RESUMEN
BACKGROUND AND AIMS: Dipeptidyl peptidase 3 (DPP3) is a protease involved in the degradation of angiotensin II which disturbs peripheral blood pressure regulation and compromises left ventricular function. This study examined the relationship of circulating DPP3 (cDPP3) with cardiogenic shock (CS) and mortality in patients presenting with acute coronary syndromes (ACS). METHODS: Plasma cDPP3 levels were assessed at baseline and 12-24 h after presentation in patients with ACS prospectively enrolled into the multi-centre SPUM-ACS study (n = 4787). RESULTS: Circulating DPP3 levels were associated with in-hospital CS when accounting for established risk factors including the ORBI risk score [per log-2 increase, hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.05-1.82, P = .021]. High cDPP3 was an independent predictor of mortality at 30 days (HR 1.87, 95% CI 1.36-2.58, P < .001) and at one year (HR 1.61, 95% CI 1.28-2.02, P < .001) after adjustment for established risk factors and the GRACE 2.0 score. Compared to values within the normal range, persistently elevated cDPP3 levels at 12-24 h were associated with 13.4-fold increased 30-day mortality risk (HR 13.42, 95% CI 4.86-37.09, P < .001) and 5.8-fold increased 1-year mortality risk (HR 5.79, 95% CI 2.70-12.42, P < .001). Results were consistent across various patient subgroups. CONCLUSIONS: This study identifies cDPP3 as a novel marker of CS and increased mortality in patients with ACS. Circulating DPP3 offers prognostic information beyond established risk factors and improves early risk assessment.
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Síndrome Coronario Agudo , Choque Cardiogénico , Humanos , Choque Cardiogénico/etiología , Síndrome Coronario Agudo/complicaciones , Pronóstico , Factores de Riesgo , Dipeptidil-Peptidasas y Tripeptidil-PeptidasasRESUMEN
BACKGROUND: The Global Registry of Acute Coronary Events (GRACE) 2.0 score was developed and validated in predominantly male patient populations. We aimed to assess its sex-specific performance in non-ST-segment elevation acute coronary syndromes (NSTE-ACS) and to develop an improved score (GRACE 3.0) that accounts for sex differences in disease characteristics. METHODS: We evaluated the GRACE 2.0 score in 420â781 consecutive patients with NSTE-ACS in contemporary nationwide cohorts from the UK and Switzerland. Machine learning models to predict in-hospital mortality were informed by the GRACE variables and developed in sex-disaggregated data from 386â591 patients from England, Wales, and Northern Ireland (split into a training cohort of 309â083 [80·0%] patients and a validation cohort of 77â508 [20·0%] patients). External validation of the GRACE 3.0 score was done in 20â727 patients from Switzerland. FINDINGS: Between Jan 1, 2005, and Aug 27, 2020, 400â054 patients with NSTE-ACS in the UK and 20â727 patients with NSTE-ACS in Switzerland were included in the study. Discrimination of in-hospital death by the GRACE 2.0 score was good in male patients (area under the receiver operating characteristic curve [AUC] 0·86, 95% CI 0·86-0·86) and notably lower in female patients (0·82, 95% CI 0·81-0·82; p<0·0001). The GRACE 2.0 score underestimated in-hospital mortality risk in female patients, favouring their incorrect stratification to the low-to-intermediate risk group, for which the score does not indicate early invasive treatment. Accounting for sex differences, GRACE 3.0 showed superior discrimination and good calibration with an AUC of 0·91 (95% CI 0·89-0·92) in male patients and 0·87 (95% CI 0·84-0·89) in female patients in an external cohort validation. GRACE 3·0 led to a clinically relevant reclassification of female patients to the high-risk group. INTERPRETATION: The GRACE 2.0 score has limited discriminatory performance and underestimates in-hospital mortality in female patients with NSTE-ACS. The GRACE 3.0 score performs better in men and women and reduces sex inequalities in risk stratification. FUNDING: Swiss National Science Foundation, Swiss Heart Foundation, Lindenhof Foundation, Foundation for Cardiovascular Research, and Theodor-Ida-Herzog-Egli Foundation.
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Síndrome Coronario Agudo , Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/terapia , Femenino , Mortalidad Hospitalaria , Humanos , Masculino , Pronóstico , Sistema de Registros , Medición de Riesgo , Suiza/epidemiología , Reino UnidoRESUMEN
AIMS: The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and its shedding product [soluble LOX-1 (sLOX-1)] are implicated in atherosclerotic cardiovascular disease (ASCVD) pathogenesis. Herein, we examined the relationship of sLOX-1 with both fatal events and plaque progression in patients with acute coronary syndromes (ACS). METHODS AND RESULTS: Plasma sLOX-1 was assessed at baseline in ACS and chronic coronary syndrome (CCS) patients prospectively recruited in the multicentre SPUM-ACS study, with sex- and age-matched healthy subjects serving as additional controls (n = 2924). Compared with both CCS and controls, ACS patients showed markedly elevated sLOX-1 levels (median, 2.00 and 2.00 vs. 35.08â pg/mL; P < 0.0001) which were independently associated with increased mortality risk over 30-day [tertile (T)3: adjusted hazard ratio (HR), 3.11; 95% confidence interval (CI), 1.44-10.61; P = 0.0055] and 1-year intervals (T3: adjusted HR, 2.04; 95% CI, 1.19-3.92; P = 0.0098). Results remained consistent after adjustment for GRACE 2.0 (T3: adjusted HR, 1.86; 95% CI, 1.04-3.74; P = 0.0391) and were primarily driven by the pronounced relationship of sLOX-1 with cardiovascular mortality at 30 days (T3: adjusted HR, 3.81; 95% CI, 1.62-19.62; P = 0.0036) and at 1 year (T3: adjusted HR, 2.29; 95% CI, 1.19-5.34; P = 0.0148). In ACS patients undergoing serial intracoronary imaging and statin therapy, sLOX-1 dropped significantly in those with coronary plaque regression at 1 year (ΔsLOX-1: -4.64 ± 1.80; P = 0.0057), and showed a good discrimination for predicting plaque progression (area under the curve = 0.74; 95% CI, 0.59-0.86; P = 0.0031). CONCLUSION: Plasma sLOX-1 levels are increased during ACS and predict fatal events beyond traditional and emerging risk factors. Persistently high sLOX-1 associates with coronary plaque progression in patients with established ASCVD. CLINICAL TRIAL REGISTRATION: NCT01000701.
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Síndrome Coronario Agudo , Aterosclerosis , Placa Aterosclerótica , Biomarcadores , Humanos , Mortalidad Prematura , Receptores Depuradores de Clase ERESUMEN
OBJECTIVE: Traumatic arteriovenous fistulas (AVFs) are rare. The vast majority occur secondary to penetrating injuries. High-output cardiac failure is a well-recognized serious complication of AVFs, associated with high morbidity and mortality. The objective of the present study was to identify predictors of heart failure (HF) in patients with traumatic AVF. METHODS: Both PubMed/MEDLINE (Ovid) and CINAHL were searched (up to June 2019) for studies reporting individual patient data on the clinical and demographic characteristics of patients with AVF secondary to penetrating trauma. Exclusion criteria were age <18 years, no specification of symptoms, a cranial, spinal, or cardiac AVF location, and an iatrogenic mechanism of injury. The present study was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. RESULTS: A total of 274 AVF patients from 15 case series and 177 case reports were included. The median age at presentation was 32 years (interquartile range, 24-43 years), 90% were men. The most frequent mechanisms of injury were stab wounds (43%) and gunshot wounds (32%). The AVF location was the abdomen (n = 86; 31%), lower limb (n = 79; 29%), neck (n = 61; 22%), thorax (n = 38; 14%), and upper limb (n = 10; 4%). Of the 274 patients, 35 (13%) had presented with HF and 239 (87%) with other symptoms. The risk of HF increased with an increased feeding artery diameter (P < .001). On univariate analysis, HF was significantly associated with a longer median time from injury to presentation with AVF (11.2 years vs 0.1 years; P < .001), older median age at presentation (43 years vs 31 years; P = .002), involvement of a large feeding artery (ie, aorta, pulmonary artery, subclavian artery, external iliac artery; 40% vs 13%; P < .001), shrapnel injuries (11% vs 2%; P = .011), and injuries to the trunk or lower limb (94% vs 71%; P = .004). After adjusting for clinical and demographic patient characteristics, involvement of a large feeding artery (odds ratio, 3.25; 95% confidence interval, 1.26-8.42; P = .015) and every 6 years of delay to presentation (odds ratio, 1.30; 95% confidence interval, 1.03-1.63; P = .026) remained independent predictors for HF. CONCLUSIONS: HF occurs in a small but important fraction of traumatic AVF patients and develops after highly variable latency periods. Large feeding arteries and delayed presentation independently predicted HF in this cohort.
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Fístula Arteriovenosa/complicaciones , Insuficiencia Cardíaca/etiología , Arteria Ilíaca/lesiones , Arteria Subclavia/lesiones , Heridas por Arma de Fuego/complicaciones , Fístula Arteriovenosa/diagnóstico , Humanos , Enfermedades Raras , Índices de Gravedad del Trauma , Heridas por Arma de Fuego/diagnósticoRESUMEN
BACKGROUND: Post-cardiac injury syndrome (PCIS) is an inflammatory condition following myocardial or pericardial damage. In response to catheter ablation, PCIS most frequently occurs after extensive radiofrequency (RF) ablation of large areas of atrial myocardium. Minor myocardial injury from right septal slow pathway ablation for atrioventricular nodal reentrant tachycardia (AVNRT) is not an established cause of the syndrome. CASE PRESENTATION: A 62-year-old women with a 6-year history of symptomatic narrow-complex tachycardia was referred to perform an electrophysiological study. During the procedure AVNRT was recorded and a total of two RF burns were applied to the region between the coronary sinus and the tricuspid annulus. Pericardial effusion was routinely ruled out by focused cardiac ultrasound. In the following days, the patient developed fever, elevated inflammatory and cardiac markers, new-onset pericardial effusion, characteristic ECG changes, and complained of pleuritic chest pain. An extensive workup for infectious, metabolic, rheumatologic, neoplastic, and toxic causes of pericarditis and myocarditis was unremarkable. Cardiac magnetic resonance imaging showed no signs of ischemia, infiltrative disease or structural abnormalities. The patient was diagnosed with PCIS and initiated on aspirin and low-dose colchicine. At a 1-month follow-up visit the patient was free of symptoms but still had a small pericardial effusion. After three months of treatment the pericardial effusion had resolved completely. CONCLUSIONS: Inflammatory pericardial reactions can occur after minor myocardial damage from RF ablation without involvement of structures in close proximity to the pericardium.
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Ablación por Catéter/efectos adversos , Lesiones Cardíacas/etiología , Derrame Pericárdico/etiología , Taquicardia por Reentrada en el Nodo Atrioventricular/cirugía , Antiinflamatorios no Esteroideos/uso terapéutico , Aspirina/uso terapéutico , Colchicina/uso terapéutico , Femenino , Lesiones Cardíacas/diagnóstico , Lesiones Cardíacas/tratamiento farmacológico , Lesiones Cardíacas/fisiopatología , Humanos , Persona de Mediana Edad , Derrame Pericárdico/diagnóstico , Derrame Pericárdico/tratamiento farmacológico , Derrame Pericárdico/fisiopatología , Pericarditis/diagnóstico , Pericarditis/tratamiento farmacológico , Pericarditis/etiología , Pericarditis/fisiopatología , Síndrome , Taquicardia por Reentrada en el Nodo Atrioventricular/diagnóstico , Taquicardia por Reentrada en el Nodo Atrioventricular/fisiopatología , Resultado del TratamientoRESUMEN
BACKGROUND: Penetrating vertebral artery injuries (VAIs) are rare. Because of their rarity, complex anatomy, and difficult surgical exposures, few surgeons and trauma centers have developed significant experience with their management. The objectives of this study were to review their incidence, clinical presentation, radiologic identification, management, complications, and outcomes and to provide a review of anatomic exposures and surgical techniques for their management. METHODS: A literature search on MEDLINE Complete-PubMed, Cochrane, Ovid, and Embase for the period of 1893 to 2018 was conducted. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used. Our literature search yielded a total of 181 potentially eligible articles with 71 confirmed articles, consisting of 21 penetrating neck injury series, 13 VAI-specific series, and 37 case reports. Operative procedures and outcomes were recorded along with methods of angiographic imaging and operative management. All articles were reviewed by at least two independent authors, and data were analyzed collectively. RESULTS: There were a total of 462 patients with penetrating VAIs. The incidence of VAI in the civilian population was 3.1% vs 0.3% in the military population. More complete data were available from 13 collected VAI-specific series and 37 case reports for a total of 362 patients. Mechanism of injury data were available for 341 patients (94.2%). There were gunshot wounds (178 patients [49.2%]), stab wounds (131 [73.6%]), and miscellaneous mechanisms of injury (32 [8.8%]). Anatomic site of injury data were available for 177 (49%) patients: 92 (25.4%) left, 84 (23.2%) right, and 1 (0.3%) bilateral. Anatomic segment of injury data were available for 204 patients (56.4%): 28 (7.7%) V1, 125 (34.5%) V2, and 51 (14.1%) V3. Treatment data were available for 212 patients. Computed tomography angiography was the most common imaging modality (163 patients [77%]). Injuries were addressed by operative management (94 [44.3%]), angiography and angioembolization (72 [34%]), combined approaches (11 [5.2%]), and observation (58 [27.4%]). Stenting and repair were less frequently employed (10 [4.7%]). The incidence of aneurysms or pseudoaneurysms was 18.5% (67); the incidence of arteriovenous fistula was 16.9% (61). The calculated mortality in VAI-specific series was 15.1%; in the individual case report group, it was 10.5%. CONCLUSIONS: The majority of VAIs present without neurologic symptoms, although some may present with exsanguinating hemorrhage. Computed tomography angiography should be considered first line to establish diagnosis. Gunshot wounds account for most injuries. The most frequently injured segment is V2. Surgical ligation is the most common intervention, followed by angioembolization, both of which constitute important management approaches.
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Procedimientos Endovasculares , Procedimientos Quirúrgicos Vasculares , Lesiones del Sistema Vascular/cirugía , Arteria Vertebral/cirugía , Heridas Penetrantes/cirugía , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/mortalidad , Humanos , Incidencia , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Procedimientos Quirúrgicos Vasculares/efectos adversos , Procedimientos Quirúrgicos Vasculares/mortalidad , Lesiones del Sistema Vascular/diagnóstico por imagen , Lesiones del Sistema Vascular/mortalidad , Lesiones del Sistema Vascular/fisiopatología , Arteria Vertebral/diagnóstico por imagen , Arteria Vertebral/lesiones , Arteria Vertebral/fisiopatología , Heridas Penetrantes/diagnóstico por imagen , Heridas Penetrantes/mortalidad , Heridas Penetrantes/fisiopatologíaRESUMEN
BACKGROUND: Brachial artery injuries are rare. The objectives of the study are to report our experience and identify predictors of outcome. The hypothesis of the study is that maintaining ischemic times less than six hours results in improved outcomes. METHODS: This is a retrospective 118-month study. The outcome measure is total operative time from admission to restoration of blood flow, and outcomes are survival and limb salvage. Statistical analyses used in the study are univariate and multivariate stepwise logistic regression. RESULTS: There were 124 patients with 131 brachial artery injuries. Mechanism of injury (MOI) included the following: penetrating: 108 (87%) and blunt: 16 (13%). Operative management included the following: 77 (62%) reverse saphenous vein interposition grafts, 37 (29.8%) end-to-end anastomosis, and 4 (3.2%) ligation. Fasciotomies were performed in 23 (19.2%) patients. Outcomes of the study were as follows: 120 patients survived and the overall survival rate was 96.8%, adjusted survival rate excluding intraoperative deaths was 100%, overall limb salvage/amputation rate was 95.1%/4.9%, and adjusted limb salvage/amputation rates excluding intraoperative deaths were 98.3%/1.67%. Univariate analysis showed the mean ischemic times for survivors as 5 ± 3.1 hrs (300 ± 186 min) versus ischemic times for non survivors as 3 ± 2.2 hrs (180 ± 132 min) (P = 0.017); Injury Severity Score (ISS) (P = 0.002); and estimated blood loss (EBL) (P = 0.024). Logistic regression identified independent predictors of outcome for survival: MOI: penetrating [P = 0.015, RR - 4.29, 95% CI: 1.49-12.36]; Glasgow Coma Score < 7 [P < 0.001, RR - 21.71, 95% CI: 9.37-50.32]; ISS > 15 [P < 0.005, RR - 4.98, 95% CI: 1.68-14.73]; and patients not requiring ED thoracotomy [P = 0.009, RR - 7.48, 95% CI: 2.58-21.69]. CONCLUSIONS: Brachial artery injuries are rare. For patients not requiring ED thoracotomy, Glasgow Coma Score, ISS, and EBL predicted survival. The adjusted limb salvage rate was 98.3%. Patients with brachial artery injuries die from associated injuries, experiencing less ischemic times than survivors who are able to undergo repairs.
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Arteria Braquial/cirugía , Vena Safena/trasplante , Lesiones del Sistema Vascular/cirugía , Heridas no Penetrantes/cirugía , Heridas Penetrantes/cirugía , Adolescente , Adulto , Amputación Quirúrgica , Anastomosis Quirúrgica , Arteria Braquial/diagnóstico por imagen , Arteria Braquial/lesiones , Femenino , Humanos , Ligadura , Recuperación del Miembro , Masculino , Persona de Mediana Edad , Tempo Operativo , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Lesiones del Sistema Vascular/diagnóstico por imagen , Heridas no Penetrantes/diagnóstico por imagen , Heridas Penetrantes/diagnóstico por imagen , Adulto JovenRESUMEN
AIMS: Data on glycoprotein IIb/IIIa inhibitor (GPI) use in real-world acute coronary syndrome (ACS) patients following the introduction of potent P2Y12 inhibitors and newer-generation stents are scant. Here, we aimed to assess the utilization, effectiveness, and safety of GPI in a large prospective multicentre cohort of contemporary ACS patients. METHODS AND RESULTS: SPUM-ACS prospectively recruited patients presenting with ACS between 2009 and 2017. The primary endpoint of the present study was major adverse cardiovascular events (MACE), a composite of all-cause death, non-fatal myocardial infarction, and non-fatal stroke at 1 year. Secondary endpoints were defined as any bleeding events, Bleeding Academic Research Consortium (BARC) 3-5 bleeding, and net adverse cardiovascular events (NACE). A total of 4395 ACS patients were included in the analysis. GPI-treated patients had more total coronary artery occlusion (56% vs. 35%, P < 0.001) and thrombus (60% vs. 35%, P < 0.001) at angiography. Among the propensity score-matched (PSM) population (1992 patients equally split into two groups), GPI-treated patients showed lower risk of MACE [PSM adjusted hazard ratio (HR) 0.70, 95% CI 0.49-0.99], but a higher risk of any (PSM adjusted HR 1.46, 95% CI 1.06-1.99) and major bleedings (PSM adjusted HR 1.73, 95% CI 1.09-2.76), resulting in a neutral effect on NACE (PSM adjusted HR 0.87, 95% CI 0.65-1.17). These results remained consistent across all subgroups. CONCLUSIONS: In patients with ACS undergoing percutaneous coronary intervention and receiving potent P2Y12 inhibitors, we observed a reduced risk of MACE and an increased risk of major bleedings at 1 year in patients treated with GPI. Although the routine use of GPI is currently not recommended, they might be considered in selected patients following a personalized balancing between ischaemic and bleeding risks.
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Síndrome Coronario Agudo , Hemorragia , Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria , Humanos , Síndrome Coronario Agudo/mortalidad , Síndrome Coronario Agudo/terapia , Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/diagnóstico , Masculino , Femenino , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Anciano , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Estudios Prospectivos , Hemorragia/inducido químicamente , Hemorragia/epidemiología , Persona de Mediana Edad , Resultado del Tratamiento , Intervención Coronaria Percutánea/efectos adversos , Intervención Coronaria Percutánea/mortalidad , Factores de Riesgo , Factores de Tiempo , Medición de Riesgo , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Antagonistas del Receptor Purinérgico P2Y/administración & dosificaciónRESUMEN
AIMS: Outcomes after acute coronary syndromes (ACS) are determined by baseline risk profiles, including initial systolic blood pressure (sBP) levels. Herein, we aimed to characterize ACS patients stratified by initial sBP levels and study their relation to inflammation, myocardial injury and post-ACS outcomes. METHODS AND RESULTS: We analysed 4724 prospectively recruited ACS patients according to invasively assessed sBP (<100, 100-139, and ≥140 mmHg) at admission. Biomarkers of systemic inflammation [high-sensitivity C-reactive protein (hs-CRP)] and myocardial injury [high-sensitivity cardiac troponin T (hs-cTnT)] were measured centrally. Major adverse cardiovascular events (MACE; composite measure of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death) were externally adjudicated. Leukocyte counts, hs-CRP, hs-cTnT, and creatine kinase (CK) levels decreased from low to high sBP strata (ptrend < 0.001). Patients with sBP < 100 mmHg developed more often cardiogenic shock (CS; P < 0.001), and had a 1.7-fold increased multivariable-adjusted MACE risk at 30 days (HR 1.68, 95% CI 1.05-2.69, P = 0.031) which did not persist at one year (HR 1.38, 95% CI 0.92-2.05, P = 0.117). Those with sBP < 100 mmHg and CS showed a higher leukocyte count (P < 0.001), an increased neutrophil-to-lymphocyte-ratio (P = 0.031), and higher hs-cTnT and CK levels relative to those without CS (P < 0.001 and P = 0.002, respectively), whereas hs-CRP levels did not differ. Patients who developed CS had a 3.6- and 2.9-fold increased MACE risk at 30 days (HR 3.58, 95% CI 1.77-7.24, P < 0.001) and at one year (HR 2.94 95% CI, 1.57-5.53, P < 0.001), which was intriguingely attenuated after controlling for distinct inflammatory profiles. CONCLUSION: In patients with ACS, proxies of systemic inflammation and myocardial injury are inversely associated with initial sBP levels, with highest biomarker levels observed in those <100 mmHg. If linked to high levels of cellular inflammation, these patients are prone to develop CS and are at high MACE and mortality risk.
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Síndrome Coronario Agudo , Humanos , Síndrome Coronario Agudo/complicaciones , Síndrome Coronario Agudo/diagnóstico , Proteína C-Reactiva/análisis , Presión Sanguínea , Factores de Riesgo , Inflamación , Biomarcadores , Troponina TRESUMEN
BACKGROUND: Carnitine metabolism produces numerous molecular species of short-, medium-, and long-chain acylcarnitines, which play important roles in energy homeostasis and fatty acid transport in the myocardium. Given that disturbances in the carnitine metabolism are linked to cardiometabolic disease, we studied the relationship of circulating acylcarnitines with outcomes in patients with acute coronary syndromes (ACS) and evaluated differences in circulating levels of these metabolites between diabetic and non-diabetic patients. METHODS: Harnessing a prospective multicentre cohort study (SPUM-ACS; NCT01000701), we measured plasma levels of acylcarnitines, carnitine, and carnitine metabolites to assess their relationship with adjudicated major adverse cardiac events (MACE), defined as composite of myocardial infarction, stroke, clinically indicated revascularization, or death of any cause. The SPUM-ACS study enrolled patients presenting with ACS to Swiss University Hospitals between 2009 and 2012. Acetylcarnitine, octanoylcarnitine, proprionylcarnitine, butyrylcarnitine, pentanoylcarnitine, hexanoylcarnitine, carnitine, γ-butyrobetaine, and trimethylamine N-oxide were measured in plasma using stable isotope dilution high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry. RESULTS: A total of 1683 patients with ACS were included in the study. All measured metabolites except γ-butyrobetaine and carnitine were higher in diabetic subject (n = 294) than in non-diabetic subjects (n = 1389). On univariate analysis, all metabolites, apart from octenoylcarnitine, were significantly associated with MACE at 1 year. After multivariable adjustment for established risk factors, acetylcarnitine remained an independent predictor of MACE at 1-year (quartile 4 vs. quartile 1, adjusted hazard ratio 2.06; 95% confidence interval 1.12-3.80, P = 0.020). CONCLUSION: Circulating levels of acetylcarnitine independently predict residual cardiovascular risk in patients with ACS.
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Síndrome Coronario Agudo , Diabetes Mellitus , Humanos , Acetilcarnitina , Síndrome Coronario Agudo/diagnóstico , Carnitina , Estudios de Cohortes , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Estudios Multicéntricos como Asunto , Estudios Prospectivos , Estudios Clínicos como AsuntoRESUMEN
BACKGROUND: Patients with ST-segment elevation typically feature total coronary occlusion (TCO) of the infarct-related artery (IRA) on angiography, which may result in worse outcomes. Yet, relying solely on electrocardiogram (ECG) findings may be misleading and those presenting with non-ST-segment elevation acute coronary syndromes (NSTE-ACSs) may have TCO as well. Herein, we aimed to delineate clinical characteristics and outcomes of patients with ACS stratified by IRA location. METHODS: A total of 4787 ACS patients were prospectively recruited between 2009 and 2017 in SPUM-ACS (ClinicalTrials.gov Identifier: NCT01000701). The primary endpoint was major adverse cardiovascular events (MACEs), a composite of all-cause death, non-fatal myocardial infarction and non-fatal stroke at 1 year. Multivariable-adjusted survival models were fitted using backward selection. RESULTS: A total of 4412 ACS patients were included in this analysis, 56.0% (n = 2469) ST-elevation myocardial infarction (STEMI) and 44.0% (n = 1943) NSTE-ACS. The IRA was the right coronary artery (RCA) in 33.9% (n = 1494), the left-anterior descending coronary artery (LAD) in 45.6% (n = 2013), and the left circumflex (LCx) in 20.5% (n = 905) patients. In STEMI patients, TCO (defined as TIMI 0 flow at angiography) was observed in 55% of cases with LAD, in 63% with RCA, and in 55% with LCx. In those presenting with NSTE-ACS, TCO was more frequent in those with LCx and RCA as compared to the LAD (27 and 24%, respectively, vs. 9%, P < 0.001). Among patients with NSTE-ACS, occlusion of the LCx was associated with an increased risk of MACE during 1 year after the index ACS (fully adjusted hazard ratio 1.68, 95% confidence interval 1.10-2.59, P = 0.02; reference: RCA and LAD). Features of patients with NSTE-ACS associated with TCO of the IRA included elevated lymphocyte and neutrophil counts, higher levels of high-sensitivity C reactive protein (hs-CRP) and high-sensitivity cardiac troponin T, lower eGFR, and notably a negative history of MI. CONCLUSION: In NSTE-ACS, both LCx and RCA involvement was associated with TCO at angiography despite the absence of ST-segment elevation. Involvement of the LCx, but not the LAD or RCA, as the IRA represented an independent predictor of MACE during 1-year follow-up. Hs-CRP, lymphocyte, and neutrophil counts were independent predictors of total IRA occlusion, suggesting a possible role of systemic inflammation in the detection of TCO irrespective of ECG presentation.
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Síndrome Coronario Agudo , Oclusión Coronaria , Infarto del Miocardio con Elevación del ST , Humanos , Síndrome Coronario Agudo/complicaciones , Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/epidemiología , Infarto del Miocardio con Elevación del ST/complicaciones , Infarto del Miocardio con Elevación del ST/diagnóstico , Infarto del Miocardio con Elevación del ST/epidemiología , Vasos Coronarios/diagnóstico por imagen , Proteína C-Reactiva , Estudios Prospectivos , Electrocardiografía , Oclusión Coronaria/complicaciones , Oclusión Coronaria/diagnóstico , Inflamación , Arritmias CardíacasRESUMEN
AIMS: Low-grade inflammation couples dysmetabolic states to insulin resistance and atherosclerotic cardiovascular (CV) disease (ASCVD). Selective sodium-glucose co-transporter 2 (SGLT-2) inhibition by empagliflozin improves clinical outcomes in patients with ASCVD independently of its glucose lowering effects. Yet, its mechanism of action remains largely undetermined. Here, we aimed to test whether empagliflozin affects arterial thrombus formation in baseline (BSL) conditions or low-grade inflammatory states, a systemic milieu shared among patients with ASCVD. METHODS AND RESULTS: Sixteen-week-old C57BL/6 mice were randomly assigned to acute administration of empagliflozin (25 mg/kg body weight) or vehicle, of which a subgroup was pre-treated biweekly over 4 weeks with super-low-dose lipopolysaccharide (LPS; 5 ng/kg body weight), before carotid thrombosis was induced by photochemical injury. The between-group difference in Doppler-flow probe detected time-to-occlusion remained within the predefined equivalence margin (Δ = |10.50|), irrespective of low-grade inflammation (95% confidence interval, -9.82 to 8.85 and -9.20 to 9.69), while glucose dropped by 1.64 and 4.84 mmoL/L, respectively. Ex vivo platelet aggregometry suggested similar activation status, corroborated by unchanged circulating platelet-factor 4 plasma levels. In concert, carotid PAI-1 expression and tissue factor (TF) activity remained unaltered upon SGLT-2 inhibition, and no difference in plasma D-dimer levels was detected, suggesting comparable coagulation cascade activation and fibrinolytic activity. In human aortic endothelial cells pre-treated with LPS, empagliflozin neither changed TF activity nor PAI-1 expression. Accordingly, among patients with established ASCVD or at high CV risk randomized to a daily dose of 10 mg empagliflozin signatures of thrombotic (i.e. TF) and fibrinolytic activity (i.e. PAI-1) remained unchanged, while plasma glucose declined significantly during 3 months of follow-up. CONCLUSION: SGLT-2 inhibition by empagliflozin does not impact experimental arterial thrombus formation, neither under BSL conditions nor during sustained low-grade inflammation, and has no impact on proxies of thrombotic/fibrinolytic activity in patients with ASCVD. The beneficial pleiotropic effects of empagliflozin are likely independent of pathways mediating arterial thrombosis.
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Diabetes Mellitus Tipo 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Trombosis , Humanos , Ratones , Animales , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Modelos Animales de Enfermedad , Células Endoteliales , Transportador 2 de Sodio-Glucosa , Lipopolisacáridos/uso terapéutico , Inhibidor 1 de Activador Plasminogénico , Ratones Endogámicos C57BL , Trombosis/inducido químicamente , Trombosis/tratamiento farmacológico , Trombosis/prevención & control , Glucosa , Inflamación/tratamiento farmacológico , Peso Corporal , Diabetes Mellitus Tipo 2/tratamiento farmacológicoRESUMEN
AIMS: The heart rejuvenating effects of circulating growth differentiation factor 11 (GDF11), a transforming growth factor-ß superfamily member that shares 90% homology with myostatin (MSTN), remains controversial. Here, we aimed to probe the role of GDF11 in acute myocardial infarction (MI), a frequent cause of heart failure and premature death during ageing. METHODS AND RESULTS: In contrast to endogenous Mstn, myocardial Gdf11 declined during the course of ageing and was particularly reduced following ischaemia/reperfusion (I/R) injury, suggesting a therapeutic potential of GDF11 signalling in MI. Unexpectedly, boosting systemic Gdf11 by recombinant GDF11 delivery (0.1â mg/kg body weight over 30 days) prior to myocardial I/R augmented myocardial infarct size in C57BL/6 mice irrespective of their age, predominantly by accelerating pro-apoptotic signalling. While intrinsic cardioprotective signalling pathways remained unaffected by high circulating GDF11, targeted transcriptomics and immunomapping studies focusing on GDF11-associated downstream targets revealed attenuated Nkx2-5 expression confined to CD105-expressing cells, with pro-apoptotic activity, as assessed by caspase-3 levels, being particularly pronounced in adjacent cells, suggesting an indirect effect. By harnessing a highly specific and validated liquid chromatography-tandem mass spectrometry-based assay, we show that in prospectively recruited patients with MI circulating GDF11 but not MSTN levels incline with age. Moreover, GDF11 levels were particularly elevated in those at high risk for adverse outcomes following the acute event, with circulating GDF11 emerging as an independent predictor of myocardial infarct size, as estimated by standardized peak creatine kinase-MB levels. CONCLUSION: Our data challenge the initially reported heart rejuvenating effects of circulating GDF11 and suggest that high levels of systemic GDF11 exacerbate myocardial injury in mice and humans alike. Persistently high GDF11 levels during ageing may contribute to the age-dependent loss of cardioprotective mechanisms and thus poor outcomes of elderly patients following acute MI.
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Factores de Diferenciación de Crecimiento , Lesiones Cardíacas , Infarto del Miocardio , Anciano , Animales , Humanos , Ratones , Envejecimiento/metabolismo , Proteínas Morfogenéticas Óseas , Factores de Diferenciación de Crecimiento/genética , Factores de Diferenciación de Crecimiento/metabolismo , Corazón , Lesiones Cardíacas/complicaciones , Lesiones Cardíacas/metabolismo , Ratones Endogámicos C57BL , Infarto del Miocardio/complicaciones , Infarto del Miocardio/metabolismoRESUMEN
BACKGROUND AND AIMS: Low-density lipoprotein (LDL)-cholesterol (LDL-C) promotes atherosclerotic cardiovascular disease (ASCVD), with changes in LDL electronegativity modulating its pro-atherogenic/pro-thrombotic effects. Whether such alterations associate with adverse outcomes in patients with acute coronary syndromes (ACS), a patient population at particularly high cardiovascular risk, remains unknown. METHODS: This is a case-cohort study using data from a subset of 2619 ACS patients prospectively recruited at four university hospitals in Switzerland. Isolated LDL was chromatographically separated into LDL particles with increasing electronegativity (L1-L5), with the L1-L5 ratio serving as a proxy of overall LDL electronegativity. Untargeted lipidomics revealed lipid species enriched in L1 (least) vs. L5 (most electronegative subfraction). Patients were followed at 30 days and 1 year. The mortality endpoint was reviewed by an independent clinical endpoint adjudication committee. Multivariable-adjusted hazard ratios (aHR) were calculated using weighted Cox regression models. RESULTS: Changes in LDL electronegativity were associated with all-cause mortality at 30 days (aHR, 2.13, 95% CI, 1.07-4.23 per 1 SD increment in L1/L5; p=.03) and 1 year (1.84, 1.03-3.29; p=.04), with a notable association with cardiovascular mortality (2.29; 1.21-4.35; p=.01; and 1.88; 1.08-3.28; p=.03). LDL electronegativity superseded several risk factors for the prediction of 1-year death, including LDL-C, and conferred improved discrimination when added to the updated GRACE score (area under the receiver operating characteristic curve 0.74 vs. 0.79, p=.03). Top 10 lipid species enriched in L1 vs. L5 were: cholesterol ester (CE) (18:2), CE (20:4), free fatty acid (FA) (20:4), phosphatidyl-choline (PC) (36:3), PC (34:2), PC (38:5), PC (36:4), PC (34:1), triacylglycerol (TG) (54:3), and PC (38:6) (all p < .001), with CE (18:2), CE (20:4), PC (36:3), PC (34:2), PC (38:5), PC (36:4), TG (54:3), and PC (38:6) independently associating with fatal events during 1-year of follow-up (all p < .05). CONCLUSIONS: Reductions in LDL electronegativity are linked to alterations of the LDL lipidome, associate with all-cause and cardiovascular mortality beyond established risk factors, and represent a novel risk factor for adverse outcomes in patients with ACS. These associations warrant further validation in independent cohorts.
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Síndrome Coronario Agudo , Aterosclerosis , Humanos , LDL-Colesterol , Estudios de Cohortes , Triglicéridos , Colesterol , Aterosclerosis/epidemiología , Factores de RiesgoRESUMEN
OBJECTIVE: Long noncoding RNAs (lncRNAs) are involved in diabetogenesis in experimental models, yet their role in humans is unclear. We investigated whether circulating lncRNAs associate with incident type 2 diabetes in older adults. RESEARCH DESIGN AND METHODS: A preselected panel of lncRNAs was measured in serum of individuals without diabetes (n = 296) from the Vienna Transdanube Aging study, a prospective community-based cohort study. Participants were followed up over 7.5 years. A second cohort of individuals with and without type 2 diabetes (n = 90) was used to validate our findings. RESULTS: Four lncRNAs (ANRIL, MIAT, RNCR3, and PLUTO) were associated with incident type 2 diabetes and linked to hemoglobin A1c trajectories throughout the 7.5-year follow-up. Similar results (for MIAT and PLUTO also in combined analysis) were obtained in the validation cohort. CONCLUSIONS: We found a set of circulating lncRNAs that independently portends incident type 2 diabetes in older adults years before disease onset.
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Diabetes Mellitus Tipo 2 , ARN Largo no Codificante , Humanos , Anciano , ARN Largo no Codificante/genética , Estudios de Cohortes , EnvejecimientoRESUMEN
Importance: The Global Registry of Acute Coronary Events (GRACE) risk score, a guideline-recommended risk stratification tool for patients presenting with acute coronary syndromes (ACS), does not consider the extent of myocardial injury. Objective: To assess the incremental predictive value of a modified GRACE score incorporating high-sensitivity cardiac troponin (hs-cTn) T at presentation, a surrogate of the extent of myocardial injury. Design, Setting, and Participants: This retrospectively designed longitudinal cohort study examined 3 independent cohorts of 9803 patients with ACS enrolled from September 2009 to December 2017; 2 ACS derivation cohorts (Heidelberg ACS cohort and Newcastle STEMI cohort) and an ACS validation cohort (SPUM-ACS study). The Heidelberg ACS cohort included 2535 and the SPUM-ACS study 4288 consecutive patients presenting with a working diagnosis of ACS. The Newcastle STEMI cohort included 2980 consecutive patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Data were analyzed from March to June 2023. Exposures: In-hospital, 30-day, and 1-year mortality risk estimates derived from an updated risk score that incorporates continuous hs-cTn T at presentation (modified GRACE). Main Outcomes and Measures: The predictive value of continuous hs-cTn T and modified GRACE risk score compared with the original GRACE risk score. Study end points were all-cause mortality during hospitalization and at 30 days and 1 year after the index event. Results: Of 9450 included patients, 7313 (77.4%) were male, and the mean (SD) age at presentation was 64.2 (12.6) years. Using continuous rather than binary hs-cTn T conferred improved discrimination and reclassification compared with the original GRACE score (in-hospital mortality: area under the receiver operating characteristic curve [AUC], 0.835 vs 0.741; continuous net reclassification improvement [NRI], 0.208; 30-day mortality: AUC, 0.828 vs 0.740; NRI, 0.312; 1-year mortality: AUC, 0.785 vs 0.778; NRI, 0.078) in the derivation cohort. These findings were confirmed in the validation cohort. In the pooled population of 9450 patients, modified GRACE risk score showed superior performance compared with the original GRACE risk score in terms of reclassification and discrimination for in-hospital mortality end point (AUC, 0.878 vs 0.780; NRI, 0.097), 30-day mortality end point (AUC, 0.858 vs 0.771; NRI, 0.08), and 1-year mortality end point (AUC, 0.813 vs 0.797; NRI, 0.056). Conclusions and Relevance: In this study, using continuous rather than binary hs-cTn T at presentation, a proxy of the extent of myocardial injury, in the GRACE risk score improved the mortality risk prediction in patients with ACS.