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Pubblicazioni recenti - cardiovascular
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Percutaneous fluoroscopically-guided transcervical retrograde access facilitates successful thoracic duct embolization after failed antegrade transabdominal access.
Lymphology2019 ;52(2):52-60.
Bundy J J, Chick J F, Jiao A, Cline M R, Srinivasa R N, Khayat M, Gnannt R, Johnson E J, Gemmete J J, Monroe E J, Srinivasa R N,
Abstract
The purpose of this study was to demonstrate the feasibility of percutaneous fluoroscopically-guided transcervical retrograde access into the thoracic duct following unsuccessful transabdominal cisterna chyli cannulation to perform thoracic duct embolization for the treatment of chylothorax. Five patients, including three (60%) women and two (40%) men, with median age of 62 years, underwent percutaneous transcervical thoracic duct access and embolization after failed transabdominal cisterna chyli cannulation for the treatment of chylothorax. In all patients, fluoroscopically-guided percutaneous transcervical retrograde access into the distal thoracic duct was achieved using a 21-gauge needle and an 0.018-inch wire. Following advancement of a microcatheter, retrograde lymphangiography was performed to identify the location of thoracic duct injury. A combination of 2:1 ethiodized oil to cyanoacrylate mixtures, platinum microcoils, or stent-grafts were used to treat the chylous leaks. Technical successes, procedure durations, fluoroscopy times, blood losses, immediate adverse events, clinical successes, and follow-up durations were recorded. Technical success was defined as cannulation of the distal thoracic duct using a transcervical approach followed by treatment of the thoracic duct injury. Adverse events were classified according to the Society of Interventional Radiology guidelines. Clinical success was defined as resolution of the presenting chylothorax. Percutaneous transcervical retrograde thoracic duct access and treatment was technically successful in all patients (n=5). Median procedure duration was 173 minutes (range: 136-347 minutes) with a median fluoroscopy time of 94.7 minutes (range: 47-125 minutes). Median blood loss was 10 mL (range: 5-20 mL). No minor or major adverse occurred. Clinical success was achieved in all patients (n=5). Median follow-up was 372 days (range: 67-661 days). Percutaneous fluoroscopically- guided transcervical retrograde thoracic duct access is an effective and safe method to perform thoracic duct embolization following unsuccessful transabdominal cisterna chyli cannulation for the treatment of chylothorax.
Copyright by International Society of Lymphology.
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Personalized Prediction of Cardiovascular Benefits and Bleeding Harms From Aspirin for Primary Prevention: A Benefit-Harm Analysis.
Ann Intern Med2019 Sep;():. doi: 10.7326/M19-1132.
Selak Vanessa, Jackson Rod, Poppe Katrina, Wu Billy, Harwood Matire, Grey Corina, Pylypchuk Romana, Mehta Suneela, Choi Yeun-Hyang, Kerr Andrew, Wells Sue,
Abstract
Background:
Whether the benefits of aspirin for the primary prevention of cardiovascular disease (CVD) outweigh its bleeding harms in some patients is unclear.
Objective:
To identify persons without CVD for whom aspirin would probably result in a net benefit.
Design:
Individualized benefit-harm analysis based on sex-specific risk scores and estimates of the proportional effect of aspirin on CVD and major bleeding from a 2019 meta-analysis.
Setting:
New Zealand primary care.
Participants:
245 028 persons (43.6% women) aged 30 to 79 years without established CVD who had their CVD risk assessed between 2012 and 2016.
Measurements:
The net effect of aspirin was calculated for each participant by subtracting the number of CVD events likely to be prevented (CVD risk score × proportional effect of aspirin on CVD risk) from the number of major bleeds likely to be caused (major bleed risk score × proportional effect of aspirin on major bleeding risk) over 5 years.
Results:
2.5% of women and 12.1% of men were likely to have a net benefit from aspirin treatment for 5 years if 1 CVD event was assumed to be equivalent in severity to 1 major bleed, increasing to 21.4% of women and 40.7% of men if 1 CVD event was assumed to be equivalent to 2 major bleeds. Net benefit subgroups had higher baseline CVD risk, higher levels of most established CVD risk factors, and lower levels of bleeding-specific risk factors than net harm subgroups.
Limitations:
Risk scores and effect estimates were uncertain. Effects of aspirin on cancer outcomes were not considered. Applicability to non-New Zealand populations was not assessed.
Conclusion:
For some persons without CVD, aspirin is likely to result in net benefit.
Primary Funding Source:
Health Research Council of New Zealand.
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Individualize Treatment With Aspirin for Primary Prevention.
Ann Intern Med -
Effect-site concentration of remifentanil for inhibiting cardiovascular responses to double-lumen tube intubation with Airtraq videolaryngoscopy: A comparison with Macintosh laryngoscopy.
J Clin Anesth2019 Sep;60():97-98. doi: S0952-8180(19)31205-X.
Feng Miaomiao, Qiu Jin, Qian Wei, Wan Li, Zhang Chuanhan, Yao Wenlong,
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Subclinical cardiac stiffness is associated with arterial stiffness in healthy young nulligravid women: Potential links to preeclampsia.
Pregnancy Hypertens2019 Sep;18():49-54. doi: S2210-7789(19)30349-6.
Cooper Kylie M, Barrett Trace, McBride Carole A, Badger Gary J, Steiner Johannes, LeWinter Martin M, Bernstein Ira M,
Abstract
OBJECTIVES:
Preeclampsia is an independent risk factor for subsequent cardiovascular disease and diastolic dysfunction and has been linked to arterial stiffness. We hypothesized that arterial stiffness would be associated with echocardiographic markers of diastolic dysfunction in healthy nulligravid women.
STUDY DESIGN:
31 healthy nulligravid women underwent assessment of peripheral arterial stiffness via aorto-femoral pulse wave velocity, popliteal distensibility and ? stiffness measures as well as hemodynamic response to volume challenge. 22 underwent cardiac assessment via conventional and stress echocardiography with a focus on diastolic function utilizing tissue/pulse wave Doppler imaging and 3D speckle tracking. Bivariate associations between variables were evaluated using correlation coefficients (Pearson r) and Student's t-tests.
RESULTS:
No participants had echocardiographic values meeting criteria for overt diastolic dysfunction. Baseline global circumferential strain was significantly correlated with distensibility and ? stiffness (n?=?18, r?=?-0.61, p?=?0.007, n?=?18, r?=?0.56, p?=?0.01). Peak deceleration time was correlated with ?stiffness (n?=?9; r?=?0.80, p?=?0.01). Pulse wave velocity was not significantly correlated with cardiac measures (p?>?0.05). Family history of a first or second degree relative with myocardial infarction or hypertension was associated with decreased popliteal artery distensibility (p?=?0.02 and p?=?0.03, respectively).
CONCLUSIONS:
In healthy nulligravid women there is evidence that markers of decreased left ventricular relaxation are associated with increased peripheral vascular stiffness as is a family history of myocardial infarction or hypertension. These findings raise the possibility that the diastolic dysfunction and arterial stiffness observed in the setting of preeclampsia are driven by underlying properties present prior to pregnancy and contribute to lifetime cardiovascular risk.
Copyright © 2019 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.
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Interrupting providers with clinical decision support to improve care for heart failure.
Int J Med Inform2019 Sep;131():103956. doi: S1386-5056(19)30462-9.
Blecker Saul, Austrian Jonathan S, Horwitz Leora I, Kuperman Gilad, Shelley Donna, Ferrauiola Meg, Katz Stuart D,
Abstract
BACKGROUND:
Evidence-based therapy for heart failure remains underutilized at hospital discharge, particularly for patients with heart failure who are hospitalized for another cause. We developed clinical decision support (CDS) to recommend an angiotensin converting enzyme (ACE) inhibitor during hospitalization to promote its continuation at discharge. The CDS was designed to be implemented in both interruptive and non-interruptive versions.
OBJECTIVES:
To compare the effectiveness and implementation of interruptive and non-interruptive versions of a CDS to improve care for heart failure.
METHODS:
Hospitalizations of patients with reduced ejection fraction were pseudo-randomized to deliver interruptive or non-interruptive CDS alerts to providers based on even or odd medical record number. We compared discharge utilization of an ACE inhibitor or angiotensin receptor blocker (ARB) for these two implementation approaches. We also assessed adoption and implementation fidelity of the CDS.
RESULTS:
Of 958 hospitalizations, interruptive alert hospitalizations had higher rates of discharge utilization of ACE inhibitors or ARBs than non-interruptive alert hospitalizations (79.6% vs. 74.2%, p?=?0.05). Utilization was higher for interruptive alert versus non-interruptive alert hospitalizations which were principally for causes other than heart failure (79.8% vs. 73.4%; p?=?0.05) but no difference was observed among hospitalizations with a principal heart failure diagnosis (85.9% vs.81.7%; p?=?0.49). As compared to non-interruptive hospitalizations, interruptive alert hospitalizations were more likely to have had: an alert with any response (40.6% vs. 13.1%, p?
CONCLUSIONS:
A CDS implemented as an interruptive alert was associated with improved quality of care for heart failure. Whether the potential benefits of CDS in improving cardiovascular care were worth the high burden of interruptive alerts deserves further consideration. CLINICALTRIALS.
GOV IDENTIFIER:
NCT02858674.
Copyright © 2019 Elsevier B.V. All rights reserved.
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Resilience among older cardiovascular disease patients with probable sarcopenia.
Arch Gerontol Geriatr2019 Aug;86():103939. doi: S0167-4943(19)30182-7.
Lee Szu-Ying, Tung Heng-Hsin, Peng Li-Ning, Chen Liang-Kung, Hsu Ching-I, Huang Yen-Ling,
Abstract
AIM AND OBJECTIVES:
The purpose of this study was to investigate the factors associated with resilience among probable sarcopenia older adults with cardiovascular disease.
INTRODUCTION:
Resilience has been reported to be positively correlated with the mental health and physical functioning of older adults. Previous research has found that the development of resilience constitutes a form of compensation for loss of physical health. It is important for older adults, especially those with other underlying conditions, such as cardiovascular disease and sarcopenia, to have the ability to overcome adversity during the aging process. Thus, resilience becomes a critical characteristic in achieving a better life.
METHODS:
A cross-sectional study design was used. A demographic questionnaire and the Chinese version of the Resilience Scale (CRS) were used to collect data. Multiple logistic regression was used to evaluate the predictors of low resilience.
RESULTS:
A total of 267 participants were recruited, including 126 females and 141 males. Of the participants, 56% of their scores indicated low resilience. Income, education level, exercise time, primary caregiver, and having hypertension were the predictors of resilience.
CONCLUSION:
The population with sarcopenia is increasing worldwide. Understanding resilience levels among older adults with probable sarcopenia is essential for promoting their mental health. Clinicians can use the results of this study to identify populations at high risk for low resilience and design specific interventions to promote better health outcomes.
Copyright © 2019 Elsevier B.V. All rights reserved.
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Donor age significantly influences the Raman spectroscopic biomolecular fingerprint of human pancreatic extracellular matrix proteins following collagenase-based digestion.
Acta Biomater2019 Sep;():. doi: S1742-7061(19)30625-7.
Spiers Rebecca M, Marzi Julia, Brauchle Eva M, Cross Sarah E, Vaughan Rebecca H, Bateman Paul A, Hughes Stephen J, Schenke-Layland Katja, Johnson Paul R V,
Abstract
Despite the enormous advances in the field of clinical pancreatic islet transplantation over the past two decades, the human islet isolation procedure remains suboptimal. Islets are extracted (isolated) from the exocrine tissue of donor pancreases using neutral protease (NP) and collagenase-based enzymes, which digest the extracellular matrix (ECM) scaffold surrounding human islets. This process remains highly variable and current isolation enzyme blends are ineffective at digesting pancreases from younger donors with low body mass indexes (BMI). However, age-related differences in pancreatic matrix digestion have not been studied in detail at the molecular level. To address this, we investigated ECM digestion in purified ECM proteins and in pancreatic tissue sections from younger (?30 years; n=5) and older (>55 years; n=5) BMI matched donors, using Raman microspectroscopy (RMS). The Raman spectral profiles for purified collagens I, IV, VI and laminins were significantly altered following controlled enzyme treatment. Pancreatic cryosections were treated with Serva collagenase, NP, or the two enzymes combined, at clinically relevant concentrations. RMS demonstrated that the ECM at the islet-exocrine interface was differentially digested with respect to donor age. The action of collagenase was affected to a greater extent than NP. RMS is a powerful, marker-independent technology for characterising the human pancreatic ECM and demonstrating differences between donor types. Ongoing detailed studies using RMS will assist the development of donor-specific enzyme blends, increasing the overall success of human islet isolation and benefiting many people with type 1 diabetes worldwide. Statement of significance Pancreatic islet transplantation is a minimally invasive treatment, which can reverse Type 1 Diabetes Mellitus (T1DM) in selected patients. Islets of Langerhans are extracted (isolated) from the exocrine tissue of human donor pancreases using neutral protease (NP) and collagenase-based enzymes, which digest the extracellular matrix (ECM) scaffold surrounding human islets. This process remains highly variable and current enzymes are ineffective at digesting pancreases from younger donors. Using Raman microspectroscopy we demonstrate that donor age affects the enzymatic digestion of the pancreatic ECM at the molecular level. Collagenase activity is affected to a greater extent than NP. These findings will assist the development of donor-specific enzymes, thereby increasing the overall success of islet isolation and benefiting many people with T1DM worldwide.
Copyright © 2019. Published by Elsevier Ltd.
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Derivation and Validation of an Early Diagnostic Score for Mediastinitis After Cardiothoracic Surgery.
Int J Infect Dis2019 Sep;():. doi: S1201-9712(19)30372-8.
Focaccia Siciliano Rinaldo, Medina Andrea Carolina Rodas, Bittencourt Márcio Sommer, Gualandro Danielle, Uezumi Kiyomi Kato, Santos Marcus Vinicius Barbosa, Pomerantzeff Pablo Maria Alberto, Scarpa Bruna, Leal Tatiana de Carvalho Andreuci Torres, Varejão Strabelli Tania Mara,
Abstract
OBJECTIVES:
The aim of this study was to elaborate on and validate a score for the early diagnosis of mediastinitis after cardiothoracic surgery.
METHODS:
Between 2007 and 2017, patients who experienced thoracic surgical-site infection after cardiothoracic surgery were enrolled. Laboratory, clinical, and chest CT findings were retrospectively analyzed. Patients were followed up until hospital discharge or intra-hospital death. Univariate and multivariate regression analyses were performed.
RESULTS:
950 surgical-site infections were found and analyzed (131 mediastinitis, 819 superficial/deep infections). Of the 131 mediastinitis episodes, 88% required surgical thoracic debridement,Staphylococcus aureus was identified in 43%, and overall mortality was 42%. The following variables were related to mediastinitis diagnosis: sternal diastasis (OR?=?2.5; 95% confidence interval [95%CI]: 1.2-5.3; P?=?0.012), bilateral pleural effusion (OR=1.9; 95%CI: 1.0-3.6; P?=?0.04), leukocyte count ?14,000cells/mm (Bitkover et al., 1999) (OR?=?2.5; 95%CI: 1.3-4.7; P?=?0.006), male sex (OR=2; 95%CI: 1.11-4; P?=?0.022), and positive blood culture (OR=3.0; 95%CI: 1.6-5.6; P?=?0.001). The score predicted with reasonable accuracy mediastinitis in the derivation cohort (AUC-ROC, 0.7476) and the validation cohort (AUC-ROC, 0.7149). Groups with high (31%) and low (5%) risk of mediastinitis were identified.
CONCLUSIONS:
An early diagnostic score in patients with surgical-site infection after cardiothoracic surgery identified groups with a low and high risk for mediastinitis.
Copyright © 2019. Published by Elsevier Ltd.
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The impact of physiological stress conditions on protein structure and trypsin inhibition of serine protease inhibitor Kazal type 1 (SPINK1) and its N34S variant.
Biochim Biophys Acta Proteins Proteom2019 Sep;():140281. doi: S1570-9639(19)30167-0.
Buchholz Ina, Nagel Felix, Klein Annelie, Wagh Preshit R, Mahajan Ujjwal M, Greinacher Andreas, Lerch Markus M, Mayerle Julia, Delcea Mihaela,
Abstract
One of the most common mutations in the serine protease inhibitor Kazal type 1 (SPINK1) gene is the N34S variant which is strongly associated with chronic pancreatitis. Although it is assumed that N34S mutation constitutes a high-risk factor, the underlying pathologic mechanism is still unknown. In the present study, we investigated the impact of physiological stress factors on SPINK1 protein structure and trypsin inhibitor function using biophysical methods. Our circular dichroism spectroscopy data revealed differences in the secondary structure of SPINK1 and N34S mutant suggesting protein structural changes induced by the mutation as an impairment that could be disease-relevant. We further confirmed that both SPINK1 (K of 0.15?±?0.06?nM) and its N34S variant (K of 0.08?±?0.02?nM) have similar binding affinity and inhibitory effect towards trypsin as shown by surface plasmon resonance and trypsin inhibition assay studies, respectively. We found that stress conditions such as altered ion concentrations (i.e. potassium, calcium), temperature shifts, as well as environmental pH lead to insignificant differences in trypsin inhibition between SPINK1 and N34S mutant. However, we have shown that the environmental pH induces structural changes in both SPINK1 constructs in a different manner. Our findings suggest protein structural changes in the N34S variant as an impairment of SPINK1 and environmental pH shift as a trigger that could play a role in disease progression of pancreatitis.
Copyright © 2019. Published by Elsevier B.V.
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Ciprofibrate attenuates airway remodeling in cigarette smoke-exposed rats.
Respir Physiol Neurobiol2019 Sep;():103290. doi: S1569-9048(19)30160-0.
Ke Qian, Yang Lin, Cui Qinghua, Diao Wenqi, Zhang Youyi, Xu Ming, He Bei,
Abstract
Airway remodeling is a key pathological lesion in chronic obstructive pulmonary disease (COPD), and it leads to poorly reversible airway obstruction. Current pharmacological interventions are ineffective at controlling airway remodeling. To address this issue, we queried the Connectivity Map (cMap) database to screen for drug candidates that had the potential to dilate the bronchus and inhibit airway smooth muscle (ASM) proliferation. We identified ciprofibrate as a drug candidate. Ciprofibrate inhibited cigarette smoke extract-induced rat ASM cell contraction and proliferation in vitro. We exposed Sprague-Dawley (SD) rats to clean air or cigarette smoke (CS) and treated the rats with ciprofibrate. Ciprofibrate improved pulmonary function, inhibited airway hypercontraction, and ameliorated morphological small airway remodeling, including airway smooth muscle proliferation, in CS-exposed rats. Ciprofibrate also significantly reduced IL-1?, IL-12p70, IL-17A and IL-18 expression, which are related to airway remodeling, in the sera of CS-exposed rats. These findings indicate that ciprofibrate could attenuate airway remodeling in CS-exposed rats.
Copyright © 2019. Published by Elsevier B.V.
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A new approach to the diagnosis and treatment of atherosclerosis: the era of the liposome.
Drug Discov Today2019 Sep;():. doi: S1359-6446(19)30349-6.
Kiaie Nasim, Gorabi Armita Mahdavi, Penson Peter E, Watts Gerald, Johnston Thomas P, Banach Maciej, Sahebkar Amirhossein,
Abstract
The consequences of atherosclerotic cardiovascular disease (ASCVD) include myocardial infarction, ischemic stroke, and angina pectoris, which are major causes of mortality and morbidity worldwide. Despite current therapeutic strategies to reduce risk, patients still experience the consequences of ASCVD. Consequently, a current goal is to enhance visualization of early atherosclerotic lesions to improve residual ASCVD risk. The uses of liposomes, in the context of ASCVD, can include as contrast agents for imaging techniques, as well as for the delivery of antiatherosclerotic drugs, genes, and cells to established sites of plaque. Additionally, liposomes have a role as vaccine adjuvants against mediators of atherosclerosis. Here. we review the scientific and clinical evidence relating to the use of liposomes in the diagnosis and management of ASCVD.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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Recent progress in the small-molecule fluorescent probes for the detection of sulfur dioxide derivatives (HSO/SO).
Free Radic Biol Med2019 Sep;():. doi: S0891-5849(19)30666-5.
Yang Bing, Xu Jing, Zhu Hai-Liang,
Abstract
Sulfur dioxide (SO) had been recognized as an environmental pollutant produced from industrial processes. SO is water soluble and forms hydrated SO (SO·HO), bisulfite ion (HSO), and sulfite ion (SO) upon dissolution in water. SO could be also produced endogenously from sulfur-containing amino acids l-cysteine in mammals. Endogenous SO can maintain the balance of biological sulfur and redox equilibrium in vivo, regulate blood insulin levels and reduce blood pressure. Excess intake of exogenous SO can result in respiratory diseases, cardiovascular diseases and neurological disorders. As a result, fluorescent probes to detect HSO/SO have attracted great attention in recent years. Herein, a general overview was provided with the aim to highlight the typical examples of the HSO/SO fluorescent probes reported since 2010, especially those in the past five years. We have classified HSO/SO fluorescent probes through different chemical reaction mechanisms and wish this review will give some help to the researchers in this field.
Copyright © 2019. Published by Elsevier Inc.
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Redox signaling in ischemic postconditioning protection involves PKC? and Erk1/2 pathways and converges indirectly in Nrf2 activation.
Cell Signal2019 Sep;():109417. doi: S0898-6568(19)30213-X.
Díaz-Ruíz Jorge-Luis, Macías-López Arturo, Alcalá-Vargas Francisco, Guevara-Chávez José-Guadalupe, Mejía-Uribe Aída, Silva-Palacios Alejandro, Zúñiga-Muñoz Alejandra, Zazueta Cecilia, Buelna-Chontal Mabel,
Abstract
Ischemic-postconditioning (iPostC) exerts cardioprotection by preserving redox homeostasis in the reperfused heart. This protective effect has been associated with the activation of endogenous antioxidant response driven by transcription factor Nrf2 and with the activation of 'reperfusion injury salvage kinases' (RISK) as PI3K, PKC and Erk1/2. Redox homeostasis is essential for normal cell physiology since reactive oxygen species (ROS) are crucial for processes that involve protein signaling. Thus, it has become clear that not only the perturbation of redox balance to oxidative state is deleterious but also towards a reductive state contributing to pathogenesis of diseases. However, there is still a scarce knowledge about the role of ROS in the cardioprotective signals mediated by RISK in postconditioned hearts. Therefore, we studied the role of ROS as initiator of RISK signaling molecules in iPostC-conferred cardioprotection. With the aim to study the relationship between redox-dependent RISK activation and the downstream activation of the transcription factor Nrf2, we evaluated the effect of redox signaling disruption by the effect of ascorbic acid in iPostC hearts. Our results showed that PKC? and Erk1/2 activation is redox-dependent and that concurs downstream with Nrf2 deficient activation. Besides, using inhibitors we found that neither PI3K nor Erk1/2 are directly related with Nrf2 activation, indicating that these kinases have other targets. We conclude that redox signaling participates in cardioprotection triggered by iPostC through the action of kinase-dependent and -independent mechanisms and concurred with the downstream regulation of Nrf2-mediated antioxidant response to prolonged redox balance during long reperfusion.
Copyright © 2018. Published by Elsevier Inc.
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?-Adrenergic cardiac contractility is increased during early endotoxemic shock: Involvement of cyclooxygenases.
Life Sci2019 Sep;():116865. doi: S0024-3205(19)30792-1.
Roul David, Rozec Bertrand, Ferron Marine, Erfanian Mortéza, Persello Antoine, Audigane Leslie, Grabherr Amandine, Erraud Angelique, Merlet Nolwenn, Guijarro Damien, Muramatsu Ikunobu, Lauzier Benjamin, Gauthier Chantal,
Abstract
AIMS:
Endothelial dysfunction is one of the earliest symptoms in septic patients and plays an important role in the cardiovascular alterations. However, the endothelial mechanisms involved in the impaired sympathetic regulation of the cardiovascular system are not clear. This study aimed to determine the role of the endocardial endothelium (EE) in the cardiac ?-adrenergic (?-AR) remodeling at the early phase of endotoxemic shock.
MAIN METHODS:
Rats received either lipopolysaccharide (LPS) or saline (control) intravenously. Three hours later, ?-AR cardiac contractility was evaluated on papillary muscles with or without a functional EE.
KEY FINDINGS:
Isoproterenol-induced contractility was strongly increased in papillary muscles from LPS rats. A similar increase was observed with a ?-AR stimulation, whereas ?-AR and ?-AR produced similar contractility in control and LPS treatments. The removal of the EE did not modify ?-AR-induced contractility in controls, whereas it abolished the increased ?-AR response in LPS-treated muscles. In LPS-treated papillary muscle, the increased ?-AR-induced contractility was not modified by pretreatment with a NOS inhibitor or an endothelin receptor antagonist. Conversely, the increased ?-AR-induced contractility was abolished by indomethacin, a non-selective cyclooxygenase (COX) inhibitor, as well as by selective inhibitors of COX1 and COX2. An early treatment with indomethacin improved the survival of LPS rat.
SIGNIFICANCE:
Our results suggest that the EE is involved in the increased cardiac ?-AR contractility in the early phase of endotoxemic shock. This effect is mediated through the activation of COX1 and COX2 and suggests these may be novel putative therapeutic targets during endotoxemic shock.
Copyright © 2019. Published by Elsevier Inc.
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Significant Improvements in Mortality after the Fontan Operation in Children with Down Syndrome.
Ann Thorac Surg2019 Sep;():. doi: S0003-4975(19)31381-5.
Sarno Lauren A, Walters Henry L, Bondarenko Igor, Thomas Ronald, Kobayashi Daisuke,
Abstract
BACKGROUND:
Down syndrome (DS) is considered a risk factor for mortality associated with the Fontan operation. The objective was to show the contemporary short-term outcome of the Fontan operation for a functionally univentricular heart in patients with DS and non-DS, along with an analysis of significant predictors for in-hospital mortality.
METHODS:
This was a retrospective study using the Society of Thoracic Surgeons Congenital Database to assess in-hospital mortality and its predictors in patients with DS and non-DS undergoing the Fontan operation over 16 years (2001-2016). The primary outcome was in-hospital mortality. Statistical analysis was performed using univariable and multivariable logistic regression models.
RESULTS:
Our study cohort consisted of 12,074 patients (81 DS and 11,993 non-DS). The overall in-hospital mortality rate significantly improved in the recent era (2009 - 2016): 2.4% to 1.3%, p<0.001. The DS group had a higher in-hospital mortality rate (12.3% vs. 1.6%, p<0.001) with an odds ratio of 8.6 [95% confidence interval: 4.4 to 17.0]. The DS group had a higher 30-day mortality rate, a longer median post-operative length of stay, and a higher incidence of post-operative complications. The multivariable model showed that DS was the strongest predictor of in-hospital mortality with an odds ratio of 11.6 [95% confidence interval 5.1 to 26.4], adjusted for other significant variables including era effect, weight and primary cardiac diagnosis.
CONCLUSIONS:
The in-hospital mortality for the Fontan operation significantly improved in the contemporary era. Down syndrome was a significant risk factor for in-hospital morbidity and mortality associated with the Fontan operation.
Copyright © 2019. Published by Elsevier Inc.
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Hemodynamic Phenotypes of Hypertension Based on Cardiac Output and Systemic Vascular Resistance.
Am J Med2019 Sep;():. doi: S0002-9343(19)30766-1.
Mahajan Shiwani, Gu Jianlei, Lu Yuan, Khera Rohan, Spatz Erica S, Zhang MaoZhen, Sun NingLing, Zheng Xin, Zhao Hongyu, Lu Hui, Ma Zheng J, Krumholz Harlan M,
Abstract
BACKGROUND:
Blood pressure is a physiologic measure that reflects cardiac output and systemic vascular resistance. Classification by these components could be useful in characterizing subtypes of hypertension which may have a role in selecting treatment strategies. However, hemodynamic phenotypes of a large, stable, outpatient population with hypertension remain unknown.
METHODS:
We included 34,238 people, with systolic blood pressure of ?130mmHg, who underwent impedance cardiography at 51 sites of iKang Health Checkup Centers throughout China between 2012 and 2018. Hemodynamic parameters measured included: stroke volume, stroke volume index, heart rate, cardiac output, cardiac index, systemic vascular resistance, and systemic vascular resistance index. We characterized these by systolic blood pressure categories and assessed patient characteristics associated with the ratio of cardiac index to systemic vascular resistance index.
RESULTS:
Among the study cohort (n=33,414; mean age 52±13years; 36.6% female), 49%, 40%, and 11% had systolic blood pressure130-139, 140-159, and?160mmHg, respectively. Among patients with systolic blood pressure 140-159mmHg, 9353 (70%) had high systemic vascular resistance index but normal/low cardiac index, 1949 (15%) had high cardiac index but low/normal systemic vascular resistance index, and 2053 (15%) had low/normal cardiac index and systemic vascular resistance index. Using multivariable analysis, we found that cardiac index to systemic vascular resistance index ratio was negatively associated with age and body mass index (all P<0.05; R-square 0.16, 0.12 and 0.09 for systolic blood pressure 130-139, 140-159 and?160mmHg, respectively).
CONCLUSIONS:
Different hemodynamic blood pressure phenotypes were identified across all hypertensive blood pressure categories. While individual characteristics were associated with the cardiac index to systemic vascular resistance index ratio, they only weakly explained the variation.
Copyright © 2019. Published by Elsevier Inc.
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The homozygous variant c.245G>A/p.G82D in PNPLA2 is associated with arrhythmogenic cardiomyopathy phenotypic manifestations.
Clin Genet2019 Sep;():. doi: 10.1111/cge.13642.
Rao Man, Guo Guang-Ran, Li Meng-Meng, Chen Shi, Chen Kai, Chen Xiao, Song Jiang-Ping, Hu Sheng-Shou,
Abstract
Arrhythmogenic cardiomyopathy (ACM) is a familial cardiomyopathy featured by fibro-fatty replacement of cardiomyocytes. Responsible genetic factors are not discernible in approximately one third of ACM probands. To investigate this further, we performed whole genome sequencing (WGS) in 14 mutation-negative ACM probands who underwent cardiac transplantation, and we identified one ACM proband with a rare homozygous missense variant in PNPLA2 (c.245G>A, p.G82D), a rate-limiting enzyme that hydrolyzes triglycerides into fatty-acids and diacylglycerol. Bioinformatic analysis suggested that this missense variant may lead to loss-of-function and therefore impair lipid catabolism. Genetic screening in this proband's family also inferred that the homozygous variant co-segregated with disease. To validate the pathogenicity of this variant and confirm its association with ACM, we established a knock-in mouse model carrying the orthologous human homozygous PNPLA2 variant. Interestingly, mice with the homozygous variant presented with arrhythmias and significant cardiac dysfunction at 12-weeks, whereas heterozygous mice were not affected. Moreover, those homozygous mice suffered sudden death and/or heart failure by age of 14-weeks. Pathological examination showed that extensive lipogenesis in cardiomyocytes and cardiac fibrosis were prominent in the myocardium. Herein, our data demonstrated that the homozygous missense variant PNPLA2 (c.245G>A, p.G82D) associated with a recessive form of ACM. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
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GPR40 full agonism exerts feeding suppression and weight loss through afferent vagal nerve.
PLoS One2019 ;14(9):e0222653. doi: 10.1371/journal.pone.0222653.
Ueno Hikaru, Ito Ryo, Abe Shin-Ichi, Ogino Hitomi, Maruyama Minoru, Miyashita Hirohisa, Miyamoto Yasufumi, Moritoh Yusuke, Tsujihata Yoshiyuki, Takeuchi Koji, Nishigaki Nobuhiro,
Abstract
GPR40/FFAR1 is a Gq protein-coupled receptor expressed in pancreatic ? cells and enteroendocrine cells, and mediates insulin and incretin secretion to regulate feeding behavior. Several GPR40 full agonists have been reported to reduce food intake in rodents by regulating gut hormone secretion in addition to their potent glucose-lowering effects; however, detailed mechanisms of feeding suppression are still unknown. In the present study, we characterized T-3601386, a novel compound with potent full agonistic activity for GPR40, by using in vitro Ca2+ mobilization assay in Chinese hamster ovary (CHO) cells expressing FFAR1 and in vivo hormone secretion assay. We also evaluated feeding suppression and weight loss after the administration of T-3601386 and investigated the involvement of the vagal nerve in these effects. T-3601386, but not a partial agonist fasiglifam, increased intracellular Ca2+ levels in CHO cells with low FFAR1 expression, and single dosing of T-3601386 in diet-induced obese (DIO) rats elevated plasma incretin levels, suggesting full agonistic properties of T-3601386 against GPR40. Multiple doses of T-3601386, but not fasiglifam, in DIO rats showed dose-dependent weight loss accompanied by feeding suppression and durable glucagon-like peptide-1 elevation, all of which were completely abolished in Ffar1-/- mice. Immunohistochemical analysis in the nuclei of the solitary tract demonstrated that T-3601386 increased the number of c-Fos positive cells, which also disappeared in Ffar1-/- mice. Surgical vagotomy and drug-induced deafferentation counteracted the feeding suppression and weight loss induced by the administration of T-3601386. These results suggest that T-3601386 exerts incretin release and weight loss in a GPR40-dependent manner, and that afferent vagal nerves are important for the feeding suppression induced by GPR40 full agonism. Our novel findings raise the possibility that GPR40 full agonist can induce periphery-derived weight reduction, which may provide benefits such as less adverse effects in central nervous system compared to centrally-acting anti-obesity drugs.
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Identification and Analysis of Differentially Expressed Genes in Human Saphenous Vein Endothelial Cells Overexpressing Domain-Containing mTOR-Interacting Protein (DEPTOR) by RNA-Seq.
Med Sci Monit2019 Sep;25():6965-6971. doi: 10.12659/MSM.915442.
Wang Wenjun, Li Yiying, Wang Qun, Cao Yuanping, Wang Fudong, Li Wan,
Abstract
BACKGROUND Autologous saphenous vein is the most common choice for coronary artery bypass grafting. This study was conducted to identify and characterize differentially expressed genes (DEGs) induced by overexpressing DEPTOR in human saphenous vein endothelial cells (hsVECs) that might play roles in restenosis. MATERIAL AND METHODS hsVECs isolated from the saphenous veins were transfected with DEPTOR overexpression vector and analyzed for mTOR expression. RNA was prepared from the cells and sequenced using high-throughput sequencing technology (RNA-Seq). The DEGs were analyzed based on enrichment scores in GO terms and KEGG pathways. RESULTS The cells had typical hsVEC morphology and characteristics based on the HE staining and immunohistochemical and immunofluorescence assays. The expression of mTOR increased, and 102 genes were upregulated, and 409 genes were downregulated after DEPTOR overexpression. KEGG analysis showed that the DEGs were mainly enriched in 20 signal pathways, such as Focal adhesion and ECM-receptor interaction pathways. The DEGs were enriched in GO terms such as integrin binding and glycosaminoglycan binding. For cellular components, GO analysis revealed that the DEGs were enriched in main axon, plasma membrane part, cell junction, and proteinaceous extracellular matrix. DEGs included many cytokines, such as bone morphogenetic protein-7, interleukin-8, interleukin-1ß, and inhibin, which have important effects on vascular growth and inflammation. CONCLUSIONS The overexpression of DEPTOR in hsVECs results in DEGs that are involved in cell proliferation and differentiation, intercellular junction, and extracellular matrix receptor. These findings may provide valuable molecular information for improving venous permeability through manipulation of DEPTOR and related mTOR pathways.
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