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The spectrum of cardiorenal and metabolic diseases comprises many disorders, including obesity, type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), dyslipidemias, hypertension, and associated comorbidities such as pulmonary diseases and metabolism dysfunction-associated steatotic liver disease and metabolism dysfunction-associated steatohepatitis (MASLD and MASH, respectively, formerly known as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis [NAFLD and NASH]). Because cardiorenal and metabolic diseases share pathophysiologic pathways, two or more are often present in the same individual. Findings from recent outcome trials have demonstrated benefits of various treatments across a range of conditions, suggesting a need for practice recommendations that will guide clinicians to better manage complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. To meet this need, we formed an international volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM 2.0 Practice Recommendations, an updated and expanded revision of a previously published multispecialty consensus on the comprehensive management of persons living with DCRM. The recommendations are presented as 22 separate graphics covering the essentials of management to improve general health, control cardiorenal risk factors, and manage cardiorenal and metabolic comorbidities, leading to improved patient outcomes.
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INTRODUCTION: Type 2 diabetes is a common and adverse prognostic co-morbidity for patients with heart failure with reduced ejection fraction (HFrEF). The effect of diabetes on long-term outcomes for heart failure with preserved ejection fraction (HFpEF) is less established. METHODS: Prospective cohort study of patients referred to a regional HF clinic with newly diagnosed with HFrEF and HFpEF according to the 2016 European Society of Cardiology guidelines. The association between diabetes, all-cause mortality and hospitalisation was quantified using Kaplan-Meier or Cox regression analysis. RESULTS: Between 1st May 2012 and 1st May 2013, of 960 unselected consecutive patients referred with suspected HF, 464 and 314 patients met the criteria for HFpEF and HFrEF respectively. Within HFpEF and HFrEF groups, patients with diabetes were more frequently male and in both groups patients with diabetes were more likely to be treated with ß-adrenoceptor antagonists and angiotensin converting enzyme inhibitors. After adjustment for age, sex, medical therapy and co-morbidities, diabetes was associated with increased mortality in individuals with HFrEF (HR 1.46 95% CI: 1.05-2.02; p = .023), but not in those with HFpEF (HR 1.26 95% CI 0.92-1.72; p = .146). CONCLUSION: In unselected patients with newly diagnosed HF, diabetes is not an adverse prognostic marker in patients with HFpEF, but is in HFrEF.
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Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Humanos , Masculino , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Estudios Prospectivos , Volumen Sistólico/fisiología , Progresión de la Enfermedad , Pronóstico , HospitalizaciónRESUMEN
AIMS: Disturbances in circadian rhythms may promote cardiometabolic disorders in rotating night shift workers (r-NSWs). We hypothesized that timed light therapy might reverse disrupted circadian rhythms and glucose intolerance observed among r-NSWs). METHODS: R-NSWs were randomly assigned to a protocol that included 12 weeks on followed by 12 weeks off light therapy (n = 13; 6 men; mean age, 39.5 ± 7.3 years) or a no-treatment control group (n = 9; 3 men; mean age 41.7 ± 6.3 years). Experimental and control participants underwent identical metabolic evaluations that included anthropometric, metabolic (including oral glucose tolerance tests), lipid, and inflammation-associated parameters together with an assessment of sleep quality and expression of circadian transcription factors REV-ERBα and BMAL1 in peripheral blood mononuclear cells (PBMCs) at baseline, 12 weeks, and 24 weeks of the protocol. RESULTS: Twelve weeks of warm white-light exposure (10,000 lx at 35 cm for 30 min per day) had no impact on sleep, metabolic, or inflammation-associated parameters among r-NSWs in the experimental group. However, our findings revealed significant decreases in REV-ERBα gene expression (p = 0.048) and increases in the REV-ERBα/BMAL1 ratio (p = 0.040) compared to baseline in PBMCs isolated from this cohort. Diminished expression of REV-ERBα persisted, although the REV-ERBα/BMAL1 ratio returned to baseline levels after the subsequent 12-day wash-out period. CONCLUSIONS: Our results revealed that intermittent light therapy had no impact on inflammatory parameters or glucose tolerance in a defined cohort of r-NSWs. However, significant changes in the expression of circadian clock genes were detected in PBMCs of these subjects undergoing light therapy.
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Factores de Transcripción ARNTL , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares , Masculino , Humanos , Adulto , Persona de Mediana Edad , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/genética , Factores de Transcripción ARNTL/genética , Leucocitos Mononucleares/metabolismo , Ritmo Circadiano/genética , Fototerapia , Inflamación , Glucosa , LípidosRESUMEN
AIMS: Understanding of the pathophysiology of progressive heart failure (HF) in patients with heart failure with preserved ejection fraction (HFpEF) is incomplete. We sought to identify factors differentially associated with risk of progressive HF death and hospitalization in patients with HFpEF compared with patients with HF and reduced ejection fraction (HFrEF). METHODS AND RESULTS: Prospective cohort study of patients newly referred to secondary care with suspicion of HF, based on symptoms and signs of HF and elevated natriuretic peptides (NP), followed up for a minimum of 6 years. HFpEF and HFrEF were diagnosed according to the 2016 European Society of Cardiology guidelines. Of 960 patients referred, 467 had HFpEF (49%), 311 had HFrEF (32%), and 182 (19%) had neither. Atrial fibrillation (AF) was found in 37% of patients with HFpEF and 34% with HFrEF. During 6 years follow-up, 19% of HFrEF and 14% of HFpEF patients were hospitalized or died due to progressive HF, hazard ratio (HR) 0.67 (95% CI: 0.47-0.96; P = 0.028). AF was the only marker that was differentially associated with progressive HF death or hospitalization in patients with HFpEF HR 2.58 (95% CI: 1.59-4.21; P < 0.001) versus HFrEF HR 1.11 (95% CI: 0.65-1.89; P = 0.7). CONCLUSIONS: De novo patients diagnosed with HFrEF have greater risk of death or hospitalization due to progressive HF than patients with HFpEF. AF is associated with increased risk of progressive HF death or hospitalization in HFpEF but not HFrEF, raising the intriguing possibility that this may be a novel therapeutic target in this growing population.
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Fibrilación Atrial , Insuficiencia Cardíaca Diastólica , Insuficiencia Cardíaca , Humanos , Fibrilación Atrial/complicaciones , Fibrilación Atrial/epidemiología , Volumen Sistólico/fisiología , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/diagnóstico , Estudios Prospectivos , Pronóstico , Insuficiencia Cardíaca Diastólica/complicacionesRESUMEN
BACKGROUND: The enhanced thrombotic milieu in diabetes contributes to increased risk of vascular events. Aspirin, a key antiplatelet agent, has inconsistent effects on outcomes in diabetes and the best dosing regimen remains unclear. This work investigated effects of aspirin dose and interaction with glycaemia on both the cellular and protein components of thrombosis. METHODS: A total of 48 participants with type 1 diabetes and 48 healthy controls were randomised to receive aspirin 75 or 300 mg once-daily (OD) in an open-label crossover study. Light transmittance aggregometry and fibrin clot studies were performed before and at the end of each treatment period. RESULTS: Aspirin demonstrated reduced inhibition of collagen-induced platelet aggregation (PA) in participants with diabetes compared with controls, although the higher dose showed better efficacy. Higher aspirin dose facilitated clot lysis in controls but not individuals with diabetes. Collagen-induced PA correlated with glycaemic control, those in the top HbA1c tertile having a lesser inhibitory effect of aspirin. Threshold analysis suggested HbA1c levels of > 65 mmol/mol and > 70 mmol/mol were associated with poor aspirin response to 75 and 300 mg daily doses, respectively. Higher HbA1c was also associated with longer fibrin clot lysis time. CONCLUSIONS: Patients with diabetes respond differently to the antiplatelet and profibrinolytic effects of aspirin compared with controls. In particular, those with elevated HbA1c have reduced inhibition of PA with aspirin. Our findings indicate that reducing glucose levels improves the anti-thrombotic action of aspirin in diabetes, which may have future clinical implications. TRIAL REGISTRATION: EudraCT, 2008-007875-26, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2008-007875-26 .
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Aspirina/administración & dosificación , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Fibrinolíticos/administración & dosificación , Control Glucémico , Hipoglucemiantes/administración & dosificación , Insulina/uso terapéutico , Trombosis/prevención & control , Adolescente , Adulto , Aspirina/efectos adversos , Biomarcadores/sangre , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Estudios Cruzados , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/diagnóstico , Interacciones Farmacológicas , Inglaterra , Femenino , Fibrinólisis/efectos de los fármacos , Fibrinolíticos/efectos adversos , Hemoglobina Glucada/metabolismo , Control Glucémico/efectos adversos , Humanos , Hipoglucemiantes/efectos adversos , Insulina/efectos adversos , Masculino , Agregación Plaquetaria/efectos de los fármacos , Trombosis/sangre , Trombosis/diagnóstico , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Background This study aimed to assess the effectiveness of sodium-glucose cotransporter 2 inhibitors in reducing the incidence of mortality and cardiovascular outcomes in adults with type 2 diabetes. Methods and Results We conducted a Bayesian meta-analysis of randomized controlled trials comparing sodium-glucose cotransporter 2 inhibitors with placebo. We used meta-regression to examine the association between treatment effects and control group event rates as measures of cardiovascular baseline risk. Fifty-three randomized controlled trials were included in our synthesis. Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all-cause mortality (empagliflozin: rate ratio [RR], 0.79; 95% credibility interval [CrI], 0.63-0.97; canagliflozin: RR, 0.86; 95% CrI, 0.69-1.05; dapagliflozin: RR, 0.86; 95% CrI, 0.72-1.01) and cardiovascular mortality (empagliflozin: RR, 0.78; 95% CrI, 0.61-1.00; canagliflozin: RR, 0.83; 95% CrI, 0.63-1.05; dapagliflozin: RR, 0.88; 95% CrI, 0.71-1.08), with a 90.1% to 98.7% probability for the true RR to be <1.00 for both outcomes. There was little evidence for ertugliflozin and sotagliflozin versus placebo for reducing all-cause and cardiovascular mortality. There was no association between treatment effects for all-cause and cardiovascular mortality and the control group event rates. There was evidence for a reduction in the incidence of heart failure for empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin versus placebo (probability RR <1.00 of ≥99.3%) and weaker, albeit positive, evidence for acute myocardial infarction for the first 3 agents (probability RR <1.00 of 89.0%-95.2%). There was little evidence of any agent except canagliflozin for reducing the incidence of stroke. Conclusions Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all-cause and cardiovascular mortality versus placebo. Treatment effects of sodium-glucose cotransporter 2 inhibitors versus placebo do not vary by baseline risk.
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Diabetes Mellitus Tipo 2 , Accidente Cerebrovascular , Teorema de Bayes , Canagliflozina/uso terapéutico , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucosa , Humanos , SodioRESUMEN
OBJECTIVE: To detect premature gluco-metabolic defects among night shift workers with disturbances in circadian rhythms. DESIGN AND METHODS: We performed a hypothesis-generating, cross-sectional analysis of anthropometric, metabolic, lipid, and inflammation parameters, comparing active (a-NSW, n = 111) and former (f-NSW, n = 98) rotating night shift workers with diurnal workers (controls, n = 69). All participants were hospital nurses. We also evaluated the Pittsburgh Sleep Quality Index (PSQI) and assessed expression of transcription factors REV-ERBα and BMAL1 in peripheral blood mononuclear cells (PBMCs), as indicators of the molecular clock. RESULTS: Both a-NSW and f-NSW participants had significantly higher glycated hemoglobin (HbA1c) and white blood cell counts (WBC) (p < 0.001 for both), PSQI global score (p = 0.001) and diastolic blood pressure levels (p = 0.024) compared with controls. Expression of REV-ERBα/BMAL1 RNA in PBMC was significantly higher in a-NSW (p = 0.05) than in f-NSW or control participants. Multivariate regression analysis showed that working status and PSQI were independent determinants of higher HbA1c levels (p < 0.001). CONCLUSIONS: We demonstrated that young, healthy night shift workers show subclinical abnormalities in HbA1c and changes in peripheral clock gene expression.
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Factores de Transcripción ARNTL/genética , Expresión Génica , Hemoglobina Glucada/análisis , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/genética , Horario de Trabajo por Turnos , Factores de Transcripción ARNTL/sangre , Adulto , Presión Sanguínea , Ritmo Circadiano/genética , Ritmo Circadiano/fisiología , Estudios Transversales , Femenino , Hospitales , Humanos , Inflamación , Recuento de Leucocitos , Leucocitos Mononucleares/química , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/sangre , Enfermeras y Enfermeros , ARN/sangre , Sueño/fisiologíaRESUMEN
OBJECTIVES: Night shift work is associated with high rates of hypertension and cardiometabolic disease, which are linked to disrupted circadian rhythms. We hypothesized that timed light therapy might improve disrupted circadian rhythms and stabilize diurnal control of blood pressure and glucose in night shift workers. METHODS: We randomized 24 rotating night shift workers (mean age, 36â±â13âyears, 7 men) who had spent a median of 6âyears on rotating night shifts (median, six night shifts per month) to 12âweeks of light therapy or no intervention and compared them with 12 daytime workers (37â±â11âyears, 6 men). We measured oral glucose tolerance (OGTT), 24-h blood pressure and arterial stiffness, and the circadian profiles of melatonin, cortisol, metanephrine and nor-metanephrine at baseline, after 12âweeks of intervention, and 12âweeks after the end of intervention. RESULTS: At baseline, fewer night shift workers showed dipper status as compared with daytime workers (29 vs. 58%; Pâ<â0.001). After 12âweeks of light therapy, there was a highly significant increase in the proportion of dippers (to 58%; Pâ<â0.0001). We also observed a significant decrease in serum glucose during OGTT in the light therapy group (-22%; Pâ<â0.05) with no change in serum insulin. Whilst circadian profiles of melatonin and cortisol were unchanged, plasma metanephrine and nor-metanephrine levels were significantly reduced in the light therapy group (Pâ<â0.01). CONCLUSION: Timed light therapy improves diurnal blood pressure control and glucose tolerance in rotating night shift workers. This effect is unrelated to melatonin and cortisol but is paralleled by reduced catecholamine levels.
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Catecolaminas , Melatonina , Adulto , Presión Sanguínea , Ritmo Circadiano , Humanos , Masculino , Persona de Mediana Edad , Fototerapia , Adulto JovenRESUMEN
Cardiovascular outcome trials in patients with type 2 diabetes at high cardiovascular risk have led to remarkable advances in our understanding of the effectiveness of GLP-1 receptor agonists and SGLT2 inhibitors to reduce cardiorenal events. In 2019, the American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD), and European Society of Cardiology (ESC) published updated recommendations for the management of such patients. We are concerned that ongoing discussions focusing on the differences between the endocrinologists' consensus report from the ADA and EASD and cardiologists' guidelines from the ESC are contributing to clinical inertia, thereby effectively denying evidence-based treatments advocated by both groups to patients with type 2 diabetes and cardiorenal disease. A subset of members from the writing groups of the ADA-EASD consensus report and the ESC guidelines was convened to emphasise where commonalities exist and to propose an integrated framework that encompasses the views incorporated in management approaches proposed by the ESC and the ADA and EASD. Coordinated action is required to ensure that people with type 2 diabetes, cardiovascular disease, heart failure, or chronic kidney disease are treated appropriately with an SGLT2 inhibitor or GLP-1 receptor agonist. In our opinion, this course should be initiated independent of background therapy, current glycaemic control, or individualised treatment goals.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Drogas en Investigación/uso terapéutico , Guías de Práctica Clínica como Asunto/normas , Consenso , Reposicionamiento de Medicamentos/métodos , Reposicionamiento de Medicamentos/normas , Práctica Clínica Basada en la Evidencia/métodos , Práctica Clínica Basada en la Evidencia/normas , Humanos , Hipoglucemiantes/uso terapéutico , Individualidad , Planificación de Atención al Paciente/normas , Sociedades Médicas/normasRESUMEN
OBJECTIVES: Night shift workers are at cardiometabolic risk due to circadian misalignment. We investigated whether infrequent exercise before each night shift that intentionally would not improve physical performance improves glucose tolerance and 24-h blood pressure profiles and synchronizes circadian rhythms of melatonin and cortisol in rotating night shift workers. METHODS: A total of 24 rotating night shift workers (mean age, 35.7 ± 11.8 years) were randomized to exercise or no intervention. Workers in the exercise group performed 15.2 ± 4.5 exercise sessions within 2 h before each night shift. Before and after 12 weeks of exercise intervention and 12 weeks after the intervention, spiroergometry, oral glucose tolerance testing and 24-h blood pressure profiles were performed. Plasma melatonin and cortisol levels were measured in 3-hourly intervals during one 24-h period on each study day. RESULTS: Exercise did not significantly change serum glucose nor insulin levels during oral glucose tolerance testing. Timed physical exercise had no effect on physical performance, nor did it change the circadian rhythms of melatonin and cortisol or influence 24-h blood pressure profiles. CONCLUSION: Physical exercise before each night shift at a low intensity level that does not improve physical performance does not affect circadian timing, glucose tolerance or 24-h blood pressure profiles in rotating night shift workers.
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Glucemia/metabolismo , Presión Sanguínea , Ritmo Circadiano , Ejercicio Físico , Hidrocortisona/sangre , Melatonina/sangre , Horario de Trabajo por Turnos , Adulto , Biomarcadores/sangre , Monitoreo Ambulatorio de la Presión Arterial , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/sangre , Masculino , Persona de Mediana Edad , Factores de Tiempo , Adulto JovenAsunto(s)
Cardiología , Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Metformina , Estado Prediabético , Péptido 1 Similar al Glucagón , Glucosa , Humanos , Escocia , SodioRESUMEN
Obesity-related euglycaemic insulin resistance clusters with cardiometabolic risk factors, contributing to the development of both type 2 diabetes and cardiovascular disease. An increased thrombotic tendency in diabetes stems from platelet hyperactivity, enhanced activity of prothrombotic coagulation factors and impaired fibrinolysis. Furthermore, a low-grade inflammatory response and increased oxidative stress accelerate the atherosclerotic process and, together with an enhanced thrombotic environment, result in premature and more severe cardiovascular disease. The disruption of circadian cycles in man secondary to chronic obesity and loss of circadian cues is implicated in the increased risk of developing diabetes and cardiovascular disease. Levels of melatonin, the endogenous synchronizer of circadian rhythm, are reduced in individuals with vascular disease and those with deranged glucose metabolism. The anti-inflammatory, antihypertensive, antioxidative and antithrombotic activities of melatonin make it a potential therapeutic agent to reduce the risk of vascular occlusive disease in diabetes. The mechanisms behind melatonin-associated reduction in procoagulant response are not fully known. Current evidence suggests that melatonin inhibits platelet aggregation and might affect the coagulation cascade, altering fibrin clot structure and/or resistance to fibrinolysis. Large-scale clinical trials are warranted to investigate the effects of modulating the circadian clock on insulin resistance, glycaemia and cardiovascular outcome.
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Aterosclerosis/sangre , Ritmo Circadiano , Diabetes Mellitus Tipo 2/sangre , Melatonina/sangre , Trombosis/sangre , Animales , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/etiología , Aterosclerosis/fisiopatología , Coagulación Sanguínea , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/fisiopatología , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Fibrinólisis , Humanos , Resistencia a la Insulina , Melatonina/deficiencia , Melatonina/uso terapéutico , Vías Secretoras , Transducción de Señal , Trombosis/tratamiento farmacológico , Trombosis/etiología , Trombosis/fisiopatologíaAsunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Angiopatías Diabéticas , Adulto , Anciano , Antihipertensivos/uso terapéutico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/fisiopatología , Angiopatías Diabéticas/epidemiología , Angiopatías Diabéticas/fisiopatología , Angiopatías Diabéticas/prevención & control , Femenino , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Hipoglucemiantes/uso terapéutico , Hipolipemiantes/uso terapéutico , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Servicios Preventivos de Salud , Pronóstico , Medición de RiesgoRESUMEN
BACKGROUND: Despite increased atherothrombotic risk in type 2 diabetes mellitus, (T2DM) the best preventative antithrombotic strategy remains undetermined. We defined the effects of three antiplatelet agents on functional readout and biomarker kinetics in platelet activation and coagulation in patients with T2DM. MATERIALS AND METHODS: 56 patients with T2DM were randomised to antiplatelet monotherapy with aspirin 75 mg once daily (OD), clopidogrel 75 mg OD or prasugrel 10 mg OD during three periods of a crossover study. Platelet aggregation (PA) was determined by light-transmittance aggregometry and P-selectin expression by flow cytometry. Markers of fibrin clot dynamics, inflammation and coagulation were measured. Plasma levels of 14 miRNA were assessed by quantitative polymerase chain reactions. RESULTS: Of the 56 patients, 24 (43%) were receiving aspirin for primary prevention of ischaemic events and 32 (57%) for secondary prevention. Prasugrel was the strongest inhibitor of ADP-induced PA (mean ± SD maximum response to 20µmol/L ADP 77.6 ± 8.4% [aspirin] vs. 57.7 ± 17.6% [clopidogrel] vs. 34.1 ± 14.1% [prasugrel], p < 0.001), P-selectin expression (30 µmol/L ADP; 45.1 ± 21.4% vs. 27.1 ± 19.0% vs. 14.1 ± 14.9%, p < 0.001) and collagen-induced PA (2 µg/mL; 62.1 ± 19.4% vs. 72.3 ± 18.2% vs. 60.2 ± 18.5%, p < 0.001). Fibrin clot dynamics and levels of coagulation and inflammatory proteins were similar. Lower levels of miR-24 (p = 0.004), miR-191 (p = 0.019), miR-197 (p = 0.009) and miR-223 (p = 0.014) were demonstrated during prasugrel-therapy vs. aspirin. Circulating miR-197 was lower in those cardiovascular disease during therapy with aspirin (p = 0.039) or prasugrel (p = 0.0083). CONCLUSIONS: Prasugrel monotherapy in T2DM provided potent platelet inhibition and reduced levels of a number of platelet-associated miRNAs. miR-197 is a potential marker of cardiovascular disease in this population. Clinical outcome studies investigating prasugrel monotherapy are warranted in individuals with T2DM. Trial registration EudraCT, 2009-011907-22. Registered 15 March 2010, https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-011907-22/GB.
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Aspirina/uso terapéutico , Coagulación Sanguínea/efectos de los fármacos , Clopidogrel/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Agregación Plaquetaria/efectos de los fármacos , Clorhidrato de Prasugrel/uso terapéutico , Trombosis/prevención & control , Anciano , Aspirina/efectos adversos , Biomarcadores/sangre , Clopidogrel/efectos adversos , Estudios Cruzados , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Método Doble Ciego , Femenino , Fibrina/metabolismo , Humanos , Masculino , MicroARNs/sangre , Persona de Mediana Edad , Selectina-P/sangre , Inhibidores de Agregación Plaquetaria/efectos adversos , Clorhidrato de Prasugrel/efectos adversos , Prevención Primaria , Prevención Secundaria , Trombosis/sangre , Trombosis/diagnóstico , Factores de Tiempo , Resultado del TratamientoAsunto(s)
Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Enfermedades Cardiovasculares/etiología , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Factores de RiesgoRESUMEN
BACKGROUND AND AIMS: Transglutaminase (TG) 2 and Factor (F) XIII-A have both been implicated in cardiovascular protection and repair. This study was designed to differentiate between two competing hypotheses: that TG2 and FXIII-A mediate these functions in mice by fulfilling separate roles, or that they act redundantly in this respect. METHODS: Atherosclerosis was assessed in brachiocephalic artery plaques of fat-fed mixed strain apolipoprotein (Apo)e deficient mice that lacked either or both transglutaminases. Cardiac fibrosis was assessed both in the mixed strain mice and also in C57BL/6J Apoe expressing mice lacking either or both transglutaminases. RESULTS: No difference was found in the density of buried fibrous caps within brachiocephalic plaques from mice expressing or lacking these transglutaminases. Cardiac fibrosis developed in both Apoe/F13a1 double knockout and F13a1 single knockout mice, but not in Tgm2 knockout mice. However, concomitant Tgm2 knockout markedly increased fibrosis, as apparent in both Apoe/Tgm2/F13a1 knockout and Tgm2/F13a1 knockout mice. Amongst F13a1 knockout and Tgm2/F13a1 knockout mice, the extent of fibrosis correlated with hemosiderin deposition, suggesting that TG2 limits the extravasation of blood in the myocardium, which in turn reduces the pro-fibrotic stimulus. The resulting fibrosis was interstitial in nature and caused only minor changes in cardiac function. CONCLUSIONS: These studies confirm that FXIII-A and TG2 fulfil different roles in the mouse myocardium. FXIII-A protects against vascular leakage while TG2 contributes to the stability or repair of the vasculature. The protective function of TG2 must be considered when designing clinical anti-fibrotic therapies based upon FXIII-A or TG2 inhibition.
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Aterosclerosis/etiología , Aterosclerosis/patología , Deficiencia del Factor XIII/complicaciones , Factor XIIIa/fisiología , Proteínas de Unión al GTP/deficiencia , Transglutaminasas/deficiencia , Animales , Apolipoproteínas E/fisiología , Modelos Animales de Enfermedad , Fibrosis , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína Glutamina Gamma Glutamiltransferasa 2Asunto(s)
Cardiología , Enfermedades Cardiovasculares/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Guías de Práctica Clínica como Asunto , Estado Prediabético/diagnóstico , Sociedades Médicas , Enfermedades Cardiovasculares/etiología , Diabetes Mellitus Tipo 2/complicaciones , Europa (Continente) , Humanos , Estado Prediabético/complicacionesRESUMEN
BACKGROUND: Guanidino compounds, including asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and L-homoarginine (hArg), have been associated with cardio- and cerebrovascular events and risk. We aimed to study if low hArg/ADMA and hArg/SDMA ratios are associated with mortality and outcome after stroke. METHODS: In two prospective cohorts of acute stroke patients from Germany and the UK, we analyzed hArg, ADMA, and SDMA to determine hArg/ADMA and hArg/SDMA ratios. The guanidino compound levels were associated with mortality, adverse events, and neurological impairment, i.e., National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS). RESULTS: During 7.4 years, high hArg/ADMA and hArg/SDMA ratios were both associated with a reduction in all-cause mortality in patients with ischemic stroke in a UK stroke cohort (hArg/ADMA: hazard ratio (HR) 0.75 [95% confidence interval (CI) 0.62-0.92]; n = 394; P = 0.006; hArg/SDMA: HR 0.68 [0.54-0.85]; n = 394; P = 0.001). In a German stroke cohort, patients with high hArg/SDMA ratio experienced fewer adverse events compared with those with low hArg/SDMA ratios within 30 days after stroke (HR 0.73 [0.57-0.92]; n = 135; P = 0.009), whereas hArg/ADMA was not predictive. Furthermore, hArg/SDMA ratios inversely correlated with the degree of neurological impairment (NIHSS) (r = - 0.27; P = 0.001; n = 138). Lower hArg/SDMA ratios were also found in dependent (mRS 3-6) compared with independent patients (mRS < 3; P = 0.007; n = 138), whereas hArg/ADMA did not. CONCLUSION: These results from two prospective stroke studies reveal that hArg/SDMA ratio could prove a valuable blood-based biomarker to discriminate patients with poor short- and long-term outcome, increased neurological impairment, and severe disability after stroke.