Gas exchange calculation may estimate changes in pulmonary blood flow during veno-arterial extracorporeal membrane oxygenation in a porcine model.

Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is used as rescue therapy for severe cardiopulmonary failure. We tested whether the ratio of CO2 elimination at the lung and the V-A ECMO (V˙co2ECMO/V˙co2Lung) would reflect the ratio of respective blood flows and could be used to estimate changes in pulmonary blood flow (Q˙Lung), i.e., native cardiac output. Four healthy pigs were centrally cannulated for V-A ECMO. We measured blood flows with an ultrasonic flow probe. V˙co2ECMO and V˙co2Lung were calculated from sidestream capnographs under constant pulmonary ventilation during V-A ECMO weaning with changing sweep gas and/or V-A ECMO blood flow. If ventilation-to-perfusion ratio (V˙/Q˙) of V-A ECMO was not 1, the V˙co2ECMO was normalized to V˙/Q˙ = 1 (V˙co2ECMONorm). Changes in pulmonary blood flow were calculated using the relationship between changes in CO2 elimination and V-A ECMO blood flow (Q˙ECMO). Q˙ECMO correlated strongly with V˙co2ECMONorm (r2 0.95-0.99). Q˙Lung correlated well with V˙co2Lung (r2 0.65-0.89, P < = 0.002). Absolute Q˙Lung could not be calculated in a nonsteady state. Calculated pulmonary blood flow changes had a bias of 76 (-266 to 418) mL/min and correlated with measured Q˙Lung (r2 0.974-1.000, P = 0.1 to 0.006) for cumulative ECMO flow reductions. In conclusion, V˙co2 of the lung correlated strongly with pulmonary blood flow. Our model could predict pulmonary blood flow changes within clinically acceptable margins of error. The prediction is made possible with normalization to a V˙/Q˙ of 1 for ECMO. This approach depends on measurements readily available and may allow immediate assessment of the cardiac output response.

Determination of the effects of cryoablation for atrial fibrillation on esophageal functions.

OBJECTIVE: Periesophageal vagal plexus injury is a complication of cryoablation for atrial fibrillation (AF). The aim of this study is to investigate the effect of cryoablation on esophageal functions and to determine the relationship between esophageal temperature and esophageal motility. METHODS: Twenty patients with symptomatic paroxysmal AF who underwent cryoablation were included in this study. The lowest cryoballoon temperature for each pulmonary vein (PV) was recorded. Esophageal temperature was measured using an esophageal probe during each cryoapplication. Esophageal manometry was performed before the procedure and one day after the procedure for each patient in order to assess the esophageal functions. RESULTS: During the procedure, the highest esophageal temperature change was found in the left-side PVs in 13 patients (65%) and in the right-side PVs in seven patients (35%). No correlation was found between the lowest cryoballoon temperature and esophageal temperature change (r=0.22, p=0.05). It was detected that the lower esophageal sphincter pressure and esophageal contraction amplitude pressure decreased after the procedure (before: 19.7±9.3 mm Hg, after: 14.3±4.9 mm Hg, p=0.001; before: 84.5±28.3 mm Hg, after: 72.7±34.3 mm Hg, p=0.005, respectively). Five patients (25%) developed gastrointestinal symptoms after the procedure. CONCLUSION: During cryoablation, esophageal temperature measurement can be performed to reduce the probability of esophageal injury. Cryoablation affects esophageal motility, and esophageal manometry can be performed to detect esophageal motility impairments in patients with gastrointestinal symptoms.

Selective inhibition of electrical conduction within the pulmonary veins by α1-adrenergic receptors activation in the Rat.

Pulmonary veins (PV) are involved in the pathophysiology of paroxysmal atrial fibrillation. In the rat, left atrium (LA) and PV cardiomyocytes have different reactions to α1-adrenergic receptor activation. In freely beating atria-PV preparations, we found that electrical field potential (EFP) originated from the sino-atrial node propagated through the LA and the PV. The α1-adrenergic receptor agonist cirazoline induced a progressive loss of EFP conduction in the PV whereas it was maintained in the LA. This could be reproduced in preparations electrically paced at 5 Hz in LA. During pacing at 10 Hz in the PV where high firing rate ectopic foci can occur, cirazoline stopped EFP conduction from the PV to the LA, which allowed the sino-atrial node to resume its pace-making function. Loss of conduction in the PV was associated with depolarization of the diastolic membrane potential of PV cardiomyocytes. Adenosine, which reversed the cirazoline-induced depolarization of the diastolic membrane potential of PV cardiomyocytes, restored full over-shooting action potentials and EFP conduction in the PV. In conclusion, selective activation of α1-adrenergic receptors results in the abolition of electrical conduction within the PV. These results highlight a potentially novel pharmacological approach to treat paroxysmal atrial fibrillation by targeting directly the PV myocardium.

Effects of ANP on pulmonary vein electrophysiology, Ca2+ homeostasis and adrenergic arrhythmogenesis via PKA.

Atrial fibrillation (AF) is the most common form of arrhythmia and increases the risk of stroke and heart failure (HF). Pulmonary veins (PVs) are important sources of triggers that generate AF, and calcium (Ca2+ ) overload participates in PV arrhythmogenesis. Neurohormonal activation is an important cause of AF. Higher atrial natriuretic peptide (ANP) level predicts paroxysmal AF occurrence in HF patients. However, it is not clear if ANP directly modulates electrophysiological characteristics and Ca2+ homeostasis in the PVs. Conventional microelectrodes, whole-cell patch-clamp, and the Fluo-3 fluorimetric ratio technique were performed using isolated rabbit PV preparations or single isolated PV cardiomyocytes before and after ANP administration. We found that ANP (1, 10, and 100 nmol/L) concentration-dependently decreased spontaneous activity in PV preparations. ANP (100 nmol/L) decreased isoproterenol (1 µmol/L)-induced PV spontaneous activity and burst firing. AP811 (100 nmol/L, NPR-C agonist), H89 (1µmol/L, PKA inhibitor) decreased isoproterenol-induced PV spontaneous activity or burst firing, but successive administration of ANP had no further effect on PV activity. KT5823 (1 µmol/L, PKG inhibitor) decreased isoproterenol-induced PV spontaneous activity but did not change isoproterenol-induced PV burst firing, whereas successive administration of ANP did not change isoproterenol-induced PV burst firing. ANP decreased intracellular Ca2+ transient and sarcoplasmic reticulum Ca2+ content in single PV cardiomyocytes. ANP decreased the late sodium current, L-type Ca2+ current, but did not change nickel-sensitive Na+ -Ca2+ exchanger current in single PV cardiomyocytes. In conclusion, ANP directly regulates PV electrophysiological characteristics and Ca2+ homeostasis and attenuates isoproterenol-induced arrhythmogenesis through NPR-C/cAMP/PKA signal pathway.

Supine, prone, right and left gravitational effects on human pulmonary circulation.

BACKGROUND: Body position can be optimized for pulmonary ventilation/perfusion matching during surgery and intensive care. However, positional effects upon distribution of pulmonary blood flow and vascular distensibility measured as the pulmonary blood volume variation have not been quantitatively characterized. In order to explore the potential clinical utility of body position as a modulator of pulmonary hemodynamics, we aimed to characterize gravitational effects upon distribution of pulmonary blood flow, pulmonary vascular distension, and pulmonary vascular distensibility. METHODS: Healthy subjects (n = 10) underwent phase contrast cardiovascular magnetic resonance (CMR) pulmonary artery and vein flow measurements in the supine, prone, and right/left lateral decubitus positions. For each lung, blood volume variation was calculated by subtracting venous from arterial flow per time frame. RESULTS: Body position did not change cardiac output (p = 0.84). There was no difference in blood flow between the superior and inferior pulmonary veins in the supine (p = 0.92) or prone body positions (p = 0.43). Compared to supine, pulmonary blood flow increased to the dependent lung in the lateral positions (16-33%, p = 0.002 for both). Venous but not arterial cross-sectional vessel area increased in both lungs when dependent compared to when non-dependent in the lateral positions (22-27%, p ≤ 0.01 for both). In contrast, compared to supine, distensibility increased in the non-dependent lung in the lateral positions (68-113%, p = 0.002 for both). CONCLUSIONS: CMR demonstrates that in the lateral position, there is a shift in blood flow distribution, and venous but not arterial blood volume, from the non-dependent to the dependent lung. The non-dependent lung has a sizable pulmonary vascular distensibility reserve, possibly related to left atrial pressure. These results support the physiological basis for positioning patients with unilateral pulmonary pathology with the "good lung down" in the context of intensive care. Future studies are warranted to evaluate the diagnostic potential of these physiological insights into pulmonary hemodynamics, particularly in the context of non-invasively characterizing pulmonary hypertension.

A novel parameter for pulmonary blood flow during palliative procedures: velocity time integral of the pulmonary vein†.

OBJECTIVES: The main goal of palliative procedures for congenital heart defects is adequate pulmonary blood flow (PBF), but precise intraoperative PBF evaluation is sometimes difficult. The purpose of this preliminary study was to investigate the usefulness of velocity time integral of the pulmonary vein (PV-VTI) measured by transoesophageal echocardiography (TOE) at the time of palliative procedure as a parameter for PBF. METHODS: Case histories of 63 patients who underwent palliative procedures (bilateral pulmonary artery banding in 18 patients, main pulmonary artery banding in 22 patients and systemic-to-pulmonary artery shunt in 23 patients) and whose intraoperative PV-VTI was measured by TOE from 2011 to 2017 at our centre were retrospectively reviewed. Low-body-weight infants, cases in which cardiopulmonary bypass was used and cases that were anatomically difficult to measure were excluded. RESULTS: PV-VTIs measured at 4 orifices of the pulmonary veins were all significantly decreased in both the bilateral pulmonary artery banding and main pulmonary artery banding groups and increased in the systemic-to-pulmonary artery shunt group immediately after the procedure. There were significant correlations between the velocity time integrals of both right and left pulmonary veins and arterial oxygen saturation (r = 0.564 and 0.703). Nine patients (6 bilateral pulmonary artery banding and 3 systemic-to-pulmonary artery shunt) required unplanned early reoperation due to inadequate PBF; their PV-VTIs were significantly different from those of patients not requiring reoperation. No major complications related to TOE occurred postoperatively. CONCLUSIONS: The PV-VTI measured by TOE during palliative procedures reflected the change of PBF and could help identify patients at higher risk of early reoperation due to inadequate PBF. This parameter may be a useful additional tool for evaluating intraoperative PBF.

Plant galactolipid dLGG suppresses lung metastasis of melanoma through deregulating TNF-α-mediated pulmonary vascular permeability and circulating oxylipin dynamics in mice.

This study demonstrates the bioefficacy and gives mechanistic insights into a plant galactolipid 1,2-di-O-linolenoyl-3-O-ß-galactopyranosyl-sn-glycerol (dLGG) against metastatic melanoma using a syngeneic mouse model implanted with B16COX-2/Luc melanoma. dLGG-20 (p.o. dLGG 20 mg/kg) and anti-cancer drug CP-2 (i.p. cisplatin 2 mg/kg) treatment significantly inhibited lung metastasis of melanoma in mice 91 and 57%, respectively, as determined by bioluminescence intensity. Moreover, dLGG-20 and CP-2 treatment prolonged mouse mean survival time. dLGG-20 treatment significantly inhibited the expression levels of several molecular markers, that is, PCNA, MMP2, COX-2, VEGF, vimentin, snail, TGF-ß, ß-catenin, TNF-α, PD-1 and PD-L1 in mouse lung tissues compared to tumor control mice. Significant inhibition of macrophage and neutrophil infiltration and promotion of CD8 + Tc cell recruitment in the lung microenvironment was observed in dLGG-20-treated mice. A LC/MS-based comparative oxylipin metabolomics study showed that dLGG-20 treatment significantly induced (5.0- to 12.8-fold) the 12/15-LOX catalyzed oxylipin products in mouse serum including 17-HDHA from DHA, 15-HEPE from EPA, 8- and 12-HETEs from AA, and CYP450-derived 20-HETE from AA. CP-2 treatment increased 12/15-LOX derived 8-, 11- and 12-HETEs from AA, and CYP450 derived 11,12-EET from AA ad 9,10-DHOME from LA by 5.3- to 8.1-fold. Of note, dLGG and 17-HDHA were more effective than CP in preventing B16 melanoma cell-induced pulmonary vascular permeability in mice through inhibition of TNF-α production, up-regulation of tight junction proteins claudin1 and ZO-2 and deregulation of Src activation. In conclusion, this study shows the novel therapeutic effect of phytoagent dLGG and suggests its potential as a therapeutic agent for metastatic melanoma.

PDGF-BB regulates the pulmonary vascular tone: impact of prostaglandins, calcium, MAPK- and PI3K/AKT/mTOR signalling and actin polymerisation in pulmonary veins of guinea pigs.

BACKGROUND: Platelet-derived growth factor (PDGF)-BB and its receptor PDGFR are highly expressed in pulmonary hypertension (PH) and mediate proliferation. Recently, we showed that PDGF-BB contracts pulmonary veins (PVs) and that this contraction is prevented by inhibition of PDGFR-ß (imatinib/SU6668). Here, we studied PDGF-BB-induced contraction and downstream-signalling in isolated perfused lungs (IPL) and precision-cut lung slices (PCLS) of guinea pigs (GPs). METHODS: In IPLs, PDGF-BB was perfused after or without pre-treatment with imatinib (perfused/nebulised), the effects on the pulmonary arterial pressure (PPA), the left atrial pressure (PLA) and the capillary pressure (Pcap) were studied and the precapillary (Rpre) and postcapillary resistance (Rpost) were calculated. Perfusate samples were analysed (ELISA) to detect the PDGF-BB-induced release of prostaglandin metabolites (TXA2/PGI2). In PCLS, the contractile effect of PDGF-BB was evaluated in pulmonary arteries (PAs) and PVs. In PVs, PDGF-BB-induced contraction was studied after inhibition of PDGFR-α/ß, L-Type Ca2+-channels, ROCK/PKC, prostaglandin receptors, MAP2K, p38-MAPK, PI3K-α/γ, AKT/PKB, actin polymerisation, adenyl cyclase and NO. Changes of the vascular tone were measured by videomicroscopy. In PVs, intracellular cAMP was measured by ELISA. RESULTS: In IPLs, PDGF-BB increased PPA, Pcap and Rpost. In contrast, PDGF-BB had no effect if lungs were pre-treated with imatinib (perfused/nebulised). In PCLS, PDGF-BB significantly contracted PVs/PAs which was blocked by the PDGFR-ß antagonist SU6668. In PVs, inhibition of actin polymerisation and inhibition of L-Type Ca2+-channels reduced PDGF-BB-induced contraction, whereas inhibition of ROCK/PKC had no effect. Blocking of EP1/3- and TP-receptors or inhibition of MAP2K-, p38-MAPK-, PI3K-α/γ- and AKT/PKB-signalling prevented PDGF-BB-induced contraction, whereas inhibition of EP4 only slightly reduced it. Accordingly, PDGF-BB increased TXA2 in the perfusate, whereas PGI2 was increased in all groups after 120 min and inhibition of IP-receptors did not enhance PDGF-BB-induced contraction. Moreover, PDGF-BB increased cAMP in PVs and inhibition of adenyl cyclase enhanced PDGF-BB-induced contraction, whereas inhibition of NO-formation only slightly increased it. CONCLUSIONS: PDGF-BB/PDGFR regulates the pulmonary vascular tone by the generation of prostaglandins, the increase of calcium, the activation of MAPK- or PI3K/AKT/mTOR signalling and actin remodelling. More insights in PDGF-BB downstream-signalling may contribute to develop new therapeutics for PH.

Purinergic receptor stimulation induces calcium oscillations and smooth muscle contraction in small pulmonary veins.

KEY POINTS: We investigated the excitation-contraction coupling mechanisms in small pulmonary veins (SPVs) in rat precision-cut lung slices. We found that SPVs contract strongly and reversibly in response to extracellular ATP and other vasoconstrictors, including angiotensin-II and endothelin-1. ATP-induced vasoconstriction in SPVs was associated with the stimulation of purinergic P2Y2 receptors in vascular smooth muscle cell, activation of phospholipase C-ß and the generation of intracellular Ca2+ oscillations mediated by cyclic Ca2+ release events via the inositol 1,4,5-trisphosphate receptor. Active constriction of SPVs may play an important role in the development of pulmonary hypertension and pulmonary oedema. ABSTRACT: The small pulmonary veins (SPVs) may play a role in the development of pulmonary hypertension and pulmonary oedema via active changes in SPV diameter, mediated by vascular smooth muscle cell (VSMC) contraction. However, the excitation-contraction coupling mechanisms during vasoconstrictor stimulation remain poorly understood in these veins. We used rat precision-cut lung slices and phase-contrast and confocal microscopy to investigate dynamic changes in SPV cross-sectional luminal area and intracellular Ca2+ signalling in their VSMCs. We found that the SPV (∼150 µm in diameter) contract strongly in response to extracellular ATP and other vasoconstrictors, including angiotensin-II and endothelin-1. ATP-induced SPV contraction was fast, concentration-dependent, completely reversible upon ATP washout, and inhibited by purinergic receptor antagonists suramin and AR-C118925 but not by MRS2179. Immunofluorescence showed purinergic P2Y2 receptors expressed in SPV VSMCs. ATP-induced SPV contraction was inhibited by phospholipase Cß inhibitor U73122 and accompanied by intracellular Ca2+ oscillations in the VSMCs. These Ca2+ oscillations and SPV contraction were inhibited by the inositol 1,4,5-trisphosphate receptor inhibitor 2-APB but not by ryanodine. The results of the present study suggest that ATP-induced vasoconstriction in SPVs is associated with the activation of purinergic P2Y2 receptors in VSMCs and the generation of Ca2+ oscillations.

Impact of Thoracoscopic Pulmonary Vein Isolation on Right Ventricular Function: A Pilot Study.

OBJECTIVE: Thoracoscopic surgical pulmonary vein isolation (sPVI) has been added to the treatment of atrial fibrillation (AF), showing excellent efficacy outcomes. However, data on right ventricular (RV) function following sPVI has never been studied. Our aim was to investigate RV function following sPVI and compare it to patients who underwent endocardial cryoballoon PVI. METHODS: 25 patients underwent sPVI and were pair-matched according to age, sex, and AF type with 21 patients who underwent cryoballoon PVI. RV function was measured using tricuspid annular plane systolic excursion (TAPSE) and RV strain with 2D speckle tracking. Echocardiography was performed at baseline and at median 6-month follow-up. RESULTS: Age was 54 ± 9 years and 84% were male; AF was paroxysmal in 92%. In the sPVI group, TAPSE was reduced with 31% at follow-up echocardiography (p < 0.001) and RV strain showed a 25% reduction compared to baseline (p = 0.018). In the control group, TAPSE and RV strain did not change significantly (-3% and +13%, p = 0.410 and p = 0.148). Change in TAPSE and RV strain was significantly different between groups (p ≤ 0.001 and p = 0.005). CONCLUSIONS: This study shows that RV function is significantly decreased following sPVI. This effect was not observed in the cryoballoon PVI control group.

Variations of pulmonary vein drainage critical for lung resection assessed by three-dimensional computed tomography angiography.

BACKGROUND: It is important to understand pulmonary vein drainage pattern variations and their frequency in order to perform safe anatomical pulmonary resection. METHODS: Variations and frequencies were assessed using three-dimensional computed tomography angiography (3D-CT) in 194 patients. In cases where the tumor or lymph node caused atelectasis or compression of hilar structures, the involved lobes were excluded from the analyses. RESULTS: We confirmed variant drainage patterns in 15/189 (8.0%) patients in the right upper lobe (RUL), 29/189 (15.3%) in the right middle lobe (RML), 18/192 (9.5%) in the right lower lobe (RLL), and 5/187 (2.6%) in the left upper lobe (LUL). There was no variant type in the left lower lobe (LLL). There were 14 (7.4%) cases of anomalous superior posterior pulmonary vein of RUL (V2 ) drainage: V2 draining to the superior pulmonary vein (SPV) (n = 2, 1.1%), V2 to the inferior pulmonary vein (IPV) (n = 7, 3.7%), V2 to the left atrium (LA) (n = 2, 1.1%), and V6 to the apical pulmonary vein of the RLL (n = 3, 1.6%). There was a posterior pulmonary vein, V3 to RML pulmonary vein in one case (0.5%). The RML pulmonary vein drained into the IPV in 14 (7.4%) and into the LA in 15 (7.9%) cases. The right V6 directly drained into the LA in 15 (7.9%) and V6 into the SPV in 3 (1.6%) cases. The lingular pulmonary vein drained into the IPV in one case (0.5%) and into the LA in two cases (1.1%). The inferior lingular pulmonary vein V5 drained into the IPV and into the LA in one case (0.5%), respectively. CONCLUSION: We describe anomalous pulmonary venous drainage patterns and their frequencies particular to anatomic surgical resection. 3D-CT is useful to find such variations.

Angiotensin 1-7 modulates electrophysiological characteristics and calcium homoeostasis in pulmonary veins cardiomyocytes via MAS/PI3K/eNOS signalling pathway.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia, and pulmonary veins (PVs) play a critical role in triggering AF. Angiotensin (Ang)-(1-7) regulates calcium (Ca2+ ) homoeostasis and also plays a critical role in cardiovascular pathophysiology. However, the role of Ang-(1-7) in PV arrhythmogenesis remains unclear. MATERIALS AND METHODS: Conventional microelectrodes, whole-cell patch-clamp and the fluo-3 fluorimetric ratio technique were used to record ionic currents and intracellular Ca2+ in isolated rabbit PV preparations and in single isolated PV cardiomyocytes, before and after administration of Ang-(1-7). RESULTS: Ang (1-7) concentration dependently (0.1, 1, 10 and 100 nmol/L) decreased PV spontaneous electrical activity. Ang-(1-7) (100 nmol/L) decreased the late sodium (Na+ ), L-type Ca2+ and Na+ -Ca2+ exchanger currents, but did not affect the voltage-dependent Na+ current in PV cardiomyocytes. In addition, Ang-(1-7) decreased intracellular Ca2+ transient and sarcoplasmic reticulum Ca2+ content in PV cardiomyocytes. A779 (a Mas receptor blocker, 3 µmol/L), L-NAME (a NO synthesis inhibitor, 100 µmol/L) or wortmannin (a specific PI3K inhibitor, 10 nmol/L) attenuated the effects of Ang-(1-7) (100 nmol/L) on PV spontaneous electric activity. CONCLUSION: Ang-(1-7) regulates PV electrophysiological characteristics and Ca2+ homoeostasis via Mas/PI3K/eNOS signalling pathway.

Pulmonary Vein Doppler Patterns in Infants with Single Right Ventricle Anomalies After Initial Staged Palliations.

The aim of this study was to describe serial changes in echocardiographic Doppler pulmonary vein flow (PVF) patterns in infants with single right ventricle (RV) anomalies enrolled in the Single Ventricle Reconstruction trial. Measurement of PVF peak systolic (S) and diastolic (D) velocities, velocity time integrals (VTI), S/D peak velocity and VTI ratios, and frequency of atrial reversal (Ar) waves were made at three postoperative time points in 261 infants: early post-Norwood, pre-stage II surgery, and 14 months. Indices were compared over time, between initial shunt type [modified Blalock-Taussig shunt (MBTS) and right ventricle-to-pulmonary artery shunt (RVPAS)] and in relation to clinical outcomes. S velocities and VTI increased over time while D wave was stable, resulting in increasing S/D peak velocity and VTI ratios, with a median post-Norwood S/D VTI ratio of 1.14 versus 1.38 at pre-stage II and 1.89 at 14 months (P < 0.0001 between intervals). MBTS subjects had significantly higher S/D peak velocity and VTI ratios compared to RVPAS at the post-Norwood and pre-stage II time points (P < 0.0001) but not by 14 months. PVF patterns did not correlate with survival or hospitalization course at 1 year. PVF patterns after Norwood palliation differ from normal infants by having a dominant systolic pattern throughout infancy. PVF differences based upon shunt type resolve by 14 months and did not correlate with clinical outcomes. This study describes normative values and variations in PVF for infants with a single RV from shunt-dependent pulmonary blood flow to cavopulmonary blood flow.

Effect of Purine Co-Transmitters on Automatic Activity Caused by Norepinephrine in Myocardial Sleeves of Pulmonary Veins.

We studied the effect of extracellular purine nucleotides (NAD+ and ATP) on spontaneous arrhythmogenic activity caused by norepinephrine in myocardial sleeves of pulmonary veins. In pulmonary veins, NAD+ and ATP reduced the frequency of action potentials and their duration at regular type of spontaneous activity caused by norepinephrine. NAD+ and ATP lengthened the intervals between spike bursts at periodic (burst) type of spontaneous activity. In addition, ATP shortened the duration of spike bursts and the number of action potentials in the "bursts" caused by norepinephrine in the pulmonary veins. It was hypothesized that NAD+ and ATP attenuate the effects of sympathetic stimulation and when released together with norepinephrine from sympathetic endings in vivo, probably, reduce arrhythmogenic activity in myocardial sleeves of pulmonary veins.

Significant survival advantage of high pulmonary vein index and the presence of native pulmonary artery in pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries: results from preoperative computed tomography angiography.

OBJECTIVES: The prognosis of pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries (PA-VSD-MAPCAs) after surgery shows substantial clinical heterogeneity and predictors for outcomes are lacking. This study aimed to assess the predictive value of preoperative cardiac computed tomography angiography (CTA) for survival in patients with PA-VSD-MAPCAs. METHODS: We retrospectively analysed PA-VSD-MAPCA patients with preoperative CTA who underwent both right ventricular outflow tract reconstruction and MAPCA unifocalization ( n = 24) or pulmonary artery rehabilitation ( n = 28). The end-point was overall survival. Prognostic values of CTA were assessed using Cox univariate and multivariate analyses. The significant threshold of independent parameters was calculated using receiver-operating characteristic (ROC) curves. RESULTS: During a median follow-up of 1145 days, a total of 13 deaths were observed. Multivariate analysis identified a high pulmonary vein index (PVI) [hazard ratio (HR) = 0.03; 95% confidence interval (CI): 0.03, 0.28; P < 0.01] and the presence of native pulmonary artery (HR = 0.06; 95% CI: 0.10, 0.35; P < 0.01) as independent positive predictors of better survival. The area under the ROC curve for PVI was 0.79 ( P < 0.01), and a cut-off point of 438 mm 2 /m 2 was deemed the significant threshold for survival (sensitivity 92%, specificity 72%). CONCLUSIONS: Preoperational high PVI and native pulmonary artery presence were significant morphologic predictors of a positive survival advantage in PA-VSD-MAPCA patients. A PVI ≥438 mm 2 /m 2 may be a reliable positive prognosticator that could improve the decision-making strategy for PA-VSD-MAPCA patients.

Imatinib relaxes the pulmonary venous bed of guinea pigs.

BACKGROUND: Recently, the IMPRES study revealed that systemic imatinib improves exercise capacity in patients with advanced pulmonary arterial hypertension. Imatinib blocks the tyrosine kinase activity of the platelet-derived growth factor (PDGF)-receptor (PDGFR), acts antiproliferative and relaxes pulmonary arteries. However so far, the relaxant effects of imatinib on pulmonary veins (PVs) and on the postcapillary resistance are unknown, although pulmonary hypertension (PH) due to left heart disease (LHD) is most common and primarily affects PVs. Next, it is unknown whether activation of PDGFR alters the pulmonary venous tone. Due to the reported adverse effects of systemic imatinib, we evaluated the effects of nebulized imatinib on the postcapillary resistance. METHODS: Precision-cut lung slices (PCLS) were prepared from guinea pigs. PVs were pre-constricted with Endothelin-1 (ET-1) and the imatinib-induced relaxation was studied by videomicroscopy; PDGF-BB-related vascular properties were evaluated as well. The effects of perfused/nebulized imatinib on the postcapillary resistance were studied in cavine isolated perfused lungs (IPL). Intracellular cAMP/cGMP was measured by ELISA in PVs. RESULTS: In PCLS, imatinib (100 µM) relaxed pre-constricted PVs (126%). In PVs, imatinib increased cAMP, but not cGMP and inhibition of adenyl cyclase or protein kinase A reduced the imatinib-induced relaxation. Further, inhibition of KATP-channels, [Formula: see text]-channels or Kv-channels diminished the imatinib-induced relaxation, whereas inhibition of NO-signaling was without effect. In the IPL, perfusion or nebulization of imatinib reduced the ET-1-induced increase of the postcapillary resistance. In PCLS, PDGF-BB contracted PVs, which was blocked by imatinib and by the PDGFR-ß kinase inhibitor SU6668, whereas inhibition of PDGFR-α (ponatinib) had no significant effect. Conversely, PDGFR-ß kinase inhibitors (SU6668/DMPQ) relaxed PVs pre-constricted with ET-1 comparable to imatinib, whereas the PDGFR-α kinase inhibitor ponatinib did not. CONCLUSIONS: Imatinib-induced relaxation depends on cAMP and on the activation of K+-channels. Perfused or nebulized imatinib significantly reduces the postcapillary resistance in the pre-constricted (ET-1) pulmonary venous bed. Hence, nebulization of imatinib is feasible and might reduce systemic side effects. Conversely, PDGF-BB contracts PVs by activation of PDGFR-ß suggesting that imatinib-induced relaxation depends on PDGFR-ß-antagonism. Imatinib combines short-term relaxant and long-term antiproliferative effects. Thus, imatinib might be a promising therapy for PH due to LHD.

Concomitant Isolation of the Pulmonary Veins and Posterior Wall Using a Box Lesion Set in a Patient with Persistent Atrial Fibrillation and Variant Pulmonary Venous Anatomy.

Variant pulmonary venous anatomy is common and its pre-procedural recognition through cardiac imaging facilitates a personalized approach to ablation tailored to the individual patient. Close juxtaposition of the right and left pulmonary veins is an anatomic variation that serves as an ideal substrate for creation of a single box lesion set that concomitantly isolates the pulmonary veins and posterior wall. Isolation of the posterior wall may serve as an adjunctive ablative strategy in addition to pulmonary vein isolation that facilitates maintenance of sinus rhythm among patients with persistent atrial fibrillation.

Characterization of Electrical Reconnection Following Pulmonary Vein Isolation Using First- and Second-Generation Cryoballoon.

BACKGROUND: Second-generation cryoballoon (CB-2) is associated with improved outcomes for pulmonary vein isolation (PVI) compared to first generation (CB-1). However, data regarding the predictors of pulmonary vein (PV) electrical reconnection are limited. In this study, we aimed to characterize the predilection sites and predictors of reconnection in patients with recurrent atrial tachyarrhythmia (ATa) after PVI using CB-1 and CB-2. METHODS: A total of 59 patients (mean age: 62 ± 11 years and 66% male) with recurrent ATa after previous CB-PVI, using either a 28-mm CB-1 or CB-2, underwent repeat ablation. PV reisolation was performed by irrigated radiofrequency ablation using three-dimensional electroanatomical mapping systems. RESULTS: Electrical PV reconnection was detected in 10 of 11 (91%) of CB-1 patients compared to 41 of 48 (85%) of CB-2 patients. Time to redo procedure after index CB-1 was 8.9 ± 10.2 months and 11.2 ± 7.0 months in CB-2. Bonus freeze was applied in all patients with CB-1 and 41% of the patients with CB-2. Superior quadrants of both superior PVs and inferior quadrants of the both inferior PVs exhibited higher predilection for conduction compared to other quadrants (P < 0.001). Multivariate binary logistic analysis revealed that right inferior PV (RIPV; odds ratio [OR]: 1.52, 95% confidence interval [CI]: 1.09-2.13, P = 0.014) and minimum temperature (OR: 1.09, 95% CI: 1.03-1.15, P = 0.004) were the independent predictors of electrical reconnection after CB-2 ablation. CONCLUSION: Conduction gaps after CB-1 and CB-2 were higher in inferior PVs compared to superior PVs. The RIPV and minimum CB temperature were independent predictors of PV electrical reconnection after CB-2.

Diadenosine tetra- and pentaphosphates affect contractility and bioelectrical activity in the rat heart via P2 purinergic receptors.

Diadenosine polyphosphates (Ap(n)As) are endogenously produced molecules which have been identified in various tissues of mammalian organism, including myocardium. Ap(n)As contribute to the blood clotting and are also widely accepted as regulators of blood vascular tone. Physiological role of Ap(n)As in cardiac muscle has not been completely elucidated. The present study aimed to investigate the effects of diadenosine tetra- (Ap4A) and penta- (Ap5A) polyphosphates on contractile function and action potential (AP) waveform in rat supraventricular and ventricular myocardium. We have also demonstrated the effects of A4pA and Ap5A in myocardial sleeves of pulmonary veins (PVs), which play a crucial role in genesis of atrial fibrillation. APs were recorded with glass microelectrodes in multicellular myocardial preparations. Contractile activity was measured in isolated Langendorff-perfused rat hearts. Both Ap4A and Ap5A significantly reduced contractility of isolated Langendorff-perfused heart and produced significant reduction of AP duration in left and right auricle, interatrial septum, and especially in right ventricular wall myocardium. Ap(n)As also shortened APs in rat pulmonary veins and therefore may be considered as potential proarrhythmic factors. Cardiotropic effects of Ap4A and Ap5A were strongly antagonized by selective blockers of P2 purine receptors suramin and pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), while P1 blocker DPCPX was not effective. We conclude that Ap(n)As may be considered as new class of endogenous cardioinhibitory compounds. P2 purine receptors play the central role in mediation of Ap4A and Ap5A inhibitory effects on electrical and contractile activity in different regions of the rat heart.