This study evaluated the ability of A
1 and A
3 adenosine receptor (AR) agonism, and A
1, A
2A, A
2B and A
3AR antagonism (revealing “intrinsic” responses), to modify post-ischemic coronary ...dysfunction in mouse heart. Vascular function was assessed before and after 20 min global ischemia and 30–45 min reperfusion in Langendorff perfused C57/Bl6 mouse hearts. Ischemic insult impaired coronary sensitivity to the endothelial-dependent dilators ADP (pEC
50
=
6.8
±
0.1 vs. 7.6
±
0.1, non-ischemic) and acetylcholine (pEC
50
=
6.1
±
0.1 vs. 7.3
±
0.1 in non-ischemic), and for the mixed endothelial-dependent/independent dilator 2-chloroadenosine (pEC
50
=
7.5
±
0.1 vs. 8.4
±
0.1, non-ischemic). Endothelium-independent dilation in response to nitroprusside was unaltered (pEC
50
=
7.0
±
0.1 vs. 7.1
±
0.1 in non-ischemic). Pre-treatment with a selective A1AR agonist (50 nM CHA) failed to modify coronary dysfunction, whereas A1AR antagonism (200 nM DPCPX) worsened the effects of I/R (2-chloroadenosine pEC
50
=
6.9
±
0.1). Conversely, A
3AR agonism (100 nM Cl-IB-MECA) did reduce effects of I/R (pEC
50s
=
8.0
±
0.1 and 7.3
±
0.1 for 2-chloroadenosine and ADP, respectively), whereas antagonism (100 nM MRS1220) was without effect. While A
2AAR agonism could not be assessed (due to pronounced vasodilatation), A
2AAR antagonism (100 nM SCH58261) was found to exert no effect, and antagonism of A
2BARs (50 nM MRS1754) was also ineffective. The protective actions of A
3AR agonism were also manifest as improved reactive hyperemic responses. Interestingly, post-ischemic coronary dysfunction was also limited by: Na
+–H
+ exchange (NHE) inhibition with 10 or 50 μM BIIB-513 (2-chloroadenosine pEC
50s
=
7.8
±
0.1, either dose), an effect not additive with A
3AR agonism; Ca
2+ antagonism with 0.3 μM verapamil (2-chloroadenosine pEC
50
=
7.9
±
0.1); and Ca
2+ desensitization with 5 mM BDM (2-chloroadenosine pEC
50
=
7.8
±
0.1). In contrast, endothelin antagonism (200 nM PD142893) and anti-oxidant therapy (300 μM MPG
+
150 U/ml SOD
+
600 U/ml catalase) were ineffective. Our data collectively confirm that ischemia selectively impairs endothelial function and reactive hyperemia independently of blood cells. Vascular injury is intrinsically limited by endogenous (but not exogenous) activation of A
1ARs, whereas exogenous A
3AR activation further limits dysfunction (improving post-ischemic vasoregulation). Finally, findings suggest this form of post-ischemic coronary injury is unrelated to endothelin or oxidant stress, but may involve modulation of Ca
2+ overload and/or related ionic perturbations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A Report of the American College of Cardiology Appropriate Use Criteria Task Force, American Academy of Pediatrics, American Heart Association, American Society of Echocardiography, Heart Rhythm ...Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Pediatric Echocardiography Rating Panel Robert M. Campbell, MD, FACC, FAHA, FAAP, FHRS, Chairlow * Pamela S. Douglas, MD, MACC, FAHA, FASE, Moderatorlow * Louis I. Bezold, MD, FACC, FAAP, FASEdagger William B. Blanchard, MD, FACC, FAHA, FAAPlow * Jeffrey R. Boris, MD, FACClow * Bryan Cannon, MDdouble dagger Gregory J. Ensing, MD, FACC, FASE§ Craig E. Fleishman, MD, FACC, FASE|| Mark A. Fogel, MD, FACC, FAHA, FAAP¶ B. Kelly Han, MD, FACC# Shabnam Jain, MD, MPH, FAAPlow * Mark B. Lewin, MD|| Richard Lockwood, MDlow *low * G. Paul Matherne, MD, MBA, FACC, FAHAdaggerdagger David Nykanen, MD, FACCdouble daggerdouble dagger Catherine L. Webb, MD, FACC, FAHA, FASEdaggerdagger Robert Wiskind, MD, FAAPlow *American College of Cardiology representative.American Academy of Pediatrics representative.Heart Rhythm Society representative.American Society of Echocardiography representative.Society of Pediatric Echocardiography representative.Society for Cardiovascular Magnetic Resonance representative.Society of Cardiovascular Computed Tomography representative.Health Plan representative.American Heart Association representative.Society for Cardiovascular Angiography and Interventions representative.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
For hypoplastic left heart syndrome (HLHS), there have been concerns regarding pulmonary artery growth and ventricular dysfunction after first stage surgery consisting of the Norwood procedure ...modified with a right ventricle-to-pulmonary artery conduit. We report our experience using cardiovascular magnetic resonance (CMR) to determine and follow pulmonary arterial growth and ventricular function in this cohort. Following first stage palliation, serial CMR was performed at 1 and 10 weeks post-operatively, followed by cardiac catheterization at 4-6 months. Thirty-four of 47 consecutive patients with HLHS (or its variations) underwent first stage palliation. Serial CMR was performed in 20 patients. Between studies, ejection fraction decreased (58 +/- 9% vs. 50 +/- 5%, p < 0.05). Pulmonary artery growth occurred on the left (6 +/- 1 mm vs. 4 +/- 1 mm at baseline, p < 0.05) but not significantly in the right. This trend continued to cardiac catheterization 4-6 months post surgery, with the left pulmonary artery of greater size than the right (8.8 +/- 2.2 mm vs. 6.7 +/- 1.9 mm, p < 0.05). By CMR, 5 had pulmonary artery stenoses initially, and at 2 months, 9 had stenoses. Three of the 9 underwent percutaneous intervention prior to the second stage procedure. In this cohort, reasonable growth of pulmonary arteries occurred following first stage palliation with this modification, although that growth was preferential to the left. Serial studies demonstrate worsening of ventricular function for the cohort. CMR was instrumental for detecting pulmonary artery stenosis and right ventricular dysfunction.
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DOBA, GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, UILJ, UKNU, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A total of 14 patients with congenital heart disease underwent aortic valve repair, with transesophageal echocardiograms performed to determine severity, mechanism, and direction of aortic ...insufficiency (AI) jet to tailor the surgical approach. Patient age was 13 +/- 10 years, and accompanying diagnoses were: truncus arteriosus, subaortic stenosis, ventricular septal defect, and tetralogy of Fallot. Repeat transesophageal echocardiography was performed after each cardiopulmonary bypass run to determine residual AI and mechanism. Aortic valve leaflet number ranged from 2 to 4. AI was graded 2 to 4+, and postoperatively 0 to 2+. Primary mechanisms were: cusp prolapse (7), leaflet holes (4), restricted leaflet motion (2), and annular dilation (3). Patients required 1 to 3 cardiopulmonary bypass runs until primary AI mechanism was abolished. In all, 12 of 14 patients were free from death or repeated surgery at 2 years. Surgical repair of congenital AI may be aided by transesophageal echocardiographic guidance, with repeat short cardiopulmonary bypass as needed. Long-term studies are needed to determine durability of repair.
Greater than 20% of cases and 0.4% of deaths from COVID-19 occur in children. Following demonstration of the safety and efficacy of the adjuvanted, recombinant spike protein vaccine NVX-CoV2373 in ...adults, the PREVENT-19 trial immediately expanded to adolescents.
To evaluate the safety, immunogenicity, and efficacy of NVX-CoV2373 in adolescents.
The NVX-CoV2373 vaccine was evaluated in adolescents aged 12 to 17 years in an expansion of PREVENT-19, a phase 3, randomized, observer-blinded, placebo-controlled multicenter clinical trial in the US. Participants were enrolled from April 26 to June 5, 2021, and the study is ongoing. A blinded crossover was implemented after 2 months of safety follow-up to offer active vaccine to all participants. Key exclusion criteria included known previous laboratory-confirmed SARS-CoV-2 infection or known immunosuppression. Of 2304 participants assessed for eligibility, 57 were excluded and 2247 were randomized.
Participants were randomized 2:1 to 2 intramuscular injections of NVX-CoV2373 or placebo, 21 days apart.
Serologic noninferiority of neutralizing antibody responses compared with those in young adults (aged 18-25 years) in PREVENT-19, protective efficacy against laboratory-confirmed COVID-19, and assessment of reactogenicity and safety.
Among 2232 participants (1487 NVX-CoV2373 and 745 placebo recipients), the mean (SD) age was 13.8 (1.4) years, 1172 (52.5%) were male, 1660 (74.4%) were White individuals, and 359 (16.1%) had had a previous SARS-CoV-2 infection at baseline. After vaccination, the ratio of neutralizing antibody geometric mean titers in adolescents compared with those in young adults was 1.5 (95% CI, 1.3-1.7). Twenty mild COVID-19 cases occurred after a median of 64 (IQR, 57-69) days of follow-up, including 6 among NVX-CoV2373 recipients (incidence, 2.90 95% CI, 1.31-6.46 cases per 100 person-years) and 14 among placebo recipients (incidence, 14.20 95% CI, 8.42-23.93 cases per 100 person-years), yielding a vaccine efficacy of 79.5% (95% CI, 46.8%-92.1%). Vaccine efficacy for the Delta variant (the only viral variant identified by sequencing n = 11) was 82.0% (95% CI, 32.4%-95.2%). Reactogenicity was largely mild to moderate and transient, with a trend toward greater frequency after the second dose of NVX-CoV2373. Serious adverse events were rare and balanced between treatments. No adverse events led to study discontinuation.
The findings of this randomized clinical trial indicate that NVX-CoV2373 is safe, immunogenic, and efficacious in preventing COVID-19, including the predominant Delta variant, in adolescents.
ClinicalTrials.gov Identifier: NCT04611802.
We investigated the roles of A 1 , A 2A , or A 3 receptors and purine salvage in cardioprotection with exogenous adenosine, and tested whether A 2A -mediated reductions in perfusion pressure modify ...post-ischemic recovery. Treatment with 10 or 5 × 10 M adenosine improved contractile recovery from 20 min ischemia 45 min reperfusion in isolated mouse hearts. Protection was attenuated by adenosine kinase inhibition (10 M iodotubercidin) and receptor antagonism (5 × 10 M 8-ρ-sulfophenyltheophylline, 8-SPT). Enzyme efflux mirrored contractile recoveries. A 3 agonism with 10 M 2-chloro-N -(3-iodobenzyl)-adenosine-5´-N-methyluronamide (Cl-IB-MECA) improved ischemic tolerance whereas A 1 agonism with 5 × 10 M N -cyclopentyladenosine (CPA) and A 2A agonism with 10 M 2-p-(2-carboxyethyl) phenethylamino-5´-N-ethylcarboxamidoadenosine (CGS21680) or 2 × 10 M methyl-4-(3-{9-4S,5S,2R,3R)-5-(N-ethylcarbamoyl)-3,4-dihydroxyoxolan-2-yl-6-aminopurin-2-yl)}prop-2-ynyl) cyclohexane-carboxylate (ATL-146e) were ineffective. Protection via A 1 receptor overexpression was enhanced by adenosine, but unaltered by A 1 or A 2A agonists. Finally, post-ischemic dysfunction in hearts perfused at constant flow was dependent on coronary pressure, with A 2A AR-mediated reductions in pressure reducing diastolic contracture, and elevated perfusion pressure worsening contracture. Data indicate that cardioprotection with exogenous adenosine in asanguinous hearts involves purine salvage and activation of A 3 but not A 1 or A 2A receptors.
Departments of 1 Pediatrics,
2 Surgery, and 3 Biochemistry and
Molecular Genetics, and the 4 Cardiovascular Research
Center, University of Virginia Health System, Charlottesville,
Virginia 22908
...We tested
the hypothesis that myocardial ischemia-reperfusion
(I/R)-induced apoptosis is attenuated in transgenic mice
overexpressing cardiac A 1 adenosine receptors. Isolated
hearts from transgenic (TG, n = 19) and wild-type (WT,
n = 22) mice underwent 30 min of ischemia and
2 h of reperfusion, with evaluation of apoptosis, caspase
3 activity, function, and necrosis. I/R-induced apoptosis was
attenuated in TG hearts. TG hearts had less I/R-induced apoptotic nuclei (0.88 ± 0.10% vs. 4.22 ± 0.24% terminal
deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive
cells in WT, P < 0.05), less DNA fragmentation
(3.30 ± 0.38-fold vs. 4.90 ± 0.39-fold over control in WT,
P < 0.05), and less I/R-induced caspase 3 activity
(145 ± 25% over nonischemic control vs. 234 ± 31%
in WT, P < 0.05). TG hearts also had improved recovery
of function and less necrosis than WT hearts. In TG hearts pretreated with LY-294002 (3 µM) to evaluate the role of
phosphosinositol-3-kinase in acute signaling, there was no change in
the functional protection or apoptotic response to I/R. These data
suggest that cardioprotection with transgenic overexpression of
A 1 adenosine receptors involves attenuation of I/R-induced
apoptosis that does not involve acute signaling through
phosphoinositol-3-kinase.
cardioprotection; ischemia-reperfusion injury; transgenic
mice; phosphoinositol-3-kinase
Abstract The adenosine receptor system has been attributed with a broad range of both physiological and so-called ‘retaliatory’ functions in the heart and vessels. Despite many years of research, the ...precise roles of adenosine within the cardiovascular system continue to be debated, and new functions are continually emerging. Adenosine acts via 4 known G-protein-coupled receptor (GPCR) sub-types: A1 , A2A , A2B , and A3 adenosine receptors (ARs). In addition to roles in cardiovascular control, these receptors may represent therapeutic targets, having been attributed with roles in modifying cell death and injury, inflammatory processes, and cardiac and vascular remodeling during/after ischemic or hypoxic insult. A number of models have been developed in which AR sub-types and adenosine handling enzymes have been genetically deleted or transgenically overexpressed in an attempt to more equivocally identify the regulatory functions of these proteins, to identify their potential value as therapeutic targets, and to uncover new regulatory functions of this receptor family. Findings generally support current dogma regarding cardioprotection via A1 and A3 ARs, and coronary vasoregulation via A2 AR sub-types. However, some outcomes are both novel and controversial. This review outlines AR-modified murine models currently under study from the perspective of cardiovascular phenotype.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We review our 16-year experience using the large, multi-institutional database of the University HealthSystem Consortium to study management and outcomes in congenital heart surgery for hypoplastic ...left heart syndrome, transposition of the great arteries, and neonatal coarctation. The advantages, limitations, and use of administrative databases by others to study congenital heart surgery are reviewed.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
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