O2 pulse slope correlates with stroke volume during exercise in patients with a Fontan circulation.

BACKGROUND: Peak oxygen pulse (O2pulse=oxygen consumption/heart rate) is calculated by the product of stroke volume (SV) and oxygen extraction. It has been shown to be reduced in patients with a Fontan circulation. However, in the Fontan population, it may be a poor marker of SV. We propose that the slope of the O2 pulse curve may be more reflective of SV during exercise. METHODS: We analysed cardiopulmonary exercise test data in 22 subjects with a Fontan circulation (cohort A) and examined the association between peak SV during exercise (aortic flow measured on exercise cardiac MRI), and O2 pulse parameters (absolute O2 pulse and O2 pulse slopes up to anaerobic threshold (AT) and peak exercise). In a separate Fontan cohort (cohort B, n=131), associations between clinical characteristics and O2 pulse kinetics were examined. RESULTS: In cohort A, peak aortic flow was moderately and significantly associated with O2pulseslopePEAK (r=0.47, p=0.02). However, neither absolute O2pulseAT nor O2pulsePEAK was significantly associated with peak aortic flow. In cohort B, O2pulseslopePEAK and O2pulseslopeAT were not significantly associated with clinical parameters, apart from a weak association with forced vital capacity. CONCLUSION: The slope of the O2 pulse curve to peak exercise may be more reflective of peak SV in the Fontan population than a single peak O2 pulse value.

Scaling Peak Oxygen Consumption for Body Size and Composition in People With a Fontan Circulation.

Background Peak oxygen consumption (peak V̇O2$$ \dot{\mathrm{V}}{\mathrm{O}}_2 $$) is traditionally divided ("ratio-scaled") by body mass (BM) for clinical interpretation. Yet, it is unknown whether ratio-scaling to BM can produce a valid size-independent expression of peak V̇O2$$ \dot{\mathrm{V}}{\mathrm{O}}_2 $$ in people with a Fontan circulation. Furthermore, people with a Fontan circulation have deficits in lean mass, and it is unexplored whether using different measures of body composition may improve scaling validity. The objective was to assess the validity of different scaling denominators (BM, stature, body surface area, fat-free mass, lean mass, and appendicular lean mass using ratio and allometric scaling). Methods and Results Eighty-nine participants (age: 23.3±6.7 years; 53% female) with a Fontan circulation had their cardiorespiratory fitness and body composition measured by cardiopulmonary exercise testing and dual-energy x-ray absorptiometry. Ratio and allometric (log-linear regression) scaling was performed and Pearson correlations assessed scaling validity. Scaling denominators BM (r=-0.25, P=0.02), stature (r=0.46, P<0.001), and body surface area (0.23, P=0.03) were significantly correlated with their respective ratio-scaled expressions of peak V̇O2$$ \dot{\mathrm{V}}{\mathrm{O}}_2 $$, but fat-free mass, lean mass, or appendicular lean mass were not (r≤0.11; R2=1%). Allometrically expressed peak V̇O2$$ \dot{\mathrm{V}}{\mathrm{O}}_2 $$ resulted in no significant correlation with any scaling denominator (r=≤0.23; R2=≤4%). Conclusions The traditional and accepted method of ratio-scaling to BM is invalid because it fails to create a size-independent expression of peak V̇O2$$ \dot{\mathrm{V}}{\mathrm{O}}_2 $$ in people with a Fontan circulation. However, ratio-scaling to measures of body composition (fat-free mass, lean mass, and appendicular lean mass) and allometric techniques can produce size-independent expressions of peak V̇O2$$ \dot{\mathrm{V}}{\mathrm{O}}_2 $$ in people with a Fontan circulation.

Older age at Fontan completion is associated with reduced lung volumes and increased lung reactance.

BACKGROUND: Fontan patients have abnormal lung function, in particular restrictive lung disease and low diffusing capacity of carbon monoxide (DLCO). We sought to further characterise these abnormalities with detailed pulmonary function testing and examine associations with clinical parameters. METHODS: 132 Fontan patients across Australia and New Zealand underwent spirometry, with 126 subjects included in final analyses. Measurement of diffusion capacity (DLCO) including its components (alveolar volume (VA) and rate of uptake of CO (KCO)) and oscillometry (reactance (X5) and resistance (R5)) were assessed in a subset of Fontan patients (n = 44) and healthy controls (n = 12). Double diffusion (to assess diffusing capacity of nitric oxide (DLNO), capillary blood volume (Vc), alveolar capillary membrane function (DmCO)) was performed in Fontan patients (n = 18) and healthy controls (n = 12). RESULTS: FEV1 and FVC z-scores were low in Fontan subjects (mean - 1.67 ± 1.24 and - 1.61 ± 1.29, respectively) and correlated with exercise capacity. Compared to controls, z-scores for X5, DLCO, KCO, VA and DLNO were significantly lower in Fontan patients. R5, Vc and DmCO z-scores were preserved. X5 was associated with VA (r = 0.41,p = 0.009) and DmCO (r = 0.61,p = 0.008). Older age at Fontan completion was associated with lower z-scores for FEV1 (r = -0.46,p = 0.002), FVC (r = -0.47,p = 0.002), X5 (r = -0.32,p = 0.033) and VA (r = -0.36,p = 0.022). CONCLUSION: Fontan patients have a reduced DLCO which is largely driven by low VA. Lung stiffness (X5) is increased which is associated with VA and DmCO. These parameters negatively correlate with older age of Fontan completion suggesting that earlier Fontan completion may have a beneficial effect on lung function.

Impairments in Pulmonary Function in Fontan Patients: Their Causes and Consequences.

Patients with a Fontan circulation lack a sub-pulmonary ventricle with pulmonary blood flow passively redirected to the lungs. In the Fontan circulation, ventilation has a significant influence on pulmonary blood flow and cardiac output both at rest and with exercise. Children and adults with a Fontan circulation have abnormalities in lung function. In particular, restrictive ventilatory patterns, as measured by spirometry, and impaired gas transfer, as measured by the diffusing capacity of carbon monoxide, have been frequently observed. These abnormalities in lung function are associated with reduced exercise capacity and quality of life. Moderate to severe impairment in lung volumes is independently associated with reduced survival in adults with congenital heart disease. Skeletal and inspiratory muscle weakness has also been reported in patients with a Fontan circulation, with the prospect of improving respiratory muscle function through exercise training programs. In this review, we will present data on cardiopulmonary interactions in the Fontan circulation, the prevalence and severity of impaired lung function, and respiratory muscle function in this population. We will discuss potential causes for and consequence of respiratory impairments, and their impact on exercise capacity and longer-term Fontan outcome. We aim to shed light on possible strategies to reduce morbidity by improving respiratory function in this growing population of patients.

The Degree of Left Ventricular Hypoplasia Is Associated with Tricuspid Regurgitation Severity in Infants with Hypoplastic Left Heart Syndrome.

Tricuspid valve regurgitation (TR) increases adverse outcomes in children with hypoplastic left heart syndrome (HLHS). Changes in tricuspid valve (TV) annulus and leaflet geometry have been described but the underlying causes for TR in HLHS remain uncertain. We aimed to examine the association between left ventricular (LV) size and TR in infants with HLHS as right ventricular (RV)-LV interactions may be important in TR development. Echocardiograms of 50 infants with HLHS were reviewed. LV size, RV function, TR grade, TV annulus z-score, and aortic arch obstruction were examined at birth and 1 year of age (or the latest study post-bidirectional Glenn anastomosis if the patient was < 1 year of age). 24/50 (48%) had severe LV hypoplasia and 26/50 (52%) had mild/moderate LV hypoplasia. At 1 year, 10/24 (42%) with severe LV hypoplasia had moderate/severe TR versus 0/26 in the mild/moderate LV hypoplasia group (p = 0.0002). TR progressed ( ≥ 1 grade) in 14/24(58%) with severe LV hypoplasia versus 5/26 (19%) with mild/moderate LV hypoplasia (p = 0.008). In this cohort, no association was found between the degree of TR and either RV function, TV annular z-score, or arch obstruction; or between the degree of LV hypoplasia and either RV function or TV annular z-score. In infants with HLHS, the severity and progression of TR is associated with the severity of LV hypoplasia. The mechanism for this association needs further exploration but suggests a role for RV-LV interactions in the development of TR.

Inspiratory Muscle Training Is Associated With Improved Inspiratory Muscle Strength, Resting Cardiac Output, and the Ventilatory Efficiency of Exercise in Patients With a Fontan Circulation.

BACKGROUND: Patients with a Fontan circulation have reduced exercise capacity and respiratory muscle strength. Inspiratory muscle training (IMT) improves exercise capacity and quality of life in adults with heart failure. We assessed whether 6 weeks of a home-based program of IMT improves inspiratory muscle strength and the ventilatory efficiency of exercise in adolescent patients with a Fontan circulation. METHODS AND RESULTS: Twenty-three adolescent participants (aged 16±2 years) with a Fontan circulation underwent 6 weeks of IMT for 30 minutes daily. Respiratory muscle strength (maximal inspiratory pressure and expiratory pressure), lung function, and exercise capacity (cardiopulmonary exercise testing) were assessed. Fourteen of 23 participants also underwent exercise cardiac magnetic resonance imaging to examine the effects of IMT on cardiac output and systemic and pulmonary blood flow. Six weeks of IMT improved maximal inspiratory pressure by 36±24 cm H2O (61±46%) with no change in maximal expiratory pressure. Ventilatory efficiency of exercise improved after 6 weeks of IMT (from 34.2±7.8 to 32.2±5.6, P=0.04). In those who underwent exercise cardiac magnetic resonance imaging, IMT increased resting cardiac output (from 4.2±1.2 to 4.5±1.0 L/min, P=0.03) and ejection fraction (from 50.1±4.3 to 52.8±6.1%, P=0.03). CONCLUSIONS: Six weeks of IMT is associated with improved inspiratory muscle strength, ventilatory efficiency of exercise, and resting cardiac output in young Fontan patients. IMT may be a simple beneficial addition to the current management of Fontan patients, potentially reducing exercise intolerance and long-term morbidity and mortality.

Isolated Anomalous Origin of Left Pulmonary Artery From the Descending Aorta: An Embryologic Ambiguity.

Anomalous origin of a branch pulmonary artery from the aorta is a rare malformation, accounting for 0.12% of all congenital heart defects. Anomalous origin of the left pulmonary artery from the aorta (ALPA) constitutes a small proportion of these cases. ALPA has been reported to arise from the ascending aorta with various embryologic postulates. We report a case of isolated ALPA arising from the descending aorta in association with a patent ductus arteriosus, to emphasize its embryologic ambiguity.

Quinacrine blocks PrP (106-126)-formed channels.

We investigated the action of the acridine derivative, quinacrine (QC), which has been shown to act as a noncompetitive channel inhibitor. The main effects of QC are voltage- and concentration-dependent changes in the kinetics of the prion protein fragment (PrP[106-126])-formed cation channels. The current-voltage relationships show that the maximal current (I) was not affected whereas the physiologically important mean current (I') was reduced as a result of changes in channel kinetics. These findings suggest that QC acts on the open state of the channels. The half-inhibitory concentration (IC50) for the dose-dependent effects of [QC]cis on the kinetic parameters of the PrP(106-126)-formed cation channel shows a reduction in the ratios Po(QC)/Po, Fo(QC)/Fo, and To(QC)/To, whereas Tc(QC)/Tc increases. Of these ratios, Po(QC)/Po was more sensitive than the others. The corresponding IC50 for these ratios were 51, 94, 86, and 250 microM QC, respectively. The QC-induced changes in the kinetic parameters were more apparent at positive voltages. IC50 values for Po were 95, 75, and 51 microM at +20, +80, and +140 mV, respectively. The fact that QC induced changes in the kinetics of this channel, although the conductance of the channel remained unchanged, indicates that QC may bind at the mouth of the channel via a mechanism known as fast channel block. The QC-induced changes in the kinetic parameters of this channel suggest that they are pathophysiologically significant because these channels could be the mechanisms by which amyloids induce membrane damage in vivo.

The role of bacterial and non-bacterial toxins in the induction of changes in membrane transport: implications for diarrhea.

Bacterial toxins induce changes in membrane transport which underlie the loss of electrolyte homeostasis associated with diarrhea. Bacterial- and their secreted toxin-types which have been linked with diarrhea include: (a) Vibrio cholerae (cholera toxin, E1 Tor hemolysin and accessory cholera enterotoxin); (b) Escherichia coli (heat stable enterotoxin, heat-labile enterotoxin and colicins); (c) Shigella dysenteriae (shiga-toxin); (d) Clostridium perfringens (C. perfringens enterotoxin, alpha-toxin, beta-toxin and theta-toxin); (e) Clostridium difficile (toxins A and B); (f) Staphylococcus aureus (alpha-haemolysin); (g) Bacillus cereus (cytotoxin K and haemolysin BL); and (h) Aeromonas hydrophila (aerolysin, heat labile cytotoxins and heat stable cytotoxins). The mechanisms of toxin-induced diarrhea include: (a) direct effects on ion transport in intestinal epithelial cells, i.e. direct toxin interaction with intrinsic ion channels in the membrane and (b) indirect interaction with ion transport in intestinal epithelial cells mediated by toxin binding to a membrane receptor. These effects consequently cause the release of second messengers, e.g. the release of adenosine 3',5'-cyclic monophosphate/guanosine 3',5'-monophosphate, IP(3), Ca2+ and/or changes in second messengers that are the result of toxin-formed Ca2+ and K+ permeable channels, which increase Ca2+ flux and augment changes in Ca2+ homeostasis and cause depolarisation of the membrane potential. Consequently, many voltage-dependent ion transport systems, e.g. voltage-dependent Ca2+ influx, are affected. The toxin-formed ion channels may act as a pathway for loss of fluid and electrolytes. Although most of the diarrhea-causing toxins have been reported to act via cation and anion channel formation, the properties of these channels have not been well studied, and the available biophysical properties that are needed for the characterization of these channels are inadequate.

Heterogeneous amyloid-formed ion channels as a common cytotoxic mechanism: implications for therapeutic strategies against amyloidosis.

The amyloidoses consist of human and animal chronic, progressive, and sometimes fatal diseases that are characterized by the deposition of insoluble proteinaceous amyloid fibrils in various tissues. Despite the biochemical diversity of amyloids, they share certain properties. The amphipathic and the charged nature of many amyloid-forming peptides point to their intrinsic ability to form diverse beta-sheet-based aggregates and channel types in negatively charged membranes. We hypothesize that the formation of heterogeneous channels represents a common cytotoxic mechanism that accentuates the changes in the signal transduction that underlie amyloid-induced cell malfunction. One group of amyloid-forming peptides that could mediate their action via the formation of heterogeneous channels includes the extensively examined prions and amyloid beta protein that are associated with conformational neurodegenerative diseases. The aim of this study is to examine heterogeneous channels formed in bilayers with amyloid-forming peptides as a common mechanism of malfunction of signal transduction. The observed amyloid-formed channel types include the following. (1) Natriuretic peptides: (i) 68-pS H2O2- and Ba2+-sensitive channel with fast kinetics. The fast channel had three modes (spike mode, burst mode, and open mode), which differ in their kinetics but not in their conductance properties; (ii) a 273-pS inactivating large conductance channel; and (iii) a 160-pS transiently activated channel. (2) Prions: (i) a 140-pS GSSG- and TEA-sensitive channel with fast kinetics; (ii) a 41-pS dithiothreitol (DTT)-sensitive channel with slow kinetics; (iii) a 900 to 1444-pS large channel. (3) Amyloid beta protein: (i) a 17 to 63-pS AbetaP[1-40]-formed "bursting" fast cation channel, (ii) the AbetaP[1-40]-formed "spiky" fast cation channel with a similar kinetics to the "bursting" fast channel except for the absence of the long intraburst closures, (iii) 275-pS AbetaP[1-40]-formed medium conductance channel, and (iv) 589- to 704-pS AbetaP[1-40]-formed inactivating large conductance channel. This heterogeneity is one of the most common features of these charged cytotoxic amyloid-formed channels, reflecting these channels' ability to modify multiple cellular functions. Although the diversity of these aggregated-peptide-formed channels may indicate that a stochastic mechanism governs their formation, the fact that certain channel types are often observed point to preferential channel protein conformations. In addition, the fact that other amyloids have similar structural properties (e.g. hydrophobicity, charged residues, and beta-structural linkages, suggests that, despite the intrinsic ability to form diverse conformations, certain conformations and, hence, certain channel types could be a common pathologic conformation among these amyloid-forming peptides. It is concluded that conformation-based channel diversity is an important mechanism for enhancing the toxicity of amyloid-forming peptides. The cytotoxic nature of these self-associated beta-based protein channels suggests that under normal physiological conditions cells employ well-evolved protective mechanisms against seeding and/or propagation of channel-forming peptides; for example, (a) compartmentalization of these peptides as membrane bound in internal vesicles and/or (b) degradation of these peptides by enzymes. The pharmacological diversity of the amyloid-forming channels implies that multiple therapeutic interventions may be necessary for blocking and reversing heterogeneous channel formations and preventing their associated diseases.