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Arritmias Cardíacas , Cardiomiopatías , Fibrosis , Hipertensión , Serina Endopeptidasas , Humanos , Arritmias Cardíacas/genética , Cardiomiopatías/genética , Fibrosis/genética , Atrios Cardíacos/patología , Atrios Cardíacos/diagnóstico por imagen , Hipertensión/genética , Serina Endopeptidasas/genéticaRESUMEN
Symptomatic heart failure with reduced ejection fraction (HFrEF) is characterized by edema and chronic pathological activation of the classical renin-angiotensin-aldosterone system (RAAS). The soluble (pro)renin receptor (s(P)RR) is released into circulation by proteolytic cleavage of tissue expressed (P)RR and is a candidate biomarker of RAAS activation. However, previous studies linked elevated levels of s(P)RR in patients with HFrEF to renal dysfunction. Utilizing prospectively enrolled patients with comparable rEF, we show that increased plasma levels of s(P)RR are associated with symptomatic HF (characterized by edema), independent of chronic renal dysfunction. We also found that s(P)RR levels were positively correlated with patient plasma renin activity (PRA). Normotensive mice with dilated cardiomyopathy (DCM) and HFrEF, without renal dysfunction, showed plasma s(P)RR and PRA patterns similar to human HFrEF patients. Plasma s(P)RR levels positively correlated with PRA and systemic edema, but not with EF, resembling findings in patients with HFrEF without chronic kidney dysfunction. In female DCM mice with elevated PRA levels and plasma s(P)RR levels, a randomized, blinded trial comparing the direct renin inhibitor, aliskiren vs. vehicle control, showed that direct renin inhibition normalized PRA, lowered s(P)RR, and prevented symptomatic HFrEF. Considered in light of previous findings, these data suggest that, in HFrEF, in the absence of renal dysfunction, elevation of plasma s(P)RR levels is caused by increased PRA and associated with the development of systemic edema.
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In heart failure with reduced ejection fraction (HFrEF), cardiogenic edema develops from impaired cardiac function, pathological remodeling, chronic inflammation, endothelial dysfunction, neurohormonal activation, and altered nitric oxide-related pathways. Pre-clinical HFrEF studies have shown that treatment with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) stimulates natriuretic and osmotic/diuretic effects, improves overall cardiac function, attenuates maladaptive cardiac remodeling, and reduces chronic inflammation, oxidative stress, and endothelial dysfunction. Here, we review the mechanisms and effects of SGLT-2i therapy on cardiogenic edema in various models of HFrEF. Overall, the data presented suggest a high translational importance of these studies, and pre-clinical studies show that SGLT-2i therapy has a marked effect on suppressing the progression of HFrEF through multiple mechanisms, including those that affect the development of cardiogenic edema.
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Pathological sodium-water retention or edema/congestion is a primary cause of heart failure (HF) decompensation, clinical symptoms, hospitalization, reduced quality of life, and premature mortality. Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) based therapies reduce hospitalization due to HF, improve functional status, quality, and duration of life in patients with HF with reduced ejection fraction (HFrEF) independently of their glycemic status. The pathophysiologic mechanisms and molecular pathways responsible for the benefits of SGLT-2i in HFrEF remain inconclusive, but SGLT-2i may help HFrEF by normalizing salt-water homeostasis to prevent clinical edema/congestion. In HFrEF, edema and congestion are related to compromised cardiac function. Edema and congestion are further aggravated by renal and pulmonary abnormalities. Treatment of HFrEF patients with SGLT-2i enhances natriuresis/diuresis, improves cardiac function, and reduces natriuretic peptide plasma levels. In this review, we summarize current clinical research studies related to outcomes of SGLT-2i treatment in HFrEF with a specific focus on their contribution to relieving or preventing edema and congestion, slowing HF progression, and decreasing the rate of rehospitalization and cardiovascular mortality.
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Sodium restriction is often recommended in heart failure (HF) to block symptomatic edema, despite limited evidence for benefit. However, a low-sodium diet (LSD) activates the classical renin-angiotensin-aldosterone system (RAAS), which may adversely affect HF progression and mortality in patients with dilated cardiomyopathy (DCM). We performed a randomized, blinded pre-clinical trial to compare the effects of a normal (human-equivalent) sodium diet and a LSD on HF progression in a normotensive model of DCM in mice that has translational relevance to human HF. The LSD reduced HF progression by suppressing the development of pleural effusions (p < 0.01), blocking pathological increases in systemic extracellular water (p < 0.001) and prolonging median survival (15%, p < 0.01). The LSD activated the classical RAAS by increasing plasma renin activity, angiotensin II and aldosterone levels. However, the LSD also significantly up-elevated the counter-regulatory RAAS by boosting plasma angiotensin converting enzyme 2 (ACE2) and angiotensin (1-7) levels, promoting nitric oxide bioavailability and stimulating 3'-5'-cyclic guanosine monophosphate (cGMP) production. Plasma HF biomarkers associated with poor outcomes, such as B-type natriuretic peptide and neprilysin were decreased by a LSD. Cardiac systolic function, blood pressure and renal function were not affected. Although a LSD activates the classical RAAS system, we conclude that the LSD delayed HF progression and mortality in experimental DCM, in part through protective stimulation of the counter-regulatory RAAS to increase plasma ACE2 and angiotensin (1-7) levels, nitric oxide bioavailability and cGMP production.
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Angiotensina I/biosíntesis , GMP Cíclico/metabolismo , Dieta Hiposódica , Edema/prevención & control , Insuficiencia Cardíaca/complicaciones , Óxido Nítrico/metabolismo , Fragmentos de Péptidos/biosíntesis , Animales , Disponibilidad Biológica , Biomarcadores/sangre , Presión Sanguínea , Cardiomiopatía Dilatada/complicaciones , Cardiomiopatía Dilatada/fisiopatología , Edema/sangre , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/fisiopatología , Riñón/fisiopatología , Masculino , Ratones Endogámicos C57BL , Péptido Natriurético Encefálico/metabolismo , Óxido Nítrico/sangre , Óxido Nítrico Sintasa/metabolismo , Hidrolasas Diéster Fosfóricas/metabolismo , Derrame Pleural , Sistema Renina-Angiotensina , Análisis de Supervivencia , SístoleRESUMEN
BACKGROUND: Up to 50% of patients with proximal deep vein thrombosis (DVT) will develop the postthrombotic syndrome characterized by limb swelling and discomfort, hyperpigmentation, skin ulcers, and impaired quality of life. Although catheter-based interventions enabling the restoration of blood flow (RBF) have demonstrated little benefit on postthrombotic syndrome, the impact on the acuity of the thrombus and mechanisms underlying this finding remain obscure. In experimental and clinical studies, we examined whether RBF has a restricted time window for improving DVT resolution. METHODS: First, experimental stasis DVT was generated in C57/BL6 mice (n=291) by inferior vena cava ligation. To promote RBF, mice underwent mechanical deligation with or without intravenous recombinant tissue plasminogen activator administered 2 days after deligation. RBF was assessed over time by ultrasonography and intravital microscopy. Resected thrombosed inferior vena cava specimens underwent thrombus and vein wall histological and gene expression assays. Next, in a clinical study, we conducted a post hoc analysis of the ATTRACT (Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis) pharmacomechanical catheter-directed thrombolysis (PCDT) trial (NCT00790335) to assess the effects of PCDT on Venous Insufficiency Epidemiological and Economic Study quality-of-life and Villalta scores for specific symptom-onset-to-randomization timeframes. RESULTS: Mice that developed RBF by day 4, but not later, exhibited reduced day 8 thrombus burden parameters and reduced day 8 vein wall fibrosis and inflammation, compared with controls. In mice without RBF, recombinant tissue plasminogen activator administered at day 4, but not later, reduced day 8 thrombus burden and vein wall fibrosis. It is notable that, in mice already exhibiting RBF by day 4, recombinant tissue plasminogen activator administration did not further reduce thrombus burden or vein wall fibrosis. In the ATTRACT trial, patients receiving PCDT in an intermediate symptom-onset-to-randomization timeframe of 4 to 8 days demonstrated maximal benefits in Venous Insufficiency Epidemiological and Economic Study quality-of-life and Villalta scores (between-group difference=8.41 and 1.68, respectively, P<0.001 versus patients not receiving PCDT). PCDT did not improve postthrombotic syndrome scores for patients having a symptom-onset-to-randomization time of <4 days or >8 days. CONCLUSIONS: Taken together, these data illustrate that, within a restricted therapeutic window, RBF improves DVT resolution, and PCDT may improve clinical outcomes. Further studies are warranted to examine the value of time-restricted RBF strategies to reduce postthrombotic syndrome in patients with DVT.
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Circulación Sanguínea/fisiología , Endotelio Vascular/patología , Venas/patología , Trombosis de la Vena/fisiopatología , Animales , Femenino , Humanos , Masculino , Ratones , Calidad de Vida , Resultado del TratamientoRESUMEN
Matrix metalloproteinase-9 (MMP-9) degrades collagen and other cellular matrix proteins. After acute ischemic stroke, increased MMP-9 levels are correlated with hemorrhage, lack of reperfusion and stroke severity. Nevertheless, definitive data that MMP-9 itself causes poor outcomes in ischemic stroke are limited. In a model of experimental ischemic stroke with reperfusion, we examined whether ischemia and recombinant tissue plasminogen activator (r-tPA) therapy affected MMP-9 expression, and we used specific inhibitors to test if MMP-9 affects brain injury and recovery. After stroke, MMP-9 expression increased significantly in the ischemic vs. non-ischemic hemisphere of the brain (pâ¯<â¯0.001). MMP-9 expression in the ischemic, but not the non-ischemic hemisphere, was further increased by r-tPA treatment (pâ¯<â¯0.001). To determine whether MMP-9 expression contributed to stroke outcomes after r-tPA treatment, we tested three different antibody MMP-9 inhibitors. When compared to treatment with r-tPA and saline, treatment with r-tPA and MMP-9 antibody inhibitors significantly reduced brain hemorrhage by 11.3 to 38.6-fold (pâ¯<â¯0.01), brain swelling by 2.8 to 4.3-fold (pâ¯<â¯0.001) and brain infarction by 2.5 to 3.9-fold (pâ¯<â¯0.0001). Similarly, when compared to treatment with r-tPA and saline, treatment with r-tPA and an MMP-9 antibody inhibitor significantly improved neurobehavioral outcomes (pâ¯<â¯0.001), decreased weight loss (pâ¯<â¯0.001) and prolonged survival (pâ¯<â¯0.01). In summary, both prolonged ischemia and r-tPA selectively enhanced MMP-9 expression in the ischemic hemisphere. When administered with r-tPA, specific MMP-9 inhibitors markedly reduced brain hemorrhage, swelling, infarction, disability and death, which suggests that blocking the deleterious effects of MMP-9 may improve outcomes after ischemic stroke.
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Isquemia Encefálica , Accidente Cerebrovascular , Animales , Isquemia Encefálica/tratamiento farmacológico , Modelos Animales de Enfermedad , Fibrinolíticos/uso terapéutico , Isquemia/tratamiento farmacológico , Metaloproteinasa 9 de la Matriz , Accidente Cerebrovascular/tratamiento farmacológico , Activador de Tejido PlasminógenoRESUMEN
Nearly one in three people in the U.S. will develop heart failure (HF), characterized by fluid retention (edema) in the lungs and elsewhere. This leads to difficult breathing, deterioration of physical capacity, restriction of normal activities and death. There is little data about the safety and effects of sexual interactions in patients with HF. We tested whether a lack of sexual interactions affected pathophysiological outcomes in a pre-clinical mouse model of dilated cardiomyopathy that recapitulates the progressive stages of human HF. Male mice were randomly given access to, or deprived from, sexual interactions with female mice, which were confirmed by videography and generation of offspring. Cohousing with access to sexual interactions markedly prolonged survival, while cohousing without access to sexual activity did not. Sexual interactions improved systolic function, reduced HF-associated edema, altered transcription of heart contractile protein genes and decreased plasma testosterone levels. To determine whether testosterone levels contributed to survival, testosterone levels were experimentally reduced. Reduction of testosterone levels significantly prolonged survival. Taken together, in mice with dilated cardiomyopathy, sexual activity altered cardiac contractile gene transcription, improved systolic function, reduced edema and prolonged survival which may be in part due to lower testosterone levels.
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Cardiomiopatía Dilatada/prevención & control , Coito/fisiología , Insuficiencia Cardíaca/prevención & control , Conducta Sexual/fisiología , Animales , Cardiomiopatía Dilatada/fisiopatología , Modelos Animales de Enfermedad , Femenino , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Ratones , Contracción Miocárdica , Sobrevida/fisiologíaRESUMEN
Altered expression of corin, a cardiac transmembrane serine protease, has been linked to dilated and ischemic cardiomyopathy. However, the potential role of corin in myocardial infarction (MI) is lacking. This study examined the outcomes of MI in wild-type vs. cardiac-specific overexpressed corin transgenic (Corin-Tg) mice during pre-MI, early phase (3, 24, 72 h), and late phase (1, 4 weeks) post-MI. Corin overexpression significantly reduced cardiac cell apoptosis (p < 0.001), infarct size (p < 0.001), and inhibited cleavage of procaspases 3, 9, and 8 (p < 0.05 to p < 0.01), as well as altered the expression of Bcl2 family proteins, Bcl-xl, Bcl2 and Bak (p < 0.05 to p < 0.001) at 24 h post-MI. Overexpressed cardiac corin also significantly modulated heart function (ejection fraction, p < 0.0001), lung congestion (lung weight to body weight ratio, p < 0.0001), and systemic extracellular water (edema, p < 0.05) during late phase post-MI. Overall, cardiac corin overexpression significantly reduced apoptosis, infarct size, and modulated cardiac expression of key members of the apoptotic pathway in early phase post-MI; and led to significant improvement in heart function and reduced congestion in late phase post-MI. These findings suggest that corin may be a useful target to protect the heart from ischemic injury and subsequent post-infarction remodeling.
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Apoptosis/genética , Infarto del Miocardio/genética , Miocardio/metabolismo , Serina Endopeptidasas/genética , Animales , Muerte Celular/genética , Regulación de la Expresión Génica/genética , Humanos , Ratones , Ratones Transgénicos , Infarto del Miocardio/patología , Miocardio/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Remodelación Ventricular/genética , Proteína Destructora del Antagonista Homólogo bcl-2/genética , Proteína bcl-X/genéticaRESUMEN
Alpha2-antiplasmin (α2AP), the fast-reacting, serine protease inhibitor (serpin) of plasmin, was originally thought to play a key role in protection against uncontrolled, plasmin-mediated proteolysis of coagulation factors and other molecules. However, studies of humans and mice with genetic deficiency of α2AP have expanded our understanding of this serpin, particularly in disease states. Epidemiology studies have shown an association between high α2AP levels and increased risk or poor outcome in cardiovascular diseases. Mechanistic studies in disease models indicate that α2AP stops the body's own fibrinolytic system from dissolving pathologic thrombi that cause venous thrombosis, pulmonary embolism, arterial thrombosis, and ischemic stroke. In addition, α2AP fosters the development of microvascular thrombosis and enhances matrix metalloproteinase-9 expression. Through these mechanisms and others, α2AP contributes to brain injury, hemorrhage and swelling in experimental ischemic stroke. Recent studies also show that α2AP is required for the development of stasis thrombosis by inhibiting the early activation of effective fibrinolysis. In this review, we will discuss the key role played by α2AP in controlling thrombosis and fibrinolysis and, we will consider its potential value as a therapeutic target in cardiovascular diseases and ischemic stroke.
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AIMS: The impact of a history of heart failure (HF) on the outcomes of hospitalization for hyperglycemic crises (diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome) is unknown. We aimed to test the hypothesis that a history of HF has a deleterious impact on the outcomes of hospitalization for hyperglycemic crises. METHODS: We used two different datasets: National Inpatient Sample database 2003-2014 and a single University hospital cohort 2007-2017, to identify all adult hospitalizations with a primary diagnosis of hyperglycemic crises. Multivariable regression models were used to analyze the outcomes of in-hospital mortality, length of hospital stay and transfer to nursing home or similar short-term facility between HF and no-HF hospitalizations. RESULTS: Of the 1, 570,726 hyperglycemic crises related hospitalizations, a history of HF was present in 57, 520 (3.6%) hospitalizations. After multivariable risk-adjustment, HF group had a higher observed in-hospital mortality [0.4% vs. 0.2%; adjusted odds ratio (AOR)â¯=â¯1.7, 95% CI 1.4 to 2.0, Pâ¯<â¯.001] and transfer to nursing home or similar short-term facility (3.9 vs. 2.8%, AORâ¯=â¯1.4, 95% CI 1.3 to 1.5, Pâ¯<â¯.001) compared with no-HF group. Mean length of hospital stay [6.5 vs. 3.5â¯days; Pâ¯<â¯.001] was also higher for HF group than no-HF group. Data from the smaller University hospital cohort showed similar findings. CONCLUSIONS: Patients with a history of HF may be an under-recognized high-risk group among patients hospitalized for hyperglycemic crisis. Additional studies are warranted to clarify risk elements and optimize the inpatient care of individuals with hyperglycemic crises.
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Cetoacidosis Diabética/diagnóstico , Insuficiencia Cardíaca/diagnóstico , Hospitalización , Coma Hiperglucémico Hiperosmolar no Cetósico/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Cetoacidosis Diabética/complicaciones , Cetoacidosis Diabética/mortalidad , Femenino , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/mortalidad , Mortalidad Hospitalaria , Hospitalización/estadística & datos numéricos , Hospitales Universitarios , Humanos , Coma Hiperglucémico Hiperosmolar no Cetósico/complicaciones , Coma Hiperglucémico Hiperosmolar no Cetósico/mortalidad , Tiempo de Internación , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Heart failure (HF) patients frequently have elevated plasma renin activity. We examined the significance of elevated plasma renin activity in a translationally-relevant model of dilated cardiomyopathy (DCM), which replicates the progressive stages (A-D) of human HF. Female mice with DCM and elevated plasma renin activity concentrations were treated with a direct renin inhibitor (aliskiren) in a randomized, blinded fashion beginning at Stage B HF. By comparison to controls, aliskiren treatment normalized pathologically elevated plasma renin activity (p < 0.001) and neprilysin levels (p < 0.001), but did not significantly alter pathological changes in plasma aldosterone, angiotensin II, atrial natriuretic peptide, or corin levels. Aliskiren improved cardiac systolic function (ejection fraction, p < 0.05; cardiac output, p < 0.01) and significantly reduced the longitudinal development of edema (extracellular water, p < 0.0001), retarding the transition from Stage B to Stage C HF. The normalization of elevated plasma renin activity reduced the loss of body fat and lean mass (cachexia/sarcopenia), p < 0.001) and prolonged survival (p < 0.05). In summary, the normalization of plasma renin activity retards the progression of experimental HF by improving cardiac systolic function, reducing the development of systemic edema, cachexia/sarcopenia, and mortality. These data suggest that targeting pathologically elevated plasma renin activity may be beneficial in appropriately selected HF patients.
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Amidas/uso terapéutico , Cardiomiopatía Dilatada/tratamiento farmacológico , Fumaratos/uso terapéutico , Renina/antagonistas & inhibidores , Renina/sangre , Animales , Caquexia/sangre , Caquexia/complicaciones , Caquexia/tratamiento farmacológico , Cardiomiopatía Dilatada/sangre , Cardiomiopatía Dilatada/complicaciones , Modelos Animales de Enfermedad , Edema/sangre , Edema/complicaciones , Edema/tratamiento farmacológico , Femenino , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Ratones , Ratones Endogámicos C57BLRESUMEN
Stasis of venous blood triggers deep vein thrombosis by activating coagulation, yet its effects on the fibrinolytic system are not fully understood. We examined the relationship between stasis, fibrinolysis, and the development of experimental venous thrombosis. Effects of stasis-induced deep vein thrombosis and fibrinolysis on thrombosis were examined by inferior vena cava ligation in congenic mice with and without α2-antiplasmin (α2AP), the primary inhibitor of plasmin. Venous thrombus weights were measured and thrombus composition was determined by Martius scarlet blue and immunofluorescence staining. Venous thrombi from α2AP+/+ mice contained plasminogen activators, plasminogen activator inhibitor-1, plasminogen, and α2AP, which changed with thrombus age. Normal, α2AP+/+ mice developed large, occlusive thrombi within 5 hours after ligation; thrombi were even larger in plasminogen-deficient mice (P < .001). No significant thrombus formation was seen in α2AP-/- mice (P < .0001) or in α2AP+/+ mice treated with an α2AP-inactivating antibody (P < .001). Venous stasis activated fibrinolysis, measured by D-dimer levels, in α2AP-/- mice vs α2AP+/+ mice (P < .05). Inhibition of fibrinolysis by the indirect plasmin inhibitor ε-aminocaproic acid or by α2AP restored thrombosis in α2AP-/- mice. In addition to its effects on acute thrombosis, thrombus formation was also markedly suppressed in α2AP-/- mice vs α2AP+/+ mice (P < .0001) 1, 7, and 14 days after ligation. We conclude that experimental venous stasis activates the fibrinolytic system to block the development of venous thrombosis. Suppression of fibrinolysis by α2AP appears essential for stasis-induced thrombus development, which suggests that targeting α2AP may prove useful for preventing venous thrombosis.
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Fibrinólisis/fisiología , Síndrome Postrombótico/complicaciones , Trombosis de la Vena/prevención & control , alfa 2-Antiplasmina/fisiología , Animales , Modelos Animales de Enfermedad , Femenino , Fibrinólisis/genética , Ligadura , Masculino , Ratones , Ratones Congénicos , Ratones Endogámicos C57BL , Ratones Noqueados , Síndrome Postrombótico/sangre , Síndrome Postrombótico/genética , Síndrome Postrombótico/fisiopatología , Vena Cava Inferior/patología , Vena Cava Inferior/cirugía , Trombosis de la Vena/sangre , Trombosis de la Vena/genética , Trombosis de la Vena/fisiopatología , alfa 2-Antiplasmina/genéticaRESUMEN
Regardless of the cause, symptomatic heart failure (HF) with reduced ejection fraction (rEF) is characterized by pathological activation of the renin-angiotensin-aldosterone system (RAAS) with sodium retention and extracellular fluid expansion (edema). Here, we review the role of active renin, a crucial, upstream enzymatic regulator of the RAAS, as a prognostic and diagnostic plasma biomarker of heart failure with reduced ejection fraction (HFrEF) progression; we also discuss its potential as a pharmacological bio-target in HF therapy. Clinical and experimental studies indicate that plasma renin activity is elevated with symptomatic HFrEF with edema in patients, as well as in companion animals and experimental models of HF. Plasma renin activity levels are also reported to be elevated in patients and animals with rEF before the development of symptomatic HF. Modulation of renin activity in experimental HF significantly reduces edema formation and the progression of systolic dysfunction and improves survival. Thus, specific assessment and targeting of elevated renin activity may enhance diagnostic and therapeutic precision to improve outcomes in appropriate patients with HFrEF.
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Insuficiencia Cardíaca/sangre , Renina/sangre , Animales , Biomarcadores/sangre , Gasto Cardíaco , Fármacos Cardiovasculares/farmacología , Fármacos Cardiovasculares/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Humanos , Renina/antagonistas & inhibidores , SístoleRESUMEN
BACKGROUND: Excessive, plasmin-mediated fibrinolysis augments bleeding and contributes to death in some patients. Current therapies for fibrinolytic bleeding are limited by modest efficacy, low potency, and off-target effects. OBJECTIVES: To determine whether an antibody directed against unique loop structures of the plasmin protease domain may have enhanced specificity and potency for blocking plasmin activity, fibrinolysis, and experimental hemorrhage. METHODS: The binding specificity, affinity, protease cross-reactivity and antifibrinolytic properties of a monoclonal plasmin inhibitor antibody (Pi) were examined and compared with those of epsilon aminocaproic acid (EACA), which is a clinically used fibrinolysis inhibitor. RESULTS: Pi specifically recognized loop 5 of the protease domain, and did not bind to other serine proteases or nine other non-primate plasminogens. Pi was ~7 logs more potent in neutralizing plasmin cleavage of small-molecule substrates and >3 logs more potent in quenching fibrinolysis than EACA. Pi was similarly effective in blocking catalysis of a small-molecule substrate as α2 -antiplasmin, which is the most potent covalent inhibitor of plasmin, and was a more potent fibrinolysis inhibitor. Fab or chimerized Fab fragments of Pi were equivalently effective. In vivo, in a humanized model of fibrinolytic surgical bleeding, Pi significantly reduced bleeding to a greater extent than a clinical dose of EACA. CONCLUSIONS: A mAb directed against unique loop sequences in the protease domain is a highly specific, potent, competitive plasmin inhibitor that significantly reduces experimental surgical bleeding in vivo.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antifibrinolíticos/uso terapéutico , Fibrinolisina/antagonistas & inhibidores , Hemorragia/tratamiento farmacológico , Ácido Aminocaproico/farmacología , Ácido Aminocaproico/uso terapéutico , Animales , Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales Humanizados/farmacología , Afinidad de Anticuerpos , Unión Competitiva , Dominio Catalítico/inmunología , Reacciones Cruzadas , Evaluación Preclínica de Medicamentos , Femenino , Fibrinolisina/química , Fibrinolisina/inmunología , Fibrinólisis/efectos de los fármacos , Hemorragia/sangre , Humanos , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Conformación Proteica , Dominios Proteicos , Distribución Aleatoria , Proteínas Recombinantes de Fusión/inmunología , Especificidad de la Especie , Especificidad por SustratoRESUMEN
INTRODUCTION: Every year, more than 500,000 US Emergency Department visits are associated with cocaine use. People who use cocaine tend to have a lower incidence of true ST-elevation myocardial infarction (STEMI). OBJECTIVE: To identify the factors associated with true STEMI in patients with cocaine-positive (CPos) findings. METHODS: We retrospectively analyzed 1144 consecutive patients with STEMI between 2008 and 2013. True STEMI was defined as having a culprit lesion on coronary angiogram. Multivariate and univariate analyses were used to identify risk factors and create a predictive model. RESULTS: A total of 64 patients with suspected STEMI were CPos (mean age 53.1 ± 11.2 years; male = 80%). True STEMI was diagnosed in 34 patients. Patients with CPos true STEMI were more likely to be uninsured than those with false STEMI (61.8% vs 34.5%, p = 0.03) and have higher peak troponin levels (21.1 ng/mL vs 2.12 ng/mL, p = < 0.01) with no difference in mean age between the 2 groups (p = 0.24). In multivariate analyses, independent predictors of true STEMI in patients with CPos findings included age older than 65 years (odds ratio [OR] = 19.3, 95% confidence iterval [CI] = 1.2-318.3), lack of health insurance (OR = 4.9, 95% CI = 1.2-19.6), and troponin level higher than 0.05 (OR = 24.0, 95% CI = 2.6-216.8) (all p < 0.05). A multivariate risk score created with a C-statistic of 82% (95% CI = 71-93) significantly improved the identification of patients with true STEMI. CONCLUSION: Among those with suspected STEMI, patients with CPos findings had a higher incidence of false STEMI. Older age, lack of health insurance, and troponin levels outside of defined limits were associated with true STEMI in this group.
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Cocaína/efectos adversos , Angiografía Coronaria/métodos , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Infarto del Miocardio con Elevación del ST/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Obesity has been linked with increased incidence of atrial fibrillation (AF), but impact of presence of obesity on outcomes of hospitalizations for AF has not been investigated. We used the National Inpatient Sample database 2010 to 2014 to identify all adult hospitalizations aged ≥18years with a primary diagnosis of AF. Obese patients were identified using the co-morbidity variable for obesity, as defined in National Inpatient Sample databases. Multivariable logistic regression was used to compare in-hospital outcomes (mortality, acute stroke events) between obese and non-obese patients with AF. Of 431, 734 hospitalizations for AF, 66,138 (15.3%) were obese. Obese patients were younger and more likely to be African-Americans compared with non-obese patients. Despite being younger, obese patients had significantly higher prevalence of cardiovascular co-morbidities such as hypertension, diabetes mellitus, dyslipidemia, smoking, heart failure, and chronic renal failure (p <0.001 for all). After multivariate risk-adjustment, obese patients had a lower observed in-hospital mortality (0.5% vs 1.0%; unadjusted odds ratioâ¯=â¯0.52, 95% confidence interval [CI] 0.46 to 0.58, p <0.001; adjusted odds ratioâ¯=â¯0.83, 95% CI 0.73 to 0.94, p <0.001) and acute stroke events (0.4% vs 0.7%, unadjusted odds ratioâ¯=â¯0. 65, 95% CI 0.57 to 0.73, p < 0.001; adjusted odds ratioâ¯=â¯0.82, 95% CI 0.72 to 0.94) compared with non-obese patients. In conclusion, in this large retrospective analysis of an unselected nationwide cohort of patients hospitalized for AF, obese patients demonstrated lower risk-adjusted odds of in-hospital mortality and stroke events, consistent with an "obesity paradox."
Asunto(s)
Fibrilación Atrial/epidemiología , Hospitalización/estadística & datos numéricos , Pacientes Internos , Obesidad/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Comorbilidad , Femenino , Mortalidad Hospitalaria/tendencias , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Humans with dilated cardiomyopathy (DCM) and heart failure (HF) develop low levels of corin, a multi-domain, cardiac-selective serine protease involved in natriuretic peptide cleavage and sodium and water regulation. However, experimental restoration of corin levels markedly attenuates HF progression. To determine whether the beneficial effects of corin in HF require catalytic activity, we engineered cardiac overexpression of an enzymatically inactive corin transgene (corin-Tg(i)). On a wild-type (WT) background, corin-Tg(i) had no evident phenotypic effects. However, in a well-established genetic model of DCM, corin-Tg(i)/DCM mice had increased survival (p < 0.01 to 0.001) vs. littermate corin-WT/DCM controls. Pleural effusion (p < 0.01), lung edema (p < 0.05), systemic extracellular free water (p < 0.01), and heart weight were decreased (p < 0.01) in corin-Tg(i)/DCM vs. corin-WT/DCM mice. Cardiac ejection fraction and fractional shortening improved (p < 0.01), while ventricular dilation decreased (p < 0.0001) in corin-Tg(i)/DCM mice. Plasma atrial natriuretic peptide, cyclic guanosine monophosphate, and neprilysin were significantly decreased. Cardiac phosphorylated glycogen synthase kinase-3ß (pSer9-GSK3ß) levels were increased in corin(i)-Tg/DCM mice (p < 0.01). In summary, catalytically inactive corin-Tg(i) decreased fluid retention, improved contractile function, decreased HF biomarkers, and diminished cardiac GSK3ß activity. Thus, the protective effects of cardiac corin on HF progression and survival in experimental DCM do not require the serine protease activity of the molecule.