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AIMS: To characterize left atrial (LA) and left ventricular (LV) function and atrioventricular (AV) coupling in patients with moderate mixed aortic valve disease (MMAVD) against those with isolated moderate or severe aortic valve disease and controls. METHODS & RESULTS: Retrospective LA and LV peak longitudinal strain (LS) analysis were performed on 260 patients (46 MMAVD, 81 moderate aortic stenosis (AS), 50 severe AS, 48 moderate aortic regurgitation (AR), and 35 severe AR) and 66 controls. Peak LV and LA LS and AV coupling, assessed by combined peak LA and LV strain, was compared between the groups. ANOVA and 2-sided t-tests were used and a p-value of <0.01 was considered significant.LV strain was significantly lower in those with MMAVD compared to controls and those with moderate or severe isolated AR but comparable to those with moderate or severe AS (-17.1±1.1% MMAVD vs. -17.7±1.5% moderate AS p=0.02; vs. -17.0%±1.5% severe AS, p=0.74). AV coupling was significantly lower in those with MMAVD compared to controls and those with moderate AS or AR but comparable to those with severe AS or AR (47.1±6.8% MMAVD vs. 45.1±5.6% severe AS, p=0.13; vs. 50.4±9% severe AR, p=0.07). CONCLUSIONS: Impairments in AV coupling are comparable for patients with MMAVD and those with severe isolated AS or AR. Impairments in LV GLS in MMAVD mirror those found in severe AS. These findings suggest that haemodynamic consequences and adverse remodelling are similar for patients with MMAVD and isolated severe disease.
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OBJECTIVES: Echocardiography is an essential diagnostic modality known to have wide regional utilization variations. This study's objectives were to quantify regional variations and to examine the extent to which they are explained by differences in population age, sex, cardiac disease prevalence (CDP), and social determinants of health (SDH) risk. METHODS: This is an observational study of all echocardiography exams performed in Ontario in 2019/20 (n = 695,622). We measured regional variations in echocardiography crude rates and progressively standardized rates for population age, sex, CDP, and SDH risk. RESULTS: After controlling for differences in population age, sex, and CDP, Ontario's highest rate regions had echocardiography rates 57% higher than its lowest rate regions. Forty eight percent of total variation was not explained by differences in age, sex, and CDP. CDP increased with SDH risk. Access to most cardiac diagnostics was negatively correlated with SDH risk, while cardiac catheterization rates were positively correlated with SDH risk. CONCLUSION: Variations analysis that adjusts for age and sex only without including clinical measures of need are likely to overestimate the unwarranted portion of total variation. Substantial variations persisted despite a mandatory provider accreditation policy aimed at curtailing them. The associations between variations and SDH risks imply a need to redress access and outcome inequities.
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Servicios de Diagnóstico , Determinantes Sociales de la Salud , Humanos , Ontario/epidemiología , Encuestas y CuestionariosRESUMEN
Myocardial infarction (MI) remains a leading cause of morbidity and mortality. In atherothrombotic MI (ST-elevation MI and type 1 non-ST-elevation MI), coronary artery occlusion leads to ischemia. Subsequent cardiomyocyte necrosis evolves over time as a wavefront within the territory at risk. The spectrum of ischemia and reperfusion injury is wide: it can be minimal in aborted MI or myocardial necrosis can be large and complicated by microvascular obstruction and reperfusion hemorrhage. Established risk scores and infarct classifications help with patient management but do not consider tissue injury characteristics. This document outlines the Canadian Cardiovascular Society classification of acute MI. It is an expert consensus formed on the basis of decades of data on atherothrombotic MI with reperfusion therapy. Four stages of progressively worsening myocardial tissue injury are identified: (1) aborted MI (no/minimal myocardial necrosis); (2) MI with significant cardiomyocyte necrosis, but without microvascular injury; (3) cardiomyocyte necrosis and microvascular dysfunction leading to microvascular obstruction (ie, "no-reflow"); and (4) cardiomyocyte and microvascular necrosis leading to reperfusion hemorrhage. Each stage reflects progression of tissue pathology of myocardial ischemia and reperfusion injury from the previous stage. Clinical studies have shown worse remodeling and increase in adverse clinical outcomes with progressive injury. Notably, microvascular injury is of particular importance, with the most severe form (hemorrhagic MI) leading to infarct expansion and risk of mechanical complications. This classification has the potential to stratify risk in MI patients and lay the groundwork for development of new, injury stage-specific and tissue pathology-based therapies for MI.
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Infarto del Miocardio , Daño por Reperfusión , Humanos , Canadá/epidemiología , Infarto del Miocardio/complicaciones , Infarto del Miocardio/diagnóstico , Necrosis/complicaciones , Daño por Reperfusión/complicaciones , Hemorragia/etiologíaRESUMEN
Background: Peripheral artery disease (PAD) involves atherosclerosis of the lower extremity arteries and is a major contributor to limb loss and death worldwide. Several studies have demonstrated that interleukins (ILs) play an important role in the development and progression of PAD; however, a comprehensive literature review has not been performed. Methods: A systematic review was conducted and reported according to PRISMA guidelines. MEDLINE was searched from inception to 5 December 2022, and all studies assessing the association between ILs and PAD were included. Results: We included 17 studies from a pool of 771 unique articles. Five pro-inflammatory ILs (IL-1ß, IL-2, IL-5, IL-6, and IL-8) and one pro-atherogenic IL (IL-12) were positively correlated with PAD diagnosis and progression. In contrast, two anti-inflammatory ILs (IL-4 and IL-10) were protective against PAD diagnosis and adverse limb events. Specifically, IL-6 and IL-8 were the most strongly associated with PAD and can act as potential disease biomarkers to support the identification and treatment of PAD. Conclusions: Ongoing work to identify and validate diagnostic/prognostic inflammatory biomarkers for PAD has the potential to assist clinicians in identifying high-risk patients for further evaluation and management which could reduce the risk of adverse cardiovascular and limb events.
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Aterosclerosis , Enfermedad Arterial Periférica , Humanos , Interleucina-6 , Pronóstico , Interleucina-8 , Enfermedad Arterial Periférica/diagnóstico , Aterosclerosis/diagnóstico , Biomarcadores , Factores de RiesgoRESUMEN
Asthma is a heterogeneous disease, characterized by chronic inflammation and oxidative stress of the airways. Several inflammatory pathways including activation of the receptor for advanced glycation end products (RAGE) have been described in the course of the disease. DJ-1 is a redox-sensitive protein with multifaceted roles in mast cell homeostasis and an emerging role in the pathogenesis of asthma. Moreover, cardiac function abnormalities have been described via echocardiography in patients with asthma. The main aim of this study was to investigate the plasma levels of RAGE, its ligands and DJ-1 in asthmatic patients pre- and post-treatment along with echocardiographic indices of cardiovascular function. The study population was divided into two groups. Group A included 13 patients with newly diagnosed bronchial asthma who were free of treatment for at least two weeks and Group B included 12 patients without asthma. An echocardiography examination was performed on all patients. The plasma levels of RAGE, its ligands (AGEs, S100A12, S100B, S100A8/A9), the interleukins (IL-6, IL-1ß) and DJ-1 were measured. No differences were noted among the two groups for baseline characteristics and echocardiographic indices of cardiac function. In Group A, 31% suffered from mild asthma, 54% from moderate asthma and 15% from severe asthma. Plasma levels of IL-6, AGEs and AGE/RAGE ratio were increased and those of S100A12 and DJ-1 were decreased in asthmatics. Pharmacotherapy with corticosteroids/ß2-agonists decreased IL-6, and AGEs, and increased DJ-1. In search of novel approaches in diagnosing and treating patients with asthma, S100A12, ratio AGE/sRAGE, and DJ-1 in addition to IL-6 may prove to be useful tools.
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Asma , Proteína S100A12 , Humanos , Ligandos , Interleucina-6 , Receptor para Productos Finales de Glicación Avanzada , Productos Finales de Glicación Avanzada , Asma/diagnóstico por imagen , Asma/tratamiento farmacológico , EcocardiografíaRESUMEN
Virus-induced lung injury is associated with loss of pulmonary epithelial-endothelial tight junction integrity. While the alveolar-capillary membrane may be an indirect target of injury, viruses may interact directly and/or indirectly with miRs to augment their replication potential and evade the host antiviral defense system. Here, we expose how the influenza virus (H1N1) capitalizes on host-derived interferon-induced, microRNA (miR)-193b-5p to target occludin and compromise antiviral defenses. Lung biopsies from patients infected with H1N1 revealed increased miR-193b-5p levels, marked reduction in occludin protein, and disruption of the alveolar-capillary barrier. In C57BL/6 mice, the expression of miR-193b-5p increased, and occludin decreased, 5-6 days post-infection with influenza (PR8). Inhibition of miR-193b-5p in primary human bronchial, pulmonary microvascular, and nasal epithelial cells enhanced antiviral responses. miR-193b-deficient mice were resistant to PR8. Knockdown of occludin, both in vitro and in vivo, and overexpression of miR-193b-5p reconstituted susceptibility to viral infection. miR-193b-5p inhibitor mitigated loss of occludin, improved viral clearance, reduced lung edema, and augmented survival in infected mice. Our results elucidate how the innate immune system may be exploited by the influenza virus and how strategies that prevent loss of occludin and preserve tight junction function may limit susceptibility to virus-induced lung injury.
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Subtipo H1N1 del Virus de la Influenza A , Gripe Humana , Lesión Pulmonar , MicroARNs , Humanos , Animales , Ratones , Gripe Humana/complicaciones , Gripe Humana/genética , Gripe Humana/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Ocludina/genética , Ocludina/metabolismo , Lesión Pulmonar/metabolismo , Uniones Estrechas/metabolismo , Carga Viral , Subtipo H1N1 del Virus de la Influenza A/genética , Ratones Endogámicos C57BL , AntiviralesRESUMEN
In acute lung injury, the lung endothelial barrier is compromised. Loss of endothelial barrier integrity occurs in association with decreased levels of the tight junction protein claudin-5. Restoration of their levels by gene transfection may improve the vascular barrier, but how to limit transfection solely to regions of the lung that are injured is unknown. We hypothesized that thoracic ultrasound in combination with intravenous microbubbles (USMBs) could be used to achieve regional gene transfection in injured lung regions and improve endothelial barrier function. Since air blocks ultrasound energy, insonation of the lung is only achieved in areas of lung injury (edema and atelectasis); healthy lung is spared. Cavitation of the microbubbles achieves local tissue transfection. Here we demonstrate successful USMB-mediated gene transfection in the injured lungs of mice. After thoracic insonation, transfection was confined to the lung and only occurred in the setting of injured (but not healthy) lung. In a mouse model of acute lung injury, we observed downregulation of endogenous claudin-5 and an acute improvement in lung vascular leakage and in oxygenation after claudin-5 overexpression by transfection. The improvement occurred without any impairment of the immune response as measured by pathogen clearance, alveolar cytokines, and lung histology. In conclusion, USMB-mediated transfection targets injured lung regions and is a novel approach to the treatment of lung injury.NEW & NOTEWORTHY Acute respiratory distress syndrome is characterized by spatial heterogeneity, with severely injured lung regions adjacent to relatively normal areas. This makes targeting treatment to the injured regions difficult. Here we use thoracic ultrasound and intravenous microbubbles (USMBs) to direct gene transfection specifically to injured lung regions. Transfection of the tight junction protein claudin-5 improved oxygenation and decreased vascular leakage without impairing innate immunity. These findings suggest that USMB is a novel treatment for ARDS.
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Lesión Pulmonar Aguda , Síndrome de Dificultad Respiratoria , Animales , Ratones , Lesión Pulmonar Aguda/patología , Claudina-5/genética , Claudina-5/metabolismo , Inmunidad Innata , Pulmón/metabolismo , Síndrome de Dificultad Respiratoria/patología , Proteínas de Uniones Estrechas/metabolismo , Uniones Estrechas/metabolismo , Transfección , Ultrasonografía IntervencionalRESUMEN
Oxidative stress is considered one of the early underlying contributors of sepsis-induced myocardial depression. DJ-1, also known as PARK7, has a well-established role as an antioxidant. We have previously shown, in a clinically relevant model of polymicrobial sepsis, DJ-1 deficiency improved survival and bacterial clearance by decreasing ROS production. In the present study, we investigated the role of DJ-1 in sepsis-induced myocardial depression. Here we compared wildtype (WT) with DJ-1 deficient mice at 24 and 48 h after cecal ligation and puncture (CLP). In WT mice, DJ-1 was increased in the myocardium post-CLP. DJ-1 deficient mice, despite enhanced inflammatory and oxidative responses, had an attenuated hypertrophic phenotype, less apoptosis, improved mitochondrial function, and autophagy, that was associated with preservation of myocardial function and improved survival compared to WT mice post-CLP. Collectively, these results identify DJ-1 as a regulator of myocardial function and as such, makes it an attractive therapeutic target in the treatment of early sepsis-induced myocardial depression.
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OBJECTIVE: Intraoperative predictors of functional mitral valve (MV) stenosis after surgical repair of mitral regurgitation (MR) caused by prolapse remain poorly characterised. This study evaluated the effect of annuloplasty size on postoperative MV haemodynamics during exercise and evaluated predictors of MV hemodynamics. METHODS: 104 patients were randomly assigned to leaflet resection or preservation for surgical repair of MR in the Canadian Mitral Research Alliance CardioLink-2 study. In this post hoc analysis, we compared MV haemodynamics between the two surgical groups and examined the relationship between annuloplasty size and MV haemodynamics 1 year after repair in the combined groups. Echocardiograms were performed at baseline and intraoperatively. Exercise transthoracic echocardiography was performed 1 year postoperatively. Multivariable linear regression analysis was used to identify predictors of exercise MV gradients at follow-up. RESULTS: Mean age of participants was 65±10 years, and 83% were male. Median annuloplasty size was 34 (IQR 32-36). Dividing by the median, 48 (46%) had annuloplasty size of <34 mm and 56 (54%) had ≥34 mm. Mean and peak exercise gradients at 1 year were 11±5 mm Hg and 22±9 mm Hg in <34, and 6±3 mm Hg and 14±5 mm Hg in ≥34 (p<0.001). Rate of residual MR was similar in both groups. In multivariable analyses, annuloplasty size of ≥34 mm was associated with lower mean and peak exercise gradients at 12 months, after adjustment for repair type, age, sex, heart rate and body surface area (ß -4.1, 95% CI -6 to -3, p<0.001, and ß -7 95% CI -10 to -4, p<0.001, respectively). Intraoperative mean and peak MV gradients by transesophageal echocardiography independently predicted mean and peak resting and exercise gradients at follow-up (p<0.001). Similar results were obtained in both leaflet resection and preservation. CONCLUSION: Annuloplasty size of ≥34 mm is associated with a 4 and 7 mm Hg reduction in mean and peak exercise MV gradients, respectively, 1 year post MV repair regardless of the repair strategy used. Intraoperative TEE MV gradients predict exercise MV gradients 1 year post repair. TRIAL REGISTRATION NUMBER: NCT02552771.
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Anuloplastia de la Válvula Mitral , Insuficiencia de la Válvula Mitral , Estenosis de la Válvula Mitral , Humanos , Masculino , Persona de Mediana Edad , Anciano , Femenino , Insuficiencia de la Válvula Mitral/diagnóstico por imagen , Insuficiencia de la Válvula Mitral/cirugía , Insuficiencia de la Válvula Mitral/etiología , Válvula Mitral/diagnóstico por imagen , Válvula Mitral/cirugía , Anuloplastia de la Válvula Mitral/efectos adversos , Anuloplastia de la Válvula Mitral/métodos , Canadá , Hemodinámica , Estenosis de la Válvula Mitral/complicaciones , Resultado del TratamientoRESUMEN
BACKGROUND: Predischarge elevated mean mitral gradients (>5 mm Hg) may occur after repair for degenerative mitral regurgitation. We sought to identify risk factors associated with elevated gradients and to evaluate its impact on functional outcomes at 12 months in this subanalysis of the Canadian Mitral Research Alliance CardioLink-2 trial. METHODS: One hundred four patients with degenerative mitral regurgitation undergoing mitral repair were randomized to either a leaflet resection or preservation strategy. Logistic regression was used to identify risk factors associated with an elevated gradient. Functional outcomes at 12 months were compared between participants with and without elevated gradients. RESULTS: Elevated gradients was identified in 15 participants (14.4%), which was not significantly different based on allocation to each repair strategy (P = .10). Patients with elevated gradients were more likely to be women (odds ratio [OR], 4.28; 95% confidence interval [CI], 1.29-14.19; P = .02) and to have a lower preoperative hemoglobin level (OR, 0.93; 95% CI, 0.89-0.98; P = .01) and smaller intercommissural diameter (OR, 0.86; 95% CI, 0.76-0.97; P = .02) and mitral annuloplasty size (OR, 0.71; 95% CI, 0.57-0.87; P = .001). The ratio of intercommissural diameter-to-annuloplasty size was similar between those with and without elevated gradients (both 0.8 ± 0.1, P = .69). At 12 months those with elevated gradients had a worse New York Heart Association functional status (P = .0001), lower peak oxygen saturation in exercise test (P = .01), smaller body weight-walk distance product (P = .02), and higher Borg scale (P = .01) in the 6-minute walk test. CONCLUSIONS: Female gender, smaller mitral anatomy sizes, and lower preoperative hemoglobin levels were associated with postoperative elevated mitral gradients, which was in turn were associated with reduced functional status. Further research is warranted to investigate these potential risk factors.
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Implantación de Prótesis de Válvulas Cardíacas , Anuloplastia de la Válvula Mitral , Insuficiencia de la Válvula Mitral , Humanos , Femenino , Masculino , Insuficiencia de la Válvula Mitral/etiología , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Canadá/epidemiología , Anuloplastia de la Válvula Mitral/efectos adversos , Factores de Riesgo , Hemoglobinas , Resultado del TratamientoRESUMEN
OBJECTIVES: In the Canadian Mitral Research Alliance (CAMRA) Trial CardioLink-2 leaflet resection versus preservation techniques for posterior leaflet prolapse was investigated and no difference was shown in their effect on mean mitral gradient at peak exercise at 12 months postoperatively. The purpose of this subanalysis was to evaluate the effect of the 2 strategies on left ventricular (LV) reverse remodeling after repair. METHODS: A total of 104 patients were randomized to either a leaflet resection or leaflet preservation strategy. Echocardiograms, performed at baseline (preoperative), predischarge, and 12 months postoperatively, were analyzed in a blinded fashion at a core laboratory. RESULTS: All patients underwent successful mitral repair. At discharge, 3 patients showed moderate mitral regurgitation, whereas the remainder showed mild or less regurgitation. Compared with the baseline echocardiogram, the indexed end diastolic volume was reduced at the discharge echocardiogram (P < .0001) and was further reduced at the 12-month echocardiogram (P = .01). In contrast, the indexed end systolic volume did not significantly change from baseline assessed at the predischarge echocardiogram (P = .32) but improved at 12 months postoperatively (P < .0001), resulting in a corresponding improvement in ejection fraction at 12 months (P < .0001). The type of mitral repair strategy had no significant effect on LV reverse remodeling trends. CONCLUSIONS: The mitral repair strategies used did not influence postoperative LV reverse remodeling, which occurred in stages. Although LV end diastolic dimensions recovered before discharge, improvements in LV end systolic dimension were evident 12 months after repair.
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Implantación de Prótesis de Válvulas Cardíacas , Insuficiencia de la Válvula Mitral , Humanos , Canadá , Insuficiencia de la Válvula Mitral/diagnóstico por imagen , Insuficiencia de la Válvula Mitral/cirugía , Ecocardiografía , Implantación de Prótesis de Válvulas Cardíacas/métodos , Remodelación VentricularRESUMEN
Coronary artery ectasia (CAE) is defined as abnormal dilation of a coronary artery with a diameter exceeding that of adjacent normal arterial segment by >1.5 times. CAE is a pathological entity of the coronary arteries and characterized as a variant of coronary atherosclerosis. CAE frequently coexists with coronary artery disease (CAD). While inflammation appears to be involved, the pathophysiology of CAE remains unclear. Damage-associated molecular patterns (DAMPs), defined as endogenous molecules released from stressed or damaged tissue, are deemed as alarm signals by the innate immune system. Inflammatory agents can generate DAMPs and DAMPs can create a pro-inflammatory state. In a prospective cross-sectional study, we enrolled 29 patients with CAE and non-obstructive CAD, 19 patients with obstructive CAD without CAE, and 14 control subjects with normal (control) coronary arteries age- and sex-matched with the CAE patients, to investigate the differential expression of plasma DAMPs. Patients with CAE and non-obstructive CAD had increased plasma levels of the DAMPs S100B, S100A12, HMGB1, and HSP70, the DAMPs receptor TLR4, and miR328a-3p compared to CAD and controls. Plasma levels of the mir328a-3p target the protective soluble form of the DAMPs receptor for advanced glycation end products (sRAGE), and the antioxidant DJ-1 was decreased in both CAE and CAD compared to controls. In an in vitro human umbilical vein endothelial cells model, circulating levels of S100B, HMGB1, HSP70 as well as CAE patient plasma induced inflammatory responses. The differential expression of the DAMPs S100B, HSP70, HMGB1, and their receptors TLR4 and sRAGE in CAE versus CAD makes them attractive novel biomarkers as therapeutic targets and therapeutics.
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Enfermedad de la Arteria Coronaria , Proteína HMGB1 , Humanos , Proteína HMGB1/genética , Dilatación Patológica , Angiografía Coronaria , Estudios Prospectivos , Estudios Transversales , Células Endoteliales/patología , Receptor Toll-Like 4/genética , AlarminasRESUMEN
Angiogenesis is a critical process in tumor progression. Inhibition of angiogenesis by blocking VEGF signaling can impair existing tumor vessels and halt tumor progression. However, the benefits are transient, and most patients who initially respond to these therapies develop resistance. Accordingly, there is a need for new anti-angiogenesis therapeutics to delay the processes of resistance or eliminate the resistive effects entirely. This manuscript presents the results of a screen of the National Institutes of Health Clinical Collections Libraries I & II (NIHCCLI&II) for novel angiogenesis inhibitors. The 727 compounds of the NIHCCLI&II library were screened with a high-throughput drug discovery platform (HTP) developed previously with angiogenesis-specific protocols utilizing zebrafish. The screen resulted in 14 hit compounds that were subsequently narrowed down to one, with PD 81,723 chosen as the lead compound. PD 81,723 was validated as an inhibitor of angiogenesis in vivo in zebrafish and in vitro in human umbilical vein endothelial cells (HUVECs). Zebrafish exposed to PD 81,723 exhibited several signs of a diminished endothelial network due to the inhibition of angiogenesis. Immunochemical analysis did not reveal any significant apoptotic or mitotic activity in the zebrafish. Assays with cultured HUVECs elucidated the ability of PD 81,723 to inhibit capillary tube formation, migration, and proliferation of endothelial cells. In addition, PD 81,723 did not induce apoptosis while significantly down regulating p21, AKT, VEGFR-2, p-VEGFR-2, eNOS, and p-eNOS, with no notable change in endogenous VEGF-A in cultured HUVECs.
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Inhibidores de la Angiogénesis , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Movimiento Celular , Proliferación Celular , Células Endoteliales de la Vena Umbilical Humana , Humanos , Neovascularización Patológica/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular , Pez CebraRESUMEN
BACKGROUND: Although predictors of reverse left ventricular (LV) remodeling postmitral valve repair are critical for guiding perioperative decision-making, there remains a paucity of randomized, prospective data to support the criteria that potential predictor variables must meet. METHODS AND RESULTS: The CAMRA CardioLink-2 randomized trial allocated 104 patients to either leaflet resection or preservation strategies for mitral repair. The correlation of indexed left ventricular end-systolic volume (LVESVI), indexed left ventricular end-diastolic volume (LVEDVI), and left ventricular ejection fraction (LVEF) were tested with univariate analysis and subsequently with multivariate analysis to determine independent predictors of reverse remodeling at discharge and at 12 months postoperatively. At discharge, both LVESVI and LVEDVI were independently associated with their preoperative values (p < .001 for both) and LVEF by preoperative LVESVI (p < .001). Mitral ring size was favorably associated with the change in LVESVI (p < .05) and LVEF (p < .01) from predischarge to 12 months, while the mean mitral valve gradient after repair was adversely associated with the change in LVESVI (p < .05) and LVEDVI (p < .05). No significant associations were found between reverse remodeling and coaptation height nor mitral repair technique. CONCLUSIONS: Beyond confirming the lack of impact of mitral repair technique on reverse remodeling, this investigation suggests that recommending surgery before significant LV dilatation or dysfunction, as well as higher postoperative mitral valve hemodynamic performance, may enhance remodeling capacity following mitral repair.
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Insuficiencia de la Válvula Mitral , Humanos , Insuficiencia de la Válvula Mitral/diagnóstico por imagen , Insuficiencia de la Válvula Mitral/cirugía , Estudios Prospectivos , Volumen Sistólico , Resultado del Tratamiento , Función Ventricular Izquierda , Remodelación VentricularRESUMEN
BACKGROUND: Mitral valve repair is the gold standard treatment for degenerative mitral regurgitation (MR). The Canadian Mitral Research Alliance (CAMRA) CardioLink-2 trial showed no significant association between repair strategy, that is, leaflet resection vs preservation, and risk of functional mitral stenosis. In this subanalysis, we compared outcomes and functional tests at 12 months. METHODS: CAMRA CardioLink-2 was a multicentre randomized controlled trial that allocated patients with degenerative MR and posterior leaflet prolapse to leaflet resection (n = 54) or preservation (n = 50). Stress echocardiography and functional status assessments, including the 6-minute walk test, were compared 12 months after repair. RESULTS: Baseline demographics, stress echocardiographic findings, and mitral annuloplasty prosthesis size (33.0 ± 3.0 vs 33.6 ± 3.4 mm; P = 0.4) were similar between the two groups. There were no readmissions for heart failure or deaths during the follow-up period. At 12 months, a larger percentage of patients were in NYHA functional class ≥ 2 in the resection group compared with the preservation group (P = 0.01). Exercise capacity, rate-pressure product, 6-minute walk distance, and mean mitral valve gradients were not significantly different between the groups at 12 months. A more prominent increase in mean mitral gradient with smaller annuloplasty sizes was observed in the resection group at both rest (P = 0.03) and peak exercise (P = 0.005) in the linear regression model. CONCLUSIONS: At 12 months, there were no significant differences in mitral valve gradient, exercise capacity, and 6-minute walk test between repair strategies. Leaflet preservation may offer a larger mitral valve orifice with improved gradients in patients requiring smaller annuloplasty sizes.
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Implantación de Prótesis de Válvulas Cardíacas , Anuloplastia de la Válvula Mitral , Insuficiencia de la Válvula Mitral , Prolapso de la Válvula Mitral , Estenosis de la Válvula Mitral , Canadá/epidemiología , Humanos , Insuficiencia de la Válvula Mitral/diagnóstico , Insuficiencia de la Válvula Mitral/cirugía , Prolapso de la Válvula Mitral/cirugía , Resultado del TratamientoRESUMEN
BACKGROUND: Patients with diabetes are at a high risk for developing cardiac dysfunction in the absence of coronary artery disease or hypertension, a condition known as diabetic cardiomyopathy. Contributing to heart failure is the presence of diabetic kidney disease. The Goto-Kakizaki (GK) rat is a non-obese, non-hypertensive model of type 2 diabetes that, like humans, shares a susceptibility locus on chromosome 10. Herein, we perform a detailed analysis of cardio-renal remodeling and response to renin angiotensin system blockade in GK rats to ascertain the validity of this model for further insights into disease pathogenesis. METHODS: Study 1: Male GK rats along with age matched Wistar control animals underwent longitudinal assessment of cardiac and renal function for 32 weeks (total age 48 weeks). Animals underwent regular echocardiography every 4 weeks and at sacrifice, early (~24 weeks) and late (~48 weeks) timepoints, along with pressure volume loop analysis. Histological and molecular characteristics were determined using standard techniques. Study 2: the effect of renin angiotensin system (RAS) blockade upon cardiac and renal function was assessed in GK rats. Finally, proteomic studies were conducted in vivo and in vitro to identify novel pathways involved in remodeling responses. RESULTS: GK rats developed hyperglycaemia by 12 weeks of age (p<0.01 c/w Wistar controls). Echocardiographic assessment of cardiac function demonstrated preserved systolic function by 48 weeks of age. Invasive studies demonstrated left ventricular hypertrophy, pulmonary congestion and impaired diastolic function. Renal function was preserved with evidence of hyperfiltration. Cardiac histological analysis demonstrated myocyte hypertrophy (p<0.05) with evidence of significant interstitial fibrosis (p<0.05). RT qPCR demonstrated activation of the fetal gene program, consistent with cellular hypertrophy. RAS blockade resulted in a reduction blood pressure(P<0.05) cardiac interstitial fibrosis (p<0.05) and activation of fetal gene program. No significant change on either systolic or diastolic function was observed, along with minimal impact upon renal structure or function. Proteomic studies demonstrated significant changes in proteins involved in oxidative phosp4horylation, mitochondrial dysfunction, beta-oxidation, and PI3K/Akt signalling (all p<0.05). Further, similar changes were observed in both LV samples from GK rats and H9C2 cells incubated in high glucose media. CONCLUSION: By 48 weeks of age, the diabetic GK rat demonstrates evidence of preserved systolic function and impaired relaxation, along with cardiac hypertrophy, in the presence of hyperfiltration and elevated protein excretion. These findings suggest the GK rat demonstrates some, but not all features of diabetes induced "cardiorenal" syndrome. This has implications for the use of this model to assess preclinical strategies to treat cardiorenal disease.