetic clock or heart failure interferes with the genetically determined fate of the organ and organism is an important question. We have identified that chronological age leads to telomeric shortening in CPCs, which by necessity generate a differentiated progeny that rapidly acquires the senescent phenotype conditioning organ aging. CPC aging is mediated by attenuation of the insulin-like growth factor-1/insulin-like growth factor-1 receptor and hepatocyte growth factor/c-Met systems, which do not counteract any longer the CPC renin-angiotensin system, resulting in cellular senescence, growth arrest, and apoptosis. However, pulse-chase 5-bromodeoxyuridine-labeling assay revealed that the senescent heart contains functionally competent CPCs that have the properties of stem cells. This subset of telomerase-competent CPCs have long telomeres and, following activation, migrate to the regions of damage, where they generate a population of young cardiomyocytes, reversing partly the aging myopathy. The senescent heart phenotype and heart failure are corrected to some extent, leading to prolongation of maximum lifespan.

The young mouse heart is composed of myocytes heterogeneous in age and function.

The recognition that the adult heart continuously renews its myocyte compartment raises the possibility that the age and lifespan of myocytes does not coincide with the age and lifespan of the organ and organism. If this were the case, myocyte turnover would result at any age in a myocardium composed by a heterogeneous population of parenchymal cells which are structurally integrated but may contribute differently to myocardial performance. To test this hypothesis, left ventricular myocytes were isolated from mice at 3 months of age and the contractile, electrical, and calcium cycling characteristics of these cells were determined together with the expression of the senescence-associated protein p16(INK4a) and telomere length. The heart was characterized by the coexistence of young, aged, and senescent myocytes. Old nonreplicating, p16(INK4a)-positive, hypertrophied myocytes with severe telomeric shortening were present together with young, dividing, p16(INK4a)-negative, small myocytes with long telomeres. A class of myocytes with intermediate properties was also found. Physiologically, evidence was obtained in favor of the critical role that action potential (AP) duration and I(CaL) play in potentiating Ca(2+) cycling and the mechanical behavior of young myocytes or in decreasing Ca(2+) transients and the performance of senescent hypertrophied cells. The characteristics of the AP appeared to be modulated by the transient outward K(+) current I(to) which was influenced by the different expression of the K(+) channels subunits. Collectively, these observations at the physiological and structural cellular level document that by necessity the heart has to constantly repopulate its myocyte compartment to replace senescent poorly contracting myocytes with younger more efficient cells. Thus, cardiac homeostasis and myocyte turnover regulate cardiac function.

Adolescent feline heart contains a population of small, proliferative ventricular myocytes with immature physiological properties.

Recent studies suggest that rather than being terminally differentiated, the adult heart is a self-renewing organ with the capacity to generate new myocytes from cardiac stem/progenitor cells (CS/PCs). This study examined the hypotheses that new myocytes are generated during adolescent growth, to increase myocyte number, and these newly formed myocytes are initially small, mononucleated, proliferation competent, and have immature properties. Ventricular myocytes (VMs) and cKit(+) (stem cell receptor) CS/PCs were isolated from 11- and 22-week feline hearts. Bromodeoxyuridine incorporation (in vivo) and p16(INK4a) immunostaining were measured to assess myocyte cell cycle activity and senescence, respectively. Telomerase activity, contractions, Ca(2+) transients, and electrophysiology were compared in small mononucleated (SMMs) and large binucleated (LBMs) myocytes. Heart mass increased by 101% during adolescent growth, but left ventricular myocyte volume only increased by 77%. Most VMs were binucleated (87% versus 12% mononucleated) and larger than mononucleated myocytes. A greater percentage of SMMs was bromodeoxyuridine positive (SMMs versus LBMs: 3.1% versus 0.8%; P<0.05), and p16(INK4a) negative and small myocytes had greater telomerase activity than large myocytes. Contractions and Ca(2+) transients were prolonged in SMMs versus LBMs and Ca(2+) release was disorganized in SMMs with reduced transient outward current and T-tubule density. The T-type Ca(2+) current, usually seen in fetal/neonatal VMs, was found exclusively in SMMs and in myocytes derived from CS/PC. Myocyte number increases during adolescent cardiac growth. These new myocytes are initially small and functionally immature, with patterns of ion channel expression normally found in the fetal/neonatal period.

Impact of different bone marrow cell preparations on left ventricular remodelling after experimental myocardial infarction.

OBJECTIVE: Bone marrow (BM)-derived haematopoietic stem cells have been proposed as a potential cell source to functionally engraft the myocardium and to improve cardiac function after myocardial infarction (MI). However, experimental and clinical data are inconsistent. Since the specific characteristics of different BM cell subsets could influence their therapeutic potential we determined the effect of different BM cell populations on left ventricular remodelling after MI. METHODS AND RESULTS: MI was induced in female mice by coronary artery ligation. Surviving mice were randomised to receive either: total BM, mature Lin(+) or primitive Lin(-) cells from male mice, or saline, via intracardiac injection. Injected cells were detected in the infarct and border zone by PCR for Y-chromosomal sequences. Serial transthoracic echocardiography was performed 1, 21, and 42 days after MI. Over a period of 6 weeks, mortality was not different between the groups. After MI, animals exhibited left ventricular dilatation, as expected. Left ventricular remodelling was not influenced by Lin(+) or Lin(-) BM cells but was partially improved by unfractionated BM cell injection. Paracrine secretion of cytokines (e.g. IL-6, GM-CSF) was differentially regulated in supernatants of cultured BM cells. SUMMARY: Treatment with unfractionated BM cells, but not Lin(+), or Lin(-) cells partially improved cardiac remodelling and function after MI. This may be mediated by paracrine effects.

One-year outcomes with the HeartMate 3 left ventricular assist device.

BACKGROUND: The HeartMate 3 (HM3; Abbott Laboratories, Lake Forest, Ill) left ventricular assist device (LVAD) received its Conformité Européenne mark for Europe in October 2015 and is currently under investigation of the Food and Drug Administration to gain approval in the United States. Within this study, we present the first real-world experiences, 1-year outcomes, and adverse events of a single-center cohort treated with the HM3. METHODS: We prospectively studied midterm results of 27 consecutive patients receiving the HM3 at a single institution. After HM 3 implantation, survival, causes of death, and complications were recorded for all patients. Follow up was 100% complete. RESULTS: Twenty-seven patients were enrolled into the study. Within 1 year after HM3 implantation, 3 patients underwent heart transplantation and 3 patients died. Thirty-day survival was 88.9%, 6-month 85.2%, and 1-year survival 85.2%. No pump thrombosis and no strokes were observed within the study group. One incident of gastrointestinal bleeding was observed (3.7%). Right heart failure was diagnosed in 1 patient after HM3 implantation (3.7%). No technical complications of the pump were documented. No pump exchanges were necessary. The main complication was LVAD-related infection (22.2%). CONCLUSIONS: The novel LVAD HM3 has already shown excellent Conformité Européenne mark trial results. Within this cohort, 1-year survival after HM3 implantation was 85%. The HM3 showed excellent midterm results with 0% stroke and 0% pump thrombosis rates 1 year after implantation.

Changes in concentrations of circulating fibroblast activation protein alpha are associated with myocardial damage in patients with acute ST-elevation MI.

BACKGROUND: Fibroblast activation protein alpha (FAP) is a membrane-bound serine protease expressed by activated fibroblasts after myocardial infarction (MI). Reduced circulating FAP levels were associated with increased mortality in patients with acute coronary syndrome. We hypothesized that FAP concentrations are altered after acute ST-elevation MI (STEMI), and related to myocardial damage. METHODS: We measured circulating FAP concentrations in blood plasma of 60 patients on admission, day 1, day 3 and day 5 after STEMI, and in 25 apparently healthy blood donors as controls. RESULTS: Plasma FAP concentrations were lower in STEMI patients on admission (71ng/mL) than in blood donors (101ng/mL, P<0.0001). FAP concentrations declined in STEMI patients from admission to day 3 (66ng/mL, P<0.05) and day 5 (57ng/mL, P<0.05). FAP concentrations on day 5 were inversely correlated with maximum CK and maximum CRP levels. In a multiple linear regression analysis, maximum CRP was independently associated with low FAP concentrations on day 5 after STEMI. When stratified according to the absolute amount of FAP change from admission to day 5 (ΔFAP), patients with high ΔFAP (-22ng/mL) had worse left ventricular function, higher levels of hs-cTnT, CK on admission, maximum CK and CRP than patients with low ΔFAP (-3ng/mL). CONCLUSIONS: Our study first demonstrates alterations of circulating FAP concentrations acutely after STEMI. A greater decline of circulating FAP concentrations in the first 5days after STEMI is associated with increased myocardial damage and inflammation. Measurement of circulating FAP might help to better understand the relation of myocardial injury and inflammatory response in the individual patient.

Efficacy of prasugrel administration immediately after percutaneous coronary intervention in ST-elevation myocardial infarction.

Prasugrel, a potent thienopyridine, achieves stronger inhibition of platelet activation than clopidogrel. However, onset of inhibition is significantly delayed in patients with acute ST-elevation myocardial infarction (STEMI), as haemodynamic instability and morphine application seem to exhibit significant influence. Since rapid onset of effect was demonstrated in non-STEMI patients when prasugrel was administered only after percutaneous coronary intervention (PCI) without increasing cardiovascular event rates we assessed the efficacy of prasugrel loading immediately after PCI for STEMI instead of pre-loading before revascularisation. We investigated 50 consecutive patients with acute STEMI (mean age 56 ± 10 years) admitted for primary PCI. Prasugrel efficacy was assessed by platelet reactivity index (PRI; VASP assay) before, 1, 2, 4, 6, 12, and 24 hours following an oral loading dose of 60 mg immediately after PCI. High on-treatment platelet reactivity (HTPR) was defined as PRI>50 %. Prasugrel significantly and rapidly reduced platelet reactivity in acute STEMI patients (p<0.0001 at each time point vs control). Morphine application resulted in a significantly higher HTPR rate among patients having received morphine less than 1 hour before prasugrel loading (p<0.001) while concomitant metoclopramide (MCP) treatment did not significantly affect prasugrel efficacy. In conclusion, in contrast to previous reports describing a significant delay in onset of prasugrel-mediated P2Y12 inhibition in acute STEMI, we observed a rapid onset with low HTPR rates comparable to those observed in stable non-STEMI patients. Prasugrel administered directly after primary PCI might therefore be a useful therapeutic strategy in patients with STEMI to provide strong and effective P2Y12 inhibition.