The developing bird pelvis passes through ancestral dinosaurian conditions.

Living birds (Aves) have bodies substantially modified from the ancestral reptilian condition. The avian pelvis in particular experienced major changes during the transition from early archosaurs to living birds1,2. This stepwise transformation is well documented by an excellent fossil record2-4; however, the ontogenetic alterations that underly it are less well understood. We used embryological imaging techniques to examine the morphogenesis of avian pelvic tissues in three dimensions, allowing direct comparison with the fossil record. Many ancestral dinosaurian features2 (for example, a forward-facing pubis, short ilium and pubic 'boot') are transiently present in the early morphogenesis of birds and arrive at their typical 'avian' form after transitioning through a prenatal developmental sequence that mirrors the phylogenetic sequence of character acquisition. We demonstrate quantitatively that avian pelvic ontogeny parallels the non-avian dinosaur-to-bird transition and provide evidence for phenotypic covariance within the pelvis that is conserved across Archosauria. The presence of ancestral states in avian embryos may stem from this conserved covariant relationship. In sum, our data provide evidence that the avian pelvis, whose early development has been little studied5-7, evolved through terminal addition-a mechanism8-10 whereby new apomorphic states are added to the end of a developmental sequence, resulting in expression8,11 of ancestral character states earlier in that sequence. The phenotypic integration we detected suggests a previously unrecognized mechanism for terminal addition and hints that retention of ancestral states in development is common during evolutionary transitions.

Subaqueous foraging among carnivorous dinosaurs.

Secondary aquatic adaptations evolved independently more than 30 times from terrestrial vertebrate ancestors1,2. For decades, non-avian dinosaurs were believed to be an exception to this pattern. Only a few species have been hypothesized to be partly or predominantly aquatic3-11. However, these hypotheses remain controversial12,13, largely owing to the difficulty of identifying unambiguous anatomical adaptations for aquatic habits in extinct animals. Here we demonstrate that the relationship between bone density and aquatic ecologies across extant amniotes provides a reliable inference of aquatic habits in extinct species. We use this approach to evaluate the distribution of aquatic adaptations among non-avian dinosaurs. We find strong support for aquatic habits in spinosaurids, associated with a marked increase in bone density, which precedes the evolution of more conspicuous anatomical modifications, a pattern also observed in other aquatic reptiles and mammals14-16. Spinosaurids are revealed to be aquatic specialists with surprising ecological disparity, including subaqueous foraging behaviour in Spinosaurus and Baryonyx, and non-diving habits in Suchomimus. Adaptation to aquatic environments appeared in spinosaurids during the Early Cretaceous, following their divergence from other tetanuran theropods during the Early Jurassic17.

Pharmacological Management of Cardiac Arrhythmias in the Fetal and Neonatal Periods: A Scientific Statement From the American Heart Association: Endorsed by the Pediatric & Congenital Electrophysiology Society (PACES).

Disorders of the cardiac rhythm may occur in both the fetus and neonate. Because of the immature myocardium, the hemodynamic consequences of either bradyarrhythmias or tachyarrhythmias may be far more significant than in mature physiological states. Treatment options are limited in the fetus and neonate because of limited vascular access, patient size, and the significant risk/benefit ratio of any intervention. In addition, exposure of the fetus or neonate to either persistent arrhythmias or antiarrhythmic medications may have yet-to-be-determined long-term developmental consequences. This scientific statement discusses the mechanism of arrhythmias, pharmacological treatment options, and distinct aspects of pharmacokinetics for the fetus and neonate. From the available current data, subjects of apparent consistency/consensus are presented, as well as future directions for research in terms of aspects of care for which evidence has not been established.

Rolling of the jaw is essential for mammalian chewing and tribosphenic molar function.

Over the past two centuries, mammalian chewing and related anatomical features have been among the most discussed of all vertebrate evolutionary innovations1-3. Chief among these features are two characters: the dentary-only mandible, and the tribosphenic molar with its triangulated upper cusps and lower talonid basin3-5. The flexible mandibular joint and the unfused symphysis of ancestral mammals-in combination with transformations of the adductor musculature and palate-are thought to have permitted greater mobility of each lower jaw, or hemimandible6,7. Following the appearance of precise dental occlusion near the origin of the mammalian crown8,9, therians evolved a tribosphenic molar with a craggy topography that is presumed to have been used to catch, cut and crush food. Here we describe the ancestral tribosphenic therian chewing stroke, as conserved in the short-tailed opossum Monodelphis domestica: it is a simple symmetrical sequence of lower tooth-row eversion and inversion during jaw opening and closing, respectively, enacted by hemimandibular long-axis rotation. This sequence is coupled with an eversion-inversion rotational grinding stroke. We infer that the ancestral therian chewing stroke relied heavily on long-axis rotation, including symmetrical eversion and inversion (inherited from the first mammaliaforms) as well as a mortar-and-pestle rotational grinding stroke that was inherited from stem therians along with the tribosphenic molar. The yaw-dominated masticatory cycle of primates, ungulates and other bunodont therians is derived; it is necessitated by a secondarily fused jaw symphysis, and permitted by the reduction of high, interlocking cusps10-12. The development of an efficient masticatory system-culminating in the tribosphenic apparatus-allowed early mammals to begin the process of digestion by shearing and crushing food into small boli instead of swallowing larger pieces in the reptilian manner, which necessitates a long, slow and wholly chemical breakdown. The vast diversity of mammalian teeth has emerged from the basic tribosphenic groundplan13.

Flecainide Is Associated With a Lower Incidence of Arrhythmic Events in a Large Cohort of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia.

BACKGROUND: In severely affected patients with catecholaminergic polymorphic ventricular tachycardia, beta-blockers are often insufficiently protective. The purpose of this study was to evaluate whether flecainide is associated with a lower incidence of arrhythmic events (AEs) when added to beta-blockers in a large cohort of patients with catecholaminergic polymorphic ventricular tachycardia. METHODS: From 2 international registries, this multicenter case cross-over study included patients with a clinical or genetic diagnosis of catecholaminergic polymorphic ventricular tachycardia in whom flecainide was added to beta-blocker therapy. The study period was defined as the period in which background therapy (ie, beta-blocker type [beta1-selective or nonselective]), left cardiac sympathetic denervation, and implantable cardioverter defibrillator treatment status, remained unchanged within individual patients and was divided into pre-flecainide and on-flecainide periods. The primary end point was AEs, defined as sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter defibrillator shock, and arrhythmic syncope. The association of flecainide with AE rates was assessed using a generalized linear mixed model assuming negative binomial distribution and random effects for patients. RESULTS: A total of 247 patients (123 [50%] females; median age at start of flecainide, 18 years [interquartile range, 14-29]; median flecainide dose, 2.2 mg/kg per day [interquartile range, 1.7-3.1]) were included. At baseline, all patients used a beta-blocker, 70 (28%) had an implantable cardioverter defibrillator, and 21 (9%) had a left cardiac sympathetic denervation. During a median pre-flecainide follow-up of 2.1 years (interquartile range, 0.4-7.2), 41 patients (17%) experienced 58 AEs (annual event rate, 5.6%). During a median on-flecainide follow-up of 2.9 years (interquartile range, 1.0-6.0), 23 patients (9%) experienced 38 AEs (annual event rate, 4.0%). There were significantly fewer AEs after initiation of flecainide (incidence rate ratio, 0.55 [95% CI, 0.38-0.83]; P=0.007). Among patients who were symptomatic before diagnosis or during the pre-flecainide period (n=167), flecainide was associated with significantly fewer AEs (incidence rate ratio, 0.49 [95% CI, 0.31-0.77]; P=0.002). Among patients with ≥1 AE on beta-blocker therapy (n=41), adding flecainide was also associated with significantly fewer AEs (incidence rate ratio, 0.25 [95% CI, 0.14-0.45]; P<0.001). CONCLUSIONS: For patients with catecholaminergic polymorphic ventricular tachycardia, adding flecainide to beta-blocker therapy was associated with a lower incidence of AEs in the overall cohort, in symptomatic patients, and particularly in patients with breakthrough AEs while on beta-blocker therapy.

Complete Ichthyornis skull illuminates mosaic assembly of the avian head.

The skull of living birds is greatly modified from the condition found in their dinosaurian antecedents. Bird skulls have an enlarged, toothless premaxillary beak and an intricate kinetic system that includes a mobile palate and jaw suspensorium. The expanded avian neurocranium protects an enlarged brain and is flanked by reduced jaw adductor muscles. However, the order of appearance of these features and the nature of their earliest manifestations remain unknown. The Late Cretaceous toothed bird Ichthyornis dispar sits in a pivotal phylogenetic position outside living groups: it is close to the extant avian radiation but retains numerous ancestral characters1-3. Although its evolutionary importance continues to be affirmed3-8, no substantial new cranial material of I. dispar has been described beyond incomplete remains recovered in the 1870s. Jurassic and Cretaceous Lagerstätten have yielded important avialan fossils, but their skulls are typically crushed and distorted 9 . Here we report four three-dimensionally preserved specimens of I. dispar-including an unusually complete skull-as well as two previously overlooked elements from the Yale Peabody Museum holotype, YPM 1450. We used these specimens to generate a nearly complete three-dimensional reconstruction of the I. dispar skull using high-resolution computed tomography. Our study reveals that I. dispar had a transitional beak-small, lacking a palatal shelf and restricted to the tips of the jaws-coupled with a kinetic system similar to that of living birds. The feeding apparatus of extant birds therefore evolved earlier than previously thought and its components were functionally and developmentally coordinated. The brain was relatively modern, but the temporal region was unexpectedly dinosaurian: it retained a large adductor chamber bounded dorsally by substantial bony remnants of the ancestral reptilian upper temporal fenestra. This combination of features documents that important attributes of the avian brain and palate evolved before the reduction of jaw musculature and the full transformation of the beak.

Management of Junctional Rhythm in Patients After the Fontan Operation: A Multicenter Congenital Cardiology Survey.

Sinus node dysfunction with concomitant junctional rhythm (JR) is frequently observed among Fontan patients and has been recognized as a contributor to heart failure. The impact and management of JR is unclear. A survey was mailed to all members of the Pediatric and Congenital Electrophysiology society (PACES) and members were asked to forward the questionnaire to their non-electrophysiology colleagues. Responses were received from 154 physicians (88 electrophysiologists (EP's) and 66 non-EP's (46 pediatric cardiologists and 20 adult congenital cardiologists). There were few differences in the response between EP's and non-EP's. Overall, 57% recommended an annual ambulatory ECG (AECG). A significant majority (80%) opted to continue to follow patients with significant periods of JR on AECG as long as the patients were asymptomatic, and showed no echocardiographic signs of cardiac decompensation. However, 84% would place a pacemaker in a patient with JR who was having open chest surgery for other reasons. Finally, pacemaker placement would be performed by 91% if a patient with JR showed signs of heart failure. Most congenital cardiologists would not recommend pacemaker placement in asymptomatic Fontan patients with JR. Further studies are needed on the Fontan population to determine the impact of SND and JR on longer term outcomes and to determine the role and optimal timing of pacemaker placement in these patients.

Children's Heartbeat: A Web-Based Program to Spread Knowledge on Arrhythmias in Children.

Expertise in pediatric arrhythmia management is lacking in most low- and middle- income countries (LMIC). Strategies to disseminate education in pediatric electrophysiology are essential to meet this need. Children's Heartbeat was created to meet the growing demand for pediatric electrophysiologic consultation in LMIC. Children's Heartbeat is a virtual video-conferencing program that uses the Extension for Community Healthcare Outcomes model to disseminate knowledge about pediatric arrhythmia management from pediatric electrophysiologists to clinicians in medically under-resourced regions worldwide. Monthly virtual case-based sessions are held with pediatric electrophysiologists and clinicians in medically under-resourced settings to discuss pediatric electrophysiology management. Since its inception, Children's Heartbeat viewership has grown exponentially to include 181 total registrants, 64 average monthly participants, and an additional 121 average viewers of recorded sessions. Attendees have expressed increased confidence in pediatric arrhythmia management. Children's Heartbeat has successfully provided pediatric electrophysiology consultation to medically under-resourced regions globally and have increased clinicians' confidence in caring for children with arrhythmias. Future directions include spreading the program to general pediatric and pediatric cardiology trainees and practicing pediatricians in rural parts of high-income countries and evaluating the direct impact of Children's Heartbeat on the management of arrhythmias in pediatric patients in LMIC.

3D atlas of tinamou (Neornithes: Tinamidae) pectoral morphology: Implications for reconstructing the ancestral neornithine flight apparatus.

Palaeognathae, the extant avian clade comprising the flightless ratites and flight-capable tinamous (Tinamidae), is the sister group to all other living birds, and recent phylogenetic studies illustrate that tinamous are phylogenetically nested within a paraphyletic assemblage of ratites. As the only extant palaeognaths that have retained the ability to fly, tinamous may provide key information on the nature of the flight apparatus of ancestral crown palaeognaths-and, in turn, crown birds-as well as insight into convergent modifications to the wing apparatus among extant ratite lineages. To reveal new information about the musculoskeletal anatomy of tinamous and facilitate development of computational biomechanical models of tinamou wing function, we generated a three-dimensional musculoskeletal model of the flight apparatus of the extant Andean tinamou (Nothoprocta pentlandii) using diffusible iodine-based contrast-enhanced computed tomography (diceCT). Origins and insertions of the pectoral flight musculature of N. pentlandii are generally consistent with those of other extant volant birds specialized for burst flight, and the entire suite of presumed ancestral neornithine flight muscles are present in N. pentlandii with the exception of the biceps slip. The pectoralis and supracoracoideus muscles are robust, similar to the condition in other extant burst-flying birds such as many extant Galliformes. Contrary to the condition in most extant Neognathae (the sister clade to Palaeognathae), the insertion of the pronator superficialis has a greater distal extent than the pronator profundus, although most other anatomical observations are broadly consistent with the conditions observed in extant neognaths. This work will help form a basis for future comparative studies of the avian musculoskeletal system, with implications for reconstructing the flight apparatus of ancestral crown birds and clarifying musculoskeletal modifications underlying the convergent origins of ratite flightlessness.

Decelerated dinosaur skull evolution with the origin of birds.

The evolutionary radiation of birds has produced incredible morphological variation, including a huge range of skull form and function. Investigating how this variation arose with respect to non-avian dinosaurs is key to understanding how birds achieved their remarkable success after the Cretaceous-Paleogene extinction event. Using a high-dimensional geometric morphometric approach, we quantified the shape of the skull in unprecedented detail across 354 extant and 37 extinct avian and non-avian dinosaurs. Comparative analyses reveal fundamental differences in how skull shape evolved in birds and non-avian dinosaurs. We find that the overall skull shape evolved faster in non-avian dinosaurs than in birds across all regions of the cranium. In birds, the anterior rostrum is the most rapidly evolving skull region, whereas more posterior regions-such as the parietal, squamosal, and quadrate-exhibited high rates in non-avian dinosaurs. These fast-evolving elements in dinosaurs are strongly associated with feeding biomechanics, forming the jaw joint and supporting the jaw adductor muscles. Rapid pulses of skull evolution coincide with changes to food acquisition strategies and diets, as well as the proliferation of bony skull ornaments. In contrast to the appendicular skeleton, which has been shown to evolve more rapidly in birds, avian cranial morphology is characterised by a striking deceleration in morphological evolution relative to non-avian dinosaurs. These results may be due to the reorganisation of skull structure in birds-including loss of a separate postorbital bone in adults and the emergence of new trade-offs with development and neurosensory demands. Taken together, the remarkable cranial shape diversity in birds was not a product of accelerated evolution from their non-avian relatives, despite their frequent portrayal as an icon of adaptive radiations.

Patterns of Electrocardiographic Abnormalities in Children with Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM), a common cardiomyopathy in children, is an important cause of morbidity and mortality. Early recognition and appropriate management are important. An electrocardiogram (ECG) is often used as a screening tool in children to detect heart disease. The ECG patterns in children with HCM are not well described.ECGs collected from an international cohort of children, and adolescents (≤ 21 years) with HCM were reviewed. 482 ECGs met inclusion criteria. Age ranged from 1 day to 21 years, median 13 years. Of the 482 ECGs, 57 (12%) were normal. The most common abnormalities noted were left ventricular hypertrophy (LVH) in 108/482 (22%) and biventricular hypertrophy (BVH) in 116/482 (24%) Of the patients with LVH/BVH (n = 224), 135 (60%) also had a strain pattern (LVH in 83, BVH in 52). Isolated strain pattern (in the absence of criteria for hypertrophy) was seen in 43/482 (9%). Isolated pathologic Q waves were seen in 71/482 (15%). Pediatric HCM, 88% have an abnormal ECG. The most common ECG abnormalities were LVH or BVH with or without strain. Strain pattern without hypertrophy and a pathologic Q wave were present in a significant proportion (24%) of patients. Thus, a significant number of children with HCM have ECG abnormalities that are not typical for "hypertrophy". The presence of the ECG abnormalities described above in a child should prompt further examination with an echocardiogram to rule out HCM.

The dinosaurian femoral head experienced a morphogenetic shift from torsion to growth along the avian stem.

Significant evolutionary shifts in locomotor behaviour often involve comparatively subtle anatomical transitions. For dinosaurian and avian evolution, medial overhang of the proximal femur has been central to discussions. However, there is an apparent conflict with regard to the evolutionary origin of the dinosaurian femoral head, with neontological and palaeontological data suggesting seemingly incongruent hypotheses. To reconcile this, we reconstructed the evolutionary history of morphogenesis of the proximal end of the femur from early archosaurs to crown birds. Embryological comparison of living archosaurs (crocodylians and birds) suggests the acquisition of the greater overhang of the femoral head in dinosaurs results from additional growth of the proximal end in the medial-ward direction. On the other hand, the fossil record suggests that this overhang was acquired by torsion of the proximal end, which projected in a more rostral direction ancestrally. We reconcile this apparent conflict by inferring that the medial overhang of the dinosaur femoral head was initially acquired by torsion, which was then superseded by mediad growth. Details of anatomical shifts in fossil forms support this hypothesis, and their biomechanical implications are congruent with the general consensus regarding broader morpho-functional evolution on the avian stem.

Re-description of the early Triassic diapsid Palacrodon from the lower Fremouw formation of Antarctica.

The rapid radiation and dispersal of crown reptiles following the end-Permian mass extinction characterizes the earliest phase of the Mesozoic. Phylogenetically, this early radiation is difficult to interpret, with polytomies near the crown node, long ghost lineages, and enigmatic origins for crown group clades. Better understanding of poorly known taxa from this time can aid in our understanding of this radiation and Permo-Triassic ecology. Here, we describe an Early Triassic specimen of the diapsid Palacrodon from the Fremouw Formation of Antarctica. While Palacrodon is known throughout the Triassic and exhibits a cosmopolitan geographic range, little is known of its evolutionary relationships. We recover Palacrodon outside of crown reptiles (Sauria) but more crownward than Youngina capensis and other late Permian diapsids. Furthermore, Palacrodon possesses anatomical features that add clarity to the evolution of the stapes within the reptilian lineage, as well as incipient adaptations for arboreality and herbivory during the earliest phases of the Permo-Triassic recovery.

A developmental staging system and musculoskeletal development sequence of the common musk turtle (Sternotherus odoratus).

BACKGROUND: The extremely derived body plan of turtles has sparked a great interest in studying their developmental biology. Here, we describe the embryonic development of the Stinkpot, or common musk turtle (Sternotherus odoratus), a small aquatic turtle from the family Kinosternidae. RESULTS: We identify 20 distinct developmental stages, some comparable to stages described by previous studies on other turtles and some in between these, improving the resolution of the generalities of turtle development. We provide a detailed account of both the external morphology and skeletal development, as well as a general look at the early stages of muscular development until the attainment of the adult muscular anatomical pattern. CONCLUSIONS: Several potential skeletal and muscular apomorphies of turtles are identified or elaborated. The musk turtle, with its small size and hard-shelled egg, could become an important species for the study of turtle evolution and development, suitable for in ovo experimentation and late stage imaging of well-advanced anatomical features.

Hidden limbs in the "limbless skink" Brachymeles lukbani: Developmental observations.

Reduced limbs and limblessness have evolved independently in many lizard clades. Scincidae exhibit a wide range of limb-reduced morphologies, but only some species have been used to study the embryology of limb reduction (e.g., digit reduction in Chalcides and limb reduction in Scelotes). The genus Brachymeles, a Southeast Asian clade of skinks, includes species with a range of limb morphologies, from pentadactyl to functionally and structurally limbless species. Adults of the small, snake-like species Brachymeles lukbani show no sign of external limbs in the adult except for small depressions where they might be expected to occur. Here, we show that embryos of B. lukbani in early stages of development, on the other hand, show a truncated but well-developed limb with a stylopod and a zeugopod, but no signs of an autopod. As development proceeds, the limb's small size persists even while the embryo elongates. These observations are made based on external morphology. We used florescent whole-mount immunofluorescence to visualize the morphology of skeletal elements and muscles within the embryonic limb of B. lukabni. Early stages have a humerus and separated ulna and radius cartilages; associated with these structures are dorsal and ventral muscle masses as those found in the embryos of other limbed species. While the limb remains small, the pectoral girdle grows in proportion to the rest of the body, with well-developed skeletal elements and their associated muscles. In later stages of development, we find the small limb is still present under the skin, but there are few indications of its presence, save for the morphology of the scale covering it. By use of CT scanning, we find that the adult morphology consists of a well-developed pectoral girdle, small humerus, extremely reduced ulna and radius, and well-developed limb musculature connected to the pectoral girdle. These muscles form in association with a developing limb during embryonic stages, a hint that "limbless" lizards that possess these muscles may have or have had at least transient developing limbs, as we find in B. lukbani. Overall, this newly observed pattern of ontogenetic reduction leads to an externally limbless adult in which a limb rudiment is hidden and covered under the trunk skin, a situation called cryptomelia. The results of this work add to our growing understanding of clade-specific patterns of limb reduction and the convergent evolution of limbless phenotypes through different developmental processes.

Evolutionary origin of the turtle skull.

Transitional fossils informing the origin of turtles are among the most sought-after discoveries in palaeontology. Despite strong genomic evidence indicating that turtles evolved from within the diapsid radiation (which includes all other living reptiles), evidence of the inferred transformation between an ancestral turtle with an open, diapsid skull to the closed, anapsid condition of modern turtles remains elusive. Here we use high-resolution computed tomography and a novel character/taxon matrix to study the skull of Eunotosaurus africanus, a 260-million-year-old fossil reptile from the Karoo Basin of South Africa, whose distinctive postcranial skeleton shares many unique features with the shelled body plan of turtles. Scepticism regarding the status of Eunotosaurus as the earliest stem turtle arises from the possibility that these shell-related features are the products of evolutionary convergence. Our phylogenetic analyses indicate strong cranial support for Eunotosaurus as a critical transitional form in turtle evolution, thus fortifying a 40-million-year extension to the turtle stem and moving the ecological context of its origin back onto land. Furthermore, we find unexpected evidence that Eunotosaurus is a diapsid reptile in the process of becoming secondarily anapsid. This is important because categorizing the skull based on the number of openings in the complex of dermal bone covering the adductor chamber has long held sway in amniote systematics, and still represents a common organizational scheme for teaching the evolutionary history of the group. These discoveries allow us to articulate a detailed and testable hypothesis of fenestral closure along the turtle stem. Our results suggest that Eunotosaurus represents a crucially important link in a chain that will eventually lead to consilience in reptile systematics, paving the way for synthetic studies of amniote evolution and development.

Peramorphosis, an evolutionary developmental mechanism in neotropical bat skull diversity.

BACKGROUND: The neotropical leaf-nosed bats (Chiroptera, Phyllostomidae) are an ecologically diverse group of mammals with distinctive morphological adaptations associated with specialized modes of feeding. The dramatic skull shape changes between related species result from changes in the craniofacial development process, which brings into focus the nature of the underlying evolutionary developmental processes. RESULTS: In this study, we use three-dimensional geometric morphometrics to describe, quantify, and compare morphological modifications unfolding during evolution and development of phyllostomid bats. We examine how changes in development of the cranium may contribute to the evolution of the bat craniofacial skeleton. Comparisons of ontogenetic trajectories to evolutionary trajectories reveal two separate evolutionary developmental growth processes contributing to modifications in skull morphogenesis: acceleration and hypermorphosis. CONCLUSION: These findings are consistent with a role for peramorphosis, a form of heterochrony, in the evolution of bat dietary specialists.

A prospective 5-year study of exercise performance following Melody valve implant.

BACKGROUND: The long-term benefits of Melody valve implant for right ventricular outflow tract conduit obstruction or insufficiency on exercise capacity are undefined. METHODS: As part of the Melody valve clinical trial, 136 patients with congenital heart disease underwent serial cardiopulmonary exercise testing prior to, 6 months after, and annually for up to 5 years postimplant. RESULTS: Mean age at Melody valve implantation was 22.4 ± 0.9 years (range 7-53 years). The 95 patients who completed the study protocol provide the basis of this report. An initial improvement in % predicted workload was present at 6 months postimplant; however, at the final (5 year) follow-up, sustained or further improvements in workload were not demonstrated for the entire cohort compared to baseline. By subgroup analysis, age <17 years at implant and pulmonary regurgitation as the primary lesion were variables associated with sustained improvement in exercise performance. There were sustained improvements in the ventilatory equivalents for O2 (minute ventilation/O2 intake, P = .01) and CO2 (minute ventilation/CO2 output, P < .01) at the ventilatory anaerobic threshold at the study conclusion. Improvements in forced vital capacity were also observed during the study but not sustained at the final follow-up. CONCLUSIONS: A cautious appraisal of the cardiovascular benefits of Melody valve implant on sustained improvements in exercise performance appears warranted. Although the observed changes in pulmonary function suggest improved restrictive lung physiology and more efficient gas exchange, after an initial increase in % predicted performance, neither sustained nor further improvements in exercise performance were observed, except in specific patient subgroups.