What “FUEL”s the Fontan circulation—solvitur ambulando!

Central MessageThe relative magnitude of factors contributing to pulmonary blood flow in a Fontan circulation is unknown. Pulmonary vasoreactivity likely just one many determinants flow.This Invited Expert Opinion provides perspective on the following paper: Circulation. 2020; 141:641-651. https://doi.org/10.1161/CIRCULATIONAHA.119.044352.See Commentaries pages 1239, 1240, and 1241.Feature Editor Note—The congenital associate editors are pleased introduce expert opinion Dr Jack Rychik, who graciously accepted our invitation share his results FUEL (Fontan Udenafil Exercise Longitudinal) trial marginally positive (or negative, depending your perspective) impact phosphodiesterase-5 inhibition exercise performance population.Those caring for patients with do so amidst sense foreground hope positivity pervasive background uncertainty perhaps pessimism about long-term future their patients. All would welcome therapy that might improve current prospects Therefore, community eagerly awaited trial, Herculean effort part investigators was well-designed well executed. In interest good science, justifiably imposed several criteria, resulting exclusion 71% screened inclusion relatively “healthy” cohort circulation. Results were, put it bluntly, rather tepid. highly-recognized circulation, an interesting overview known less well-characterized governing doing so, he also constructs interpretive framework from which view trial. Please enjoy opinion.Ronald K. Woods, MD, PhD The flow. This https://doi.org/10.1161/CIRCULATIONAHA.119.044352. See 1241. Diogenes “the cynic” (404-323 BC) Greek philosopher apparently quite character. He famously carriage lamp during day perennial, endless search honest man (Figure 1). Once heated, lengthy debate reality nature motion, arose slowly walked away, thus proving point. Legend has as departed, called back colleagues Latin translation, loudly proclaimed—solvitur ambulando!—“the problem solved by walking!” Today, this phrase used imply unanswered questions best through practical experimentation. You don't believe motion or can't explain how happens? Well, watch me walk away—the solved. model experimentation acute relevance condition single-ventricle heart disease. Humans born cardiac birth defect having only effective ventricle surviving greater numbers than ever before. Towering figures such Fontan, Kreutzer deLeval—as countless others—contributed development strategy pathway survival. problem—no ventricle? solution—in stepwise manner, surgically anastomose systemic venous return directly lungs—a cavopulmonary connection. nearly 50-year experiment treating disease led us solidly conclude there no absolute need subpulmonary human survive. at least 2 3 families carrying fetus will see individual successful completion surgical reconstruction.1Liu M.Y. Zielonka B. Snarr B.S. Zhang X. Gaynor J.W. Rychik J. Longitudinal assessment outcome prenatal diagnosis operation over 500 fetuses single ventricle-type disease: Philadelphia Fetus-To-Fontan study.J Am Heart Assoc. 2018; 7: e009145Crossref PubMed Scopus (18) Google Scholar Furthermore, adolescent 90% survive 30 years age.2Dennis M. Zannino D. du Plessis Bullock A. Disney P.J.S. Radford D.J. et al.Clinical outcomes adolescents adults after procedure.J Coll Cardiol. 71: 1009-1017Crossref (63) Although far fully solved—we have not yet reached goal creating normal quality duration life these individuals—we nevertheless well-defined care survival what otherwise be lethal if left nature. Despite application surgery regular basis, we still complete picture drives forward How does circulate lungs without pump? A deeper understanding crucially important. There price pay Physiological consequences chronically elevated central pressure, lymphatic congestion, low output source complications.3Rychik Atz A.M. Celermajer D.S. Deal B.J. Gatzoulis M.A. Gewillig M.H. al.Evaluation management child adult fontan circulation: scientific statement American Association.Circulation. 2019; 140: e234-e284Crossref (158) If could better understand influence absence importantly comprehend contribution each variables driving forward, then able modify conditions, harness forces, create more favorable state. What influences drive lungs? host reasonable candidates (Table Some passive characteristics, whereas others active processes. Computational fluid modeling dynamics studies focused efficiency architecture connections arteries.4Hsia T.Y. Conover T. Figliola R. Modeling Congenital Hearts Alliance (MOCHA) InvestigatorsComputational support decision making physiology.Semin Thorac Cardiovasc Surg Pediatr Card Annu. 23: 2-10Abstract Full Text PDF (1) No doubt some “streamlining” important; however, unlikely even most optimal substantially compensate active, pulsatile ventricular thrust. Downstream, diastolic properties importance. With opening atrioventricular valve, compliance “receptacle” diastole filling impacts atrial pressures, which, elevated, certainly reduce impetus transpulmonary flow.5Gewillig Brown S.C. van de Bruaene Providing principles conceptualising circulation.Acta Paediatr. 109: 651-658Crossref (11) ScholarTable 1Potential influencing circulationSystemVariableMechanismThe systemThoracic cage musculature, diaphragm performance, respiratory mechanicsLung size parenchymal volumeArborization vascular treePeripheral microcirculation (pulmonary arterioles, capillaries)Pulmonary endothelial functionMicro-thrombo-emboli within circulationInspiratory creates intrathoracic negative pressure into thoraxMay mechanical impedance flowAllows equitable well-distributed perfusionContributes resistance flowControl tone reactivityPulmonary microemboli may obstruct small vessels flowThe systemFontan circuit (vena cava-to-pulmonary artery artery) architecturePulmonary connectionsSystolic contraction mechanicsDiastolic relaxation mechanicsCardiac rhythmOptimizes kinetics flowAnatomical aspects return, flowSystolic valve descent expansion exerts flowInfluences emptying fillingAtrioventricular synchrony (sinus rhythm) optimizes efficient emptyingExtrinsic cardiopulmonary systemsPeripheral musculatureSystemic capacitance toneIntravascular volume statusSkeletal muscle driver returnMay provide “reserve” rest exertionDetermines overall circulating volume, filling, stroke Open table new tab Less well-recognized but significance mechanics systole. can demonstrated nicely simple observation Doppler echocardiography–derived patterns connection.6Rychik Fogel Donofrio M.T. Goldmuntz E. Cohen M.S. Spray T.L. al.Comparison functional operative aortopulmonary shunt versus superior shunt.Am J 1997; 80: 922-926Abstract (25) predominance vein patient takes place systole 2). possibly case when answer lies toward apex systole, expands atrium draws veins. seen looking upstream vena cava connection, dominant peak identified high-fidelity signals obtained. Hence, contraction, twist, descent—in other words systole—may exert much, degree diastole, Cardiac magnetic resonance imaging “aspiration” veins associated accounts 70% adults.7Steding-Ehrenborg Carlsson Stephensen S. Arheden H. Atrial aspiration caval caused secures total independent resting rate size.Clin Physiol Funct Imaging. 2013; 33: 233-240Crossref (24) We know rule constant “total volume”—that normally maintaining throughout cycle, while chamber volumes change—is violated heart.8Fogel Weinberg P.M. Fellows K.E. Hoffman E.A. Magnetic center mass before staged procedure.Am 1993; 72: 1435-1443Abstract (27) Poorly coordinated inefficient twisting untwisting power its draw return.9Fogel Gupta K.B. Regional wall strain analysis across stages reconstruction tagging.Am Physiol. 1995; 269: H1132-H1152PubMed Other possible processes entail mechanisms include peripheral specifically lower-extremity musculature propulsion, thoracic inspiratory created natural respiration. recognition potential drivers flow, exertional activity—for population whole, specific individuals circulation—is largely Then question “pulmonary resistance”—a concept made up variety components. Elevated negate forces forward. Factors elements elasticity large vessels, arborization patterns, density dynamic function reflected (constriction dilation). elements—starting vessel all way down cell function—are risk disturbance ventricle. Abnormality exist, either standpoint altered acquired rigors treatment (ie, damage due high vortices association aorto-pulmonary shunt, maldevelopment absent connection). predilection thromboembolic micropulmonary emboli adds additional layer impediment flow.10Varma C. Warr M.R. Hendler A.L. Paul N.S. Webb G.D. Therrien Prevalence “silent” operation.J 2003; 41: 2252-2258Crossref (98) cases, severity circulatory derangement state prohibitive. These flagged advance considered noncandidates completion, failing, deserving take-down transplantation. However, once operatively completed ostensibly functioning well, secondarily important features ventricle, output? Manipulation leading improved status subject recently published highly anticipated trial.11Goldberg Zak V. Goldstein B.H. Schumacher K.R. Rhodes Penny al.Results trial.Circulation. 141: 641-651Crossref (31) National Institutes Health–sponsored Pediatric Network conducted multicenter Goldberg colleagues11Goldberg involving 400 subjects mean age 15 randomized placebo (PDE-5) using long-lasting agent udenafil (Dong-a Pharmaceuticals, Seoul, South Korea). Subjects were studied period 6 months, primary end point change oxygen consumption comparison baseline. Clinical experience supports efficacy vasodilator circulation–associated complications12Snarr Paridon S.M. failing rationale efficacy.Cardiol Young. 2015; 25: 1489-1492Crossref (17) Scholar, 13Rychik Dodds K.M. Glatz A.C. Rossano al.Protein losing enteropathy operation: glimpses clarity lifting Fog.World Congenit Surg. 11: 92-96Crossref 14Uzun O. Wong J.K. Bhole Stumper Resolution protein-losing normalization mesenteric sildenafil Fontan.Ann 2006; 82: e39-e40Abstract (81) number pilot PDE-5 (sildenafil)15Goldberg French McBride M.G. Marino Mirarchi N. Hanna B.D. al.Impact oral children young randomized, double-blind, placebo-controlled, crossover 2011; 123: 1185-1193Crossref (199) Scholar,16Van De La Gerche Claessen G. Meester P. Devroe Gillijns al.Sildenafil improves hemodynamics patients.Circ 2014; 265-273Crossref (88) endothelin-1 blockade (bosentan)17Hebert Mikkelsen U.R. Thilen U. Idorn L. Jensen A.S. Nagy al.Bosentan capacity TEMPO (treatment endothelin receptor antagonist patients, double-blind study measuring consumption) study.Circulation. 130: 2021-2030Crossref (119) provided signal possibility positively clinical status, capacity. Oxygen chosen end-point variable parameter surrogate models failure. work tour force, success enrolling hundreds multiple institutions largest kind undertaken care. achievement cannot overstated. Disappointingly, measured did significantly improve; measures submaximal impacted manner. Of note, modest statistically significant placebo. Specifically, ventilatory anaerobic threshold 3.2% group declined 0.9% group. enormous demonstrate? Health providers managing hunger discover employ drug therapies strategies safe tolerated young—it's very recognized established. considering initial promise expectations, somewhat disappointed gains achieved. key question—to physiological improvement translate clinically changes well-being? Practically, doubts arise value recommending routine administration twice-a-day gain slight (approximately 3%). forthcoming investigations subpopulations parameters liver fibrosis extremely valuable further clarify utility routine, general use going note exactly alike select categories benefit others. Perhaps biggest lesson learn relates complexity While appears play role, inducing vasodilation meager best. Within range expects well-functioning outpatient major determinant Where else focus attention blood? Augmenting enhancing makes sense. receiving well-deserved newfound attention. Improving tone, particular lower extremities, compression.18Tran D'Ambrosio Verrall C.E. Attard Briody D'Souza al.Body composition living myopenic profile.J 9: e015639Crossref (14) Strengthening augment deserves exploration. Interestingly, domains enhanced “cardio” type exercises vigorous walking. Finally, investigating role systolic function) insight matter determining unique somewhat-novel old concept, worthy re-exploration. morphology, myocardial contractility, annular “common” “aspirating” circuit. Whether modified influenced strategies, pharmacologic manipulation, means unclear. Practical necessary solve Strong collaborative platforms novel frameworks research open sharing data necessary. gold standard knowledge moved resources endeavor, innovative methodologies beyond traditional make timely progress. Careful consideration relevant points uniqueness thoughtfully any investigations. strongly hints “running” “walking.” ability run consume valid cardiovascular evaluation lead lives sustained exercise. As concerned, activity walking 2300-year-old wisdom today—“solvitur ambulando”—the dilemma walking; required. author reported conflicts interest. Journal policy requires reviewers disclose decline handling reviewing manuscripts they conflict article