G. Paul Matherne

Assessment of the 12-Lead ECG as a Screening Test for Detection of Cardiovascular Disease in Healthy General Populations of Young People (12–25 Years of Age) A Scientific Statement From the American Heart Association and the American College of Cardiology

TheAmericanCollegeof C follows:MaronBJ, Friedm BR,OkinPM, Saul JP, Salb GP, Bolling SF,MittenMJ, Clinical Cardiology, Advocacy Coordinating Committee, Council on Cardiovascular Disease in the Young, Council on Cardiovascular Surgery and Anesthesia, Council on Epidemiology and Prevention, Council on Functional Genomics and Translational Biology, Council on Quality of Care and Outcomes Research, and American College of Cardiology

Role of Pulse Oximetry in Examining Newborns for Congenital Heart Disease: A Scientific Statement from the AHA and AAP

BACKGROUND: The purpose of this statement is to address the state of evidence on the routine use of pulse oximetry in newborns to detect critical congenital heart disease (CCHD). METHODS AND RESULTS: A writing group appointed by the American Heart Association and the American Academy of Pediatrics reviewed the available literature addressing current detection methods for CCHD, burden of missed and/or delayed diagnosis of CCHD, rationale of oximetry screening, and clinical studies of oximetry in otherwise asymptomatic newborns. MEDLINE database searches from 1966 to 2008 were done for English-language papers using the following search terms: congenital heart disease, pulse oximetry, physical examination, murmur, echocardiography, fetal echocardiography, and newborn screening. The reference lists of identified papers were also searched. Published abstracts from major pediatric scientific meetings in 2006 to 2008 were also reviewed. The American Heart Association classification of recommendations and levels of evidence for practice guidelines were used. In an analysis of pooled studies of oximetry assessment performed after 24 hours of life, the estimated sensitivity for detecting CCHD was 69.6%, and the positive predictive value was 47.0%; however, sensitivity varied dramatically among studies from 0% to 100%. False-positive screens that required further evaluation occurred in only 0.035% of infants screened after 24 hours. CONCLUSIONS: Currently, CCHD is not detected in some newborns until after their hospital discharge, which results in significant morbidity and occasional mortality. Furthermore, routine pulse oximetry performed on asymptomatic newborns after 24 hours of life, but before hospital discharge, may detect CCHD. Routine pulse oximetry performed after 24 hours in hospitals that have on-site pediatric cardiovascular services incurs very low cost and risk of harm. Future studies in larger populations and across a broad range of newborn delivery systems are needed to determine whether this practice should become standard of care in the routine assessment of the neonate.

Role of Pulse Oximetry in Examining Newborns for Congenital Heart Disease: A Scientific Statement From the American Heart Association and American Academy of Pediatrics

Background— The purpose of this statement is to address the state of evidence on the routine use of pulse oximetry in newborns to detect critical congenital heart disease (CCHD). Methods and Results— A writing group appointed by the American Heart Association and the American Academy of Pediatrics reviewed the available literature addressing current detection methods for CCHD, burden of missed and/or delayed diagnosis of CCHD, rationale of oximetry screening, and clinical studies of oximetry in otherwise asymptomatic newborns. MEDLINE database searches from 1966 to 2008 were done for English-language papers using the following search terms: congenital heart disease, pulse oximetry, physical examination, murmur, echocardiography, fetal echocardiography, and newborn screening. The reference lists of identified papers were also searched. Published abstracts from major pediatric scientific meetings in 2006 to 2008 were also reviewed. The American Heart Association classification of recommendations and levels of evidence for practice guidelines were used. In an analysis of pooled studies of oximetry assessment performed after 24 hours of life, the estimated sensitivity for detecting CCHD was 69.6%, and the positive predictive value was 47.0%; however, sensitivity varied dramatically among studies from 0% to 100%. False-positive screens that required further evaluation occurred in only 0.035% of infants screened after 24 hours. Conclusions— Currently, CCHD is not detected in some newborns until after their hospital discharge, which results in significant morbidity and occasional mortality. Furthermore, routine pulse oximetry performed on asymptomatic newborns after 24 hours of life, but before hospital discharge, may detect CCHD. Routine pulse oximetry performed after 24 hours in hospitals that have on-site pediatric cardiovascular services incurs very low cost and risk of harm. Future studies in larger populations and across a broad range of newborn delivery systems are needed to determine whether this practice should become standard of care in the routine assessment of the neonate.

Assessment of the 12-Lead Electrocardiogram as a Screening Test for Detection of Cardiovascular Disease in Healthy General Populations of Young People (12-25 Years of Age)

Sudden death (SD) of young people because of a variety of complex, predominantly genetic/congenital cardiovascular diseases is a riveting, devastating event and a public health and policy issue of increasing concern.1–6 The reliable identification of such individuals at risk for SD has become a major focus of the cardiovascular community for a number of reasons, including the opportunity to reduce SD events through selective disqualification from sports7 and the primary prevention of SD with the implantable cardioverter-defibrillator for some high-risk patients with genetic heart diseases.8–14 In addition, those SDs caused by underlying and unsuspected genetic or congenital cardiovascular diseases that occur in young trained athletes are a highly visible issue and have become a concern in both the public arena and the physician community.15–17 Consequently, the desire to screen populations theoretically at risk for cardiovascular disease to reduce morbidity and mortality is understandable in principle, and few would empirically argue against the potential benefit of this practice for some individuals. However, a debate has emerged regarding whether the conditions responsible for these tragic events can be detected effectively in populations of various sizes by the available testing and examination techniques, and specifically, there is debate concerning which strategies are potentially the most reliable to separate those individuals with disease from those who are probably unaffected.15–29 Most of this dialogue concerning SD prevention has been limited to the screening of young populations of competitive athletes, and the available data specifically related to cardiovascular screening efficacy (on which we largely and unavoidably rely) overwhelmingly come from such populations exclusively composed of trained athletes. Periodically, this has become a polarized controversy and public health debate, triggering a large and growing body of literature, including clinical studies… but notably also an …

Ischaemic tolerance in aged mouse myocardium: the role of adenosine and effects of A1 adenosine receptor overexpression

The genesis of the ischaemia intolerant phenotype in aged myocardium is poorly understood. We tested the hypothesis that impaired adenosine‐mediated protection contributes to ischaemic intolerance, and examined whether this is countered by A1 adenosine receptor (A1AR) overexpression. Responses to 20 min ischaemia and 45 min reperfusion were assessed in perfused hearts from young (2–4 months) and moderately aged (16–18 months) mice. Post‐ischaemic contractility was impaired by ageing with elevated ventricular diastolic (32 ± 2 vs. 18 ± 2 mmHg in young) and reduced developed (37 ± 3 vs. 83 ± 6 mmHg in young) pressures. Lactate dehydrogenase (LDH) loss was exaggerated (27 ± 2 vs. 16 ± 2 IU g−1in young) whereas the incidence of tachyarrhythmias was similar in young (15 ± 1 %) and aged hearts (16 ± 1 %). Functional analysis confirmed equipotent effects of 50 μm adenosine at A1 and A2 receptors in young and aged hearts. Nonetheless, while 50 μm adenosine improved diastolic (5 ± 1 mmHg) and developed pressures (134 ± 7 mmHg) and LDH loss (6 ± 2 IU g−1) in young hearts, it did not alter these variables in the aged group. Adenosine did attenuate arrhythmogenesis for both ages (to ∼10 %). In contrast to adenosine, 50 μm diazoxide reduced ischaemic damage and arrhythmogenesis for both ages. Contractile and anti‐necrotic effects of adenosine were limited by 100 μm 5‐hydroxydecanoate (5‐HD) and 3 μm chelerythrine. Anti‐arrhythmic effects were limited by 5‐HD but not chelerythrine. Non‐selective (100 μm 8‐sulfophenyltheophylline) and A1‐selective (150 nm 8‐cyclopentyl‐1,3‐dipropylxanthine) adenosine receptor antagonism impaired ischaemic tolerance in young but not aged hearts. Quantitative real‐time PCR and radioligand analysis indicated that impaired protection is unrelated to changes in A1AR mRNA transcription, or receptor density (∼8 fmol mg−1 protein in both age groups). However, A1AR overexpression improved tolerance for both ages, restoring adenosine‐mediated protection. These data reveal impaired protection via exogenous and endogenous adenosine contributes to ischaemic intolerance with ageing. This is independent of A1AR expression, and involves ineffective activation of a 5‐HD‐/diazoxide‐sensitive process. The effects of A1AR overexpression indicate that the age‐related failure in signalling can be overcome.

Promotion of physical activity for children and adults with congenital heart disease: a scientific statement from the American Heart Association.

The American Heart Association recognizes the importance of physically active lifestyles to the health and well-being of children and adults with congenital heart defects. Counseling of patients with congenital heart defects should emphasize the importance of daily physical activity and decreasing sedentary behavior as appropriate for the patient’s clinical status. The suggested practices are based on relevant research regarding the benefits of physical activity for healthy children and adults, because research on physical activity among patients with congenital heart defects is lacking. There is no evidence regarding whether or not there is a need to restrict recreational physical activity among patients with congenital heart defects, apart from those with rhythm disorders. It is important to recognize that most patients with congenital heart defects are relatively sedentary and that the physical and psychosocial health benefits of physical activity are important for this population, which is at risk for...

Functional properties and responses to ischaemia‐reperfusion in Langendorff perfused mouse heart

Despite minimal model characterisation Langendorff perfused murine hearts are increasingly employed in cardiovascular research, and particularly in studies of myocardial ischaemia and reperfusion. Reported contractility remains poor and ischaemic recoveries variable. We characterised function in C57/BL6 mouse hearts using a ventricular balloon or apicobasal displacement and assessed responses to 10–30 min global ischaemia. We examined the functional effects of pacing, ventricular balloon design, perfusate filtration, [Ca2+] and temperature. Contractility was high in isovolumically functioning mouse hearts (measured as the change in pressure with time (+dP/dt), 6000–7000 mmHg s‐1) and was optimal at a heart rate of ±420 beats min‐1, with the vasculature sub‐maximally dilated, and the cellular energy state high. Post‐ischaemic recovery (after 40 min reperfusion) was related to the ischaemic duration: developed pressure recovered by 82 ± 5%, 73 ± 4%, 68 ± 3%, 57 ± 2% and 41 ± 5% after 10, 15, 20, 25 and 30 min ischaemia, respectively. Ventricular compliance and elastance were both reduced post‐ischaemia. Post‐ischaemic recoveries were lower in the apicobasal model (80 ± 4%, 58 ± 7%, 40 ± 3%, 32 ± 7% and 25 ± 5%) despite greater reflow and lower metabolic rate (pre‐ischaemic myocardial O2 consumption (VO2,myo) 127 ± 15 vs. 198 ± 17 μl O2 min‐1 g‐1), contracture, enzyme and purine efflux. Electrical pacing slowed recovery in both models, small ventricular balloons (unpressurised volumes < 50–60 μl) artificially depressed ventricular function and recovery from ischaemia, and failure to filter the perfusion fluid to < 0.45 μm depressed pre‐ and post‐ischaemic function. With attention to these various experimental factors, the buffer perfused isovolumically contracting mouse heart is shown to be stable and highly energised, and to possess a high level of contractility. The isovolumic model is more reliable in assessing ischaemic responses than the commonly employed apicobasal model.

Adenosine-mediated cardioprotection in ischemic-reperfused mouse heart.

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 −5 or 5 × 10 −5 M adenosine improved contractile recovery from 20 min ischemia 45 min reperfusion in isolated mouse hearts. Protection was attenuated by adenosine kinase inhibition (10 −5 M iodotubercidin) and receptor antagonism (5 × 10 −5 M 8-&rgr;-sulfophenyltheophylline, 8-SPT). Enzyme efflux mirrored contractile recoveries. A 3 agonism with 10 −7 M 2-chloro-N 6 -(3-iodobenzyl)-adenosine-5´-N-methyluronamide (Cl-IB-MECA) improved ischemic tolerance whereas A 1 agonism with 5 × 10 −8 M N 6 -cyclopentyladenosine (CPA) and A 2A agonism with 10 −9 M 2-[p-(2-carboxyethyl) phenethylamino]-5´-N-ethylcarboxamidoadenosine (CGS21680) or 2 × 10 −8 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.

Glucose regulation of load-induced mTOR signaling and ER stress in mammalian heart.

Background Changes in energy substrate metabolism are first responders to hemodynamic stress in the heart. We have previously shown that hexose‐6‐phosphate levels regulate mammalian target of rapamycin (mTOR) activation in response to insulin. We now tested the hypothesis that inotropic stimulation and increased afterload also regulate mTOR activation via glucose 6‐phosphate (G6P) accumulation. Methods and Results We subjected the working rat heart ex vivo to a high workload in the presence of different energy‐providing substrates including glucose, glucose analogues, and noncarbohydrate substrates. We observed an association between G6P accumulation, mTOR activation, endoplasmic reticulum (ER) stress, and impaired contractile function, all of which were prevented by pretreating animals with rapamycin (mTOR inhibition) or metformin (AMPK activation). The histone deacetylase inhibitor 4‐phenylbutyrate, which relieves ER stress, also improved contractile function. In contrast, adding the glucose analogue 2‐deoxy‐d‐glucose, which is phosphorylated but not further metabolized, to the perfusate resulted in mTOR activation and contractile dysfunction. Next we tested our hypothesis in vivo by transverse aortic constriction in mice. Using a micro‐PET system, we observed enhanced glucose tracer analog uptake and contractile dysfunction preceding dilatation of the left ventricle. In contrast, in hearts overexpressing SERCA2a, ER stress was reduced and contractile function was preserved with hypertrophy. Finally, we examined failing human hearts and found that mechanical unloading decreased G6P levels and ER stress markers. Conclusions We propose that glucose metabolic changes precede and regulate functional (and possibly also structural) remodeling of the heart. We implicate a critical role for G6P in load‐induced mTOR activation and ER stress.

Interstitial Transudate Purines in Normoxic and Hypoxic Immature and Mature Rabbit Hearts

ABSTRACT: Interstitial transudate and coronary venous concentrations of adenosine, inosine, and hypoxanthine were determined in isolated isovolumic immature and mature rabbit hearts during normoxia and hypoxia. During normoxia, interstitial transudate adenosine was lower in immature hearts compared with mature hearts. Interstitial transudate concentrations of adenosine, inosine, and hypoxanthine were 130 ± nM, 699 ± 88 nM, and 392 ± 80 nM, respectively, in immature rabbit hearts and 228 ± 35 nM, 1154 ± 126 nM, and 287 ± 30 nM, respectively, in mature rabbit hearts. Interstitial transudate adenosine was significantly lower in the immature hearts. Coronary venous purine concentrations were 6− and 8-fold lower than their respective intersutial transudate concentrations during normoxia in both age groups. Hypoxia significantly increased interstitial transudate purines in both age groups. Interstitial transodate adenosine, inosine, and hypoxan-thine increased to 1180 ± 231 nM, 4049 ± 500 nM, and 1099 ± 98 nM, respectively, in immature hearts and to 1225 ± 300 nM, 5220 ± 1217 nM, and 876 ± 147 nM, respectively, in mature hearts. The age-related difference in transudave adenosine levels present during normoxia was not detected during hypoxia. Venous purine levels increased during hypoxia and the gradient from interstitial transwdate fi to venous effluent was abolished for adenosine in both groups. In immature hearts, hypoxia led to higher venous effluent adenosine leyels than in the mature hearts. Coronary resistance correlated with interstitial transndate adenosine in both groups, although immature hearts displayed lower resistances at all adenosine levels. The results indicate that 1) interstitial transudate adenosine may regulate coronary resistance during hypoxia in isolated hearts from both age groups, 2) age-related differences exist in the normoxic release of interstitial transudate adenosisne, and 3) age-related differences appear to be present in the release of purines into the coronary venous effluent during hypoxia.