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1.
Serum creatine kinase and creatinine in adult spinal muscular atrophy under nusinersen treatment.
Freigang, M, Wurster, CD, Hagenacker, T, Stolte, B, Weiler, M, Kamm, C, Schreiber-Katz, O, Osmanovic, A, Petri, S, Kowski, A, et al
Annals of clinical and translational neurology. 2021;(5):1049-1063
Abstract
OBJECTIVE To determine whether serum creatine kinase activity (CK) and serum creatinine concentration (Crn) are prognostic and predictive biomarkers for disease severity, disease progression, and nusinersen treatment effects in adult patients with 5q-associated spinal muscular atrophy (SMA). METHODS Within this retrospective, multicenter observational study in 206 adult patients with SMA, we determined clinical subtypes (SMA types, ambulatory ability) and repeatedly measured CK and Crn and examined disease severity scores (Hammersmith Functional Motor Scale Expanded, Revised Upper Limb Module, and revised Amyotrophic Lateral Sclerosis Functional Rating Scale). Patients were followed under nusinersen treatment for 18 months. RESULTS CK and Crn differed between clinical subtypes and correlated strongly with disease severity scores (e.g., for Hammersmith Functional Motor Scale Expanded: (CK) ρ = 0.786/ (Crn) ρ = 0.558). During the 18 months of nusinersen treatment, CK decreased (∆CK = -17.56%, p < 0.0001), whereas Crn slightly increased (∆Crn = +4.75%, p < 0.05). INTERPRETATION Serum creatine kinase activity and serum creatinine concentration reflect disease severity of spinal muscular atrophy and are promising biomarkers to assess patients with spinal muscular atrophy during disease course and to predict treatment response. The decrease of creatine kinase activity, combined with the tendency of creatinine concentration to increase during nusinersen treatment, suggests reduced muscle mass wasting with improved muscle energy metabolism.
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2.
Creatine kinase during non-ST-segment elevation acute coronary syndromes is associated with major bleeding.
Brewster, LM, Fernand, J
Open heart. 2020;(2)
Abstract
BACKGROUND It was recently reported that highly elevated plasma activity of the ADP-scavenging enzyme creatine kinase (CK), to >10 times the upper reference limit (URL), is independently associated with fatal or non-fatal bleeding during treatment for ST-segment elevation myocardial infarction (OR 2.6 (95% CI, 1.8 to 2.7)/log CK increase). Evidence indicates that CK attenuates ADP-dependent platelet aggregation. This study investigates whether moderately elevated CK in non-ST-segment elevation acute coronary syndrome (NSTE-ACS) is associated with major bleeding. METHODS The Thrombolysis In Myocardial Ischemia (TIMI) 3B trial compared recombinant tissue-type plasminogen activator (rt-PA) (35-80 mg) with placebo and early catheterisation with conservative management in patients with NSTE-ACS. Main outcomes of the current study are the independent association of peak plasma CK (CKmax) with adjudicated fatal or non-fatal major bleeding (primary) and with combined major bleeding, stroke and hospital death (secondary), with covariables including age, sex, body mass index, systolic blood pressure, creatinine and assignment to add-on rt-PA versus placebo. Discrimination was assessed with C-statistics. RESULTS The study included 1473 patients (66% men, 80% white, mean age 59 years, SE 0.3). CKmax ranged between 15 and 19 045 IU/L (mean (SE), 450 (24) IU/L; two times URL). Major bleeding occurred in 2.0% (mean age 65 (1.3) years; mean CKmax 1015 (319) IU/L; six times URL), and the combined outcome in 4.3% of the patients, adjusted OR per log CK increase, respectively, 3.1 (1.6 to 5.9) for major bleeding and 3.9 (2.5 to 6.1) for the combined outcome; C-index 0.8 for both outcomes. The association between CK and bleeding was independent of the use of thrombolytic therapy. DISCUSSION The presented data add to the existing evidence that proportionate to its plasma activity, the ADP-binding enzyme CK is strongly and independently associated with non-fatal and fatal major bleeding during treatment for NSTE-ACS. CK might increase the accuracy of prediction models for major bleeding in patients with NSTE-ACS. TRIAL REGISTRATION NUMBER NCT00000472.
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3.
Creatine kinase is associated with bleeding after myocardial infarction.
Brewster, LM, Fernand, J
Open heart. 2020;(2)
Abstract
BACKGROUND The ADP-scavenging enzyme creatine kinase (CK) is reported to reduce ADP-dependent platelet activation. Therefore, we studied whether highly elevated CK after ST-elevation myocardial infarction (STEMI) is associated with bleeding. METHODS Data of the Thrombolysis in Myocardial Infarction Study Group phase II trial on the efficacy of angioplasty, following intravenous recombinant tissue-type plasminogen activator (rt-PA), are used to assess whether peak plasma CK (CKmax) is independently associated with adjudicated fatal or non-fatal bleeding (primary) and combined bleeding/all-cause mortality (secondary) in multivariable binomial logistic regression analysis, adjusting for baseline and treatment allocation covariates. RESULTS The included patients (n=3339, 82% men, 88% white, mean age 57 years, SE 0.2) had a history of angina pectoris (55%), hypertension (38%) and/or diabetes mellitus (13%). CKmax ranged from 16 to 55 890 IU/L (mean 2389 IU/L, SE 41), reached within 8 hours in 51% of the patients (93% within 24 hours). Adjudicated fatal/non-fatal bleeding occurred in 30% of the patients (respectively 26% in the low vs 34% in the high CK tertile), and bleeding/all-cause mortality in 35% (29% in the low vs 40% in the high CK tertile). In multivariable regression analysis, the adjusted OR for fatal/non-fatal bleeding (vs not bleeding and survival) was 2.6 (95% CI 1.8 to 3.7)/log CKmax increase, and 3.1 (2.2 to 4.4) for bleeding/all-cause mortality. CONCLUSION Highly elevated plasma CK after myocardial infarction might be an independent predictor of bleeding and haemorrhagic death. This biologically plausible association warrants further prospective study of the potential role of extracellular CK in ADP-dependent platelet activation and bleeding.
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Targeted screening for the detection of Pompe disease in patients with unclassified limb-girdle muscular dystrophy or asymptomatic hyperCKemia using dried blood: A Spanish cohort.
Gutiérrez-Rivas, E, Bautista, J, Vílchez, JJ, Muelas, N, Díaz-Manera, J, Illa, I, Martínez-Arroyo, A, Olivé, M, Sanz, I, Arpa, J, et al
Neuromuscular disorders : NMD. 2015;(7):548-53
Abstract
We aimed to screen for Pompe disease in patients with unclassified limb-girdle muscular dystrophy (LGMD) or asymptomatic hyperCKemia using dried blood spot (DBS) assays. Subsequently, we aimed to calculate the diagnostic delay between initial symptom presentation and the diagnosis. A prospective, multicenter, observational study was conducted in 348 patients: 146 with unclassified LGMD and 202 with asymptomatic or paucisymptomatic hyperCKemia. We quantified levels of acid alpha-glucosidase (GAA) from dried blood spots analyzed fluorometrically. The test was positive in 20 patients, and Pompe disease was confirmed by genetic testing in 16. Undiagnosed Pompe disease was detected in 7.5% of patients with LGMD and in 2.5% of patients with persistent, idiopathic elevation of serum creatine kinase. The c.-32-13 T > G mutation was found most commonly. The diagnostic delay was 15 years on average. In conclusion, DBS tests are useful and reliable screening tools for Pompe disease. We recommend the dried blood spot test to be included in the diagnostic work-up of patients with unclassified myopathies with proximal weakness and/or hyperCKemia of unknown cause and, when positive, to define the diagnosis, it will have to be confirmed by biochemical and/or molecular genetic analysis.
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5.
Muscle symptoms and creatine phosphokinase elevations in patients receiving raltegravir in clinical practice: Results from the SCOLTA project long-term surveillance.
Madeddu, G, De Socio, GV, Ricci, E, Quirino, T, Orofino, G, Carenzi, L, Franzetti, M, Parruti, G, Martinelli, C, Vichi, F, et al
International journal of antimicrobial agents. 2015;(3):289-94
Abstract
Muscle alterations ranging from asymptomatic creatine phosphokinase (CPK) increases to rhabdomyolysis and central nervous system (CNS) symptoms have been reported in patients receiving raltegravir. Muscle symptoms and CPK increases were investigated in a cohort of HIV-infected patients receiving raltegravir-based antiretroviral therapy, and possible associated predictors were evaluated. The SCOLTA Project is a prospective, observational, multicentre study created to assess the incidence of adverse events in patients receiving new antiretroviral drugs in clinical practice. In total, 496 HIV-infected patients were enrolled [333 (67.1%) male]. CDC stage was C in 196 patients (39.5%). Mean age at enrolment was 45.9 ± 9.3 years. Median follow-up was 21 months. Twenty-six patients (5.2%) reported muscle symptoms (16 muscle pain and 17 weakness; 7 had both). Of 342 patients with normal baseline CPK values, 72 (21.1%) had a CPK increase. Seven patients (1.4%) discontinued raltegravir because of muscular events (three for muscle pain/weakness and four CPK increases). No cases of rhabdomyolysis were observed. Patients with muscle symptoms were more frequently receiving in their regimen than those not receiving atazanavir (P=0.04) and were more likely to also report CNS symptoms (P<0.0001). Significant predictors of muscle symptoms were CNS symptoms and use of atazanavir. Female sex was associated with a reduced risk of CPK increase. In conclusion, muscle symptoms and CPK elevations occurred frequently and caused most discontinuations due to adverse events. Their monitoring in patients receiving raltegravir should be considered, especially when co-administered with atazanavir or when CNS symptoms are also present.
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Incidence, correlates, and significance of abnormal cardiac enzyme rises in patients treated with surgical or percutaneous based revascularisation: a substudy from the Synergy between Percutaneous Coronary Interventions with Taxus and Cardiac Surgery (SYNTAX) Trial.
Farooq, V, Serruys, PW, Vranckx, P, Bourantas, CV, Girasis, C, Holmes, DR, Kappetein, AP, Mack, M, Feldman, T, Morice, MC, et al
International journal of cardiology. 2013;(6):5287-92
Abstract
AIMS: The aim of the present investigation was to determine the long-term prognostic association of post-procedural cardiac enzyme elevation within the randomised Synergy between Percutaneous Coronary Intervention (PCI) with TAXUS and Cardiac Surgery (SYNTAX) Trial. METHODS 1800 patients with unprotected left main or de novo three-vessel coronary artery disease were randomised to undergo coronary artery bypass graft (CABG) surgery or PCI. Per protocol patients underwent post-procedural blood sampling with creatine kinase (CK), and the cardiac specific MB iso-enzyme (CK-MB) only if the preceding CK ratio was ≥ 2 × the upper limit of normal (ULN). An independent chemistry laboratory evaluated all collected blood samples. RESULTS Post-procedural CK sampling was available in 1629 of 1800 patients (90.5%). As per protocol, CK-MB analyses were undertaken in 474 of 491 patients (96.5%) in the CABG arm, and 53 of 61 patients (86.9%) in the PCI arm. Within the CABG arm, despite the limitations of incomplete data, a post-procedural CK-MB ratio <3/≥3 ULN separated 4-year mortality into low- and high-risk groups (2.3% vs. 9.5%, p=0.03). Additionally, in the CABG arm, a post-procedural CK-MB ratio ≥3 ULN was associated with an increased frequency of a high SYNTAX Score (≥33) tertile (high [≥33] SYNTAX Score: 39.5%, intermediate [23-32] SYNTAX Score 31.0%, low [≤22] SYNTAX Score 29.5%, p=0.02). Within the PCI arm, a post-procedural CK ratio of <2 or ≥2 ULN separated 4-year mortality into low- and high-risk groups (10.8% vs. 23.3%, p=0.001). Notably, there was an early (within 6 months) and late (after 2 years) peak in mortality in patients with a post-PCI CK ratio of ≥2 ULN. Lack of pre-procedural thienopyridine, carotid artery disease, type 1 diabetes, and presence of coronary bifurcations were independent correlates of a CK ratio ≥2 ULN post-PCI. CONCLUSION Cardiac enzyme elevations post-CABG or post-PCI are associated with an adverse long-term mortality; the causes of which are multifactorial.
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Comparison of Troponin T to creatine kinase and to radionuclide cardiac imaging infarct size in patients with ST-elevation myocardial infarction undergoing primary angioplasty.
Tzivoni, D, Koukoui, D, Guetta, V, Novack, L, Cowing, G, ,
The American journal of cardiology. 2008;(6):753-7
Abstract
Troponin is used mainly for detection of minor myocardial damage, whereas repeated measurements of creatine kinase (CK) and myocardial band (CK-MB) are used for assessing infarct size in patients with myocardial infarction. The purpose of this study was to correlate peak level and area under the curve (AUC) of troponin T to that of CK and CK-MB and with single-photon emission computed tomographic infarct size and left ventricular function in patients with ST elevation myocardial infarction. In this multicenter study (29 centers, 5 countries), we included 267 patients who underwent primary coronary intervention within 6 hours of onset of symptoms. All had repeated measurements of troponin T, CK, and CK-MB. Infarct size and left ventricular function were assessed by single-photon emission computed tomography performed on days 7 and 30. Mean infarct sizes were 14% on day 7 and 10% on day 30, and mean ejection fractions were 42% on day 7 and 45% on day 30 after the acute infarct. Very high correlation (r >0.85, Spearman correlation) was found between peak level and AUC of troponin T, CK, and CK-MB. Similar high correlation was found between peak level and AUC of troponin, CK, and CK-MB with single-photon emission computed tomographic infarct size (r >0.70). In conclusion, based on the results of this multicenter study, we suggest that peak levels and AUC of troponin are as accurate as CK and CK-MB in estimating myocardial infarct size.
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Direct coronary stenting versus stenting with balloon pre-dilation: incidence of enzyme release and follow-up results of a multicentre, prospective, randomized study. The CK and Troponin I Estimation in direct STenting (CK TEST) trial.
Balducelli, M, Varani, E, Vecchi, G, Paloscia, L, Manari, A, Santarelli, A, Cappi, B, Shoeib, A, Valenti, S, Maresta, A, et al
Minerva cardioangiologica. 2007;(3):281-9
Abstract
AIM: The aim of this study was to assess the safety of direct coronary stenting, its influence on costs, duration of the procedure, radiation exposure, clinical outcome and the incidence of periprocedural myocardial damage as assessed by enzyme release determination. METHODS We randomized 103 patients (109 lesions) to direct stent implant or stent implant following balloon predilatation. Patients with heavily calcified lesions, bifurcations, total occlusions, left main lesions and very tortuous vessels were excluded. Three samples of blood were drawn; before, 12 and 24 h after the procedure and total CK, CK MB mass and troponin I determination was carried out in a single centralized laboratory. RESULTS Direct stenting was successful in 62/62 lesions (100%). No single loss or embolization of the stent occurred. All stents in the group with predilatation were effectively deployed. The immediate post procedure angiographic results were similar with both techniques. Contrast media consumption and procedural time were significantly lower in direct stenting (150+/-82 cc and 30+/-13 min) than in pre-dilated stenting (184+/-85 cc and 36+/-14 min) (P=0.04 and P=0.036 respectively) while fluoroscopy time was similar (9.1+/-12 vs 9.19+/-15 min, P=0.97). The incidence of enzyme release was similar in the groups with only three non Q MI all in the pre-dilated group (P=0.149). Any elevation of CK MB and troponin I occurred in 7% of direct stent vs 12% of pre-dilated group (P=0.66), isolated troponin I elevation in 21% of both groups. Major adverse cardiac events during hospitalization were 0 in direct and 3 in pre-dilated stenting (P=0.66), but there were no significant differences at follow-up at 1, 6 and 12 months between the 2 groups (target lesion revascularization at 12 months 11 vs 14% in the 2 groups respectively). CONCLUSION Direct stenting is as safe as pre-dilated stenting in selected coronary lesions. Acute results and myocardial damage as assessed by enzyme release determination are similar, but procedural costs (as measured by resource consumption) and duration of the procedure are lower in direct stenting. Overall success rate and mid-term clinical outcome are similar with both techniques.
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Impact of the elevation of biochemical markers of myocardial damage on long-term mortality after percutaneous coronary intervention: results of the CK-MB and PCI study.
Cavallini, C, Savonitto, S, Violini, R, Arraiz, G, Plebani, M, Olivari, Z, Rubartelli, P, Battaglia, S, Niccoli, L, Steffenino, G, et al
European heart journal. 2005;(15):1494-8
Abstract
AIMS: Retrospective studies and post hoc analyses have suggested that mild elevations in the creatine kinase-MB (CK-MB) isoenzyme following percutaneous coronary intervention (PCI) may be associated with an increased risk of death in the long term. However, this finding is still controversial, and the prognostic significance of elevations of more sensitive markers of myocardial damage, such as the cardiac troponins, has not been established. In this multicentre prospective cohort study, we evaluated the influence of post-procedural elevations of CK-MB and troponin I (cTnI) on long-term mortality. METHODS AND RESULTS The CK-MB and PCI study included 3494 consecutive patients undergoing PCI from February 2000 to October 2000 in 16 Italian tertiary centres. Blood samples were collected at baseline, and at 8-12 and 18-24 h after the procedure, and were analysed in a core biochemistry laboratory. CK-MB elevation was detected in 16% of the patients, and was associated with increased 2-year mortality [7.2 vs. 3.8%; odds ratio (OR): 1.9; 95% confidence interval (CI): 1.3-2.8; P<0.001). The degree of CK-MB elevation (peak CK-MB ratio) independently predicted the risk of death (adjusted OR per unit: 1.04; 95% CI: 1.01-1.07; P=0.009). A cTnI elevation was detected in 44.2% of the cases and was not associated with a significant increase in mortality (4.9 vs. 4.0%; OR: 1.2; 95% CI: 0.9-1.7; P=0.2). CONCLUSION Post-procedural elevations of CK-MB, but not cTnI, influence 2-year mortality.
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Increased creatine kinase MB level predicts postoperative mortality after cardiac surgery independent of new Q waves.
Ramsay, J, Shernan, S, Fitch, J, Finnegan, P, Todaro, T, Filloon, T, Nussmeier, NA
The Journal of thoracic and cardiovascular surgery. 2005;(2):300-6
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Abstract
BACKGROUND Recent consensus statements recommend cardiac enzyme release as the essential criterion for diagnosing myocardial infarction. However, the outcome implications of cardiac enzyme release in patients undergoing coronary artery bypass grafting are controversial. METHODS Eight hundred patients were followed for 30 days after elective on-pump coronary artery bypass grafting in a multicenter, prospective, randomized trial of the anti-C5 complement antibody pexelizumab. Data from centralized electrocardiography and creatine kinase MB analyses were examined for any association with death or severe left ventricular dysfunction. RESULTS More than half of the 800 patients had peak creatine kinase MB levels of more than 5 times the upper limit of 5 ng/mL set by the core laboratory. The median peak value was 29 ng/mL. The incidence of the combined outcome (death or severe left ventricular dysfunction) was 1.7% if the peak creatine kinase MB level was less than 25 ng/mL and 18.0% if 100 ng/mL or greater (P < .01). Similarly, the incidence of new Q-wave myocardial infarction was 3.9% if the peak creatine kinase MB level was less than 25 ng/mL and 30.6% if 100 ng/mL or greater (P < .01). In a multivariate analysis that included preoperative and intraoperative factors, as well as peak enzyme release and Q-wave myocardial infarction, the strongest predictor of the combined outcome was a peak creatine kinase MB level of 100 ng/mL or greater. New Q-wave myocardial infarction did not significantly predict the combined outcome. CONCLUSIONS Increased postoperative peak creatine kinase MB level, especially when 20 times or more of the upper limit of normal, indicates increased risk of severe postoperative left ventricular dysfunction and mortality within 30 days of coronary artery bypass grafting. High peak enzyme level is a stronger predictor of adverse outcomes than is postoperative Q-wave myocardial infarction in this population.