Transthoracic Saline Contrast Echocardiography Research Articles

Impact of party balloon inflation manoeuvre during saline contrast transthoracic echocardiography to detect a patent foramen ovale: multicenter registry study

Abstract Background Paradoxical embolism due to patent foramen ovale (PFO) can cause cryptogenic stroke. Agitated saline contrast transthoracic echocardiography (ASC-TTE) is an essential diagnostic tool for PFOs, and provocation using the Valsalva manoeuvre (VM) is necessary during the examination. Although VM is the standard method, assessing whether sufficient provocation has been achieved can pose challenges for the patients and examining staff. Conversely, a party balloon inflation manoeuvre (PBIM), which we previously reported (1, 2), offered a clear visual confirmation of provocation than conventional VM and showed effectiveness in cases of inadequate provocation. However, collective evaluation of PBIM by group remains unknown. Purpose This study aimed to demonstrate the superiority of PBIM over standard provocative methods, such as conventional or inferior vena cava compression VM, during ASC-TTE. Methods This multicentre registry study was conducted across eight high-volume institutions in Japan. A total of 117 consecutive patients (62.3% men, mean age; 56.2 ± 13.8 years, as of December 31, 2023) in whom paradoxical embolism was suspected and PFO was detected by transesophageal echocardiography, underwent PBIM and standard provocative methods during ASC-TTE. We compared them using a five-point microbubble grade (none or 1–4) using the right-to-left cardiac shunt as the primary endpoint (Figure 1). Results PBIM produced microbubble upgrading in 51 (43.6%, yellow panels in Figure 2), no change in 54 (46.1%), and down-grading in 12 (10.3%, blue panels in Figure 2) patients, compared to standard provocative methods. Wilcoxon paired analysis revealed that PBIM had a significantly larger microbubble grade than the standard provocative methods (median 3.0 interquartile range (IQR) [3.0–4.0] vs 3.0 IQR [1.7–4.0], p<0.001). If significant right-to-left shunt was grade ≥2, which was considered as the indication of catheter PFO closure, the pairwise McNemar’s test showed diagnostic performance of significant right-to-left cardiac shunt using PBIM improved from 75.2% to 91.5% (improvement rate; 16.3%, 95% CI; 8.4–24.0, p<0.001). Logistic regression analysis showed insufficient balloon inflation due to inexperience and risk of paradoxical embolism score independently associated with downgrading in PBIM after adjustments for age, sex, clinically relevant variables, and other echocardiographic parameters (odds ratio (OR); 24.0, 95% interquartile range (CI); 3.3–172.1, p<0.01 and OR; 0.60, 95% CI; 0.39–0.91, p<0.05, respectively). Conclusions PBIM significantly increased the microbubble grade compared to standard provocative methods. PIBM, using a simple tool, may provide an appropriate treatment strategy for patients with potential cryptogenic stroke attributed to PFO, especially those who are falsely diagnosed as negative for significant right-to-left cardiac shunts.Primary endpointsAgreement of 5-point microbubble grade

An Automated Heart Shunt Recognition Pipeline Using Deep Neural Networks.

Automated recognition of heart shunts using saline contrast transthoracic echocardiography (SC-TTE) has the potential to transform clinical practice, enabling non-experts to assess heart shunt lesions. This study aims to develop a fully automated and scalable analysis pipeline for distinguishing heart shunts, utilizing a deep neural network-based framework. The pipeline consists of three steps: (1) chamber segmentation, (2) ultrasound microbubble localization, and (3) disease classification model establishment. The study's normal control group included 91 patients with intracardiac shunts, 61 patients with extracardiac shunts, and 84 asymptomatic individuals. Participants' SC-TTE images were segmented using the U-Net model to obtain cardiac chambers. The segmentation results were combined with ultrasound microbubble localization to generate multivariate time series data on microbubble counts in each chamber. A classification model was then trained using this data to distinguish between intracardiac and extracardiac shunts. The proposed framework accurately segmented heart chambers (dice coefficient = 0.92 ± 0.1) and localized microbubbles. The disease classification model achieved high accuracy, sensitivity, specificity, F1 score, kappa value, and AUC value for both intracardiac and extracardiac shunts. For intracardiac shunts, accuracy was 0.875 ± 0.008, sensitivity was 0.891 ± 0.002, specificity was 0.865 ± 0.012, F1 score was 0.836 ± 0.011, kappa value was 0.735 ± 0.017, and AUC value was 0.942 ± 0.014. For extracardiac shunts, accuracy was 0.902 ± 0.007, sensitivity was 0.763 ± 0.014, specificity was 0.966 ± 0.008, F1 score was 0.830 ± 0.012, kappa value was 0.762 ± 0.017, and AUC value was 0.916 ± 0.006. The proposed framework utilizing deep neural networks offers a fast, convenient, and accurate method for identifying intracardiac and extracardiac shunts. It aids in shunt recognition and generates valuable quantitative indices, assisting clinicians in diagnosing these conditions.

Hyperoxia-induced stepwise reduction in blood flow through intrapulmonary, but not intracardiac, shunt during exercise.

Blood flow through intrapulmonary arteriovenous anastomoses (IPAVA) (QIPAVA) increases during exercise breathing air, but it has been proposed that QIPAVA is reduced during exercise while breathing a fraction of inspired oxygen ([Formula: see text]) of 1.00. It has been argued that the reduction in saline contrast bubbles through IPAVA is due to altered in vivo microbubble dynamics with hyperoxia reducing bubble stability, rather than closure of IPAVA. To definitively determine whether breathing hyperoxia decreases saline contrast bubble stability in vivo, the present study included individuals with and without patent foramen ovale (PFO) to determine if hyperoxia also eliminates left heart contrast in people with an intracardiac right-to-left shunt. Thirty-two participants consisted of 16 without a PFO; 8 females, 8 with a PFO; 4 females, and 8 with late-appearing left-sided contrast (4 females) completed five, 4-min bouts of constant-load cycle ergometer exercise (males: 250 W, females: 175 W), breathing an [Formula: see text] = 0.21, 0.40, 0.60, 0.80, and 1.00 in a balanced Latin Squares design. QIPAVA was assessed at rest and 3 min into each exercise bout via transthoracic saline contrast echocardiography and our previously used bubble scoring system. Bubble scores at [Formula: see text]= 0.21, 0.40, and 0.60 were unchanged and significantly greater than at [Formula: see text]= 0.80 and 1.00 in those without a PFO. Participants with a PFO had greater bubble scores at [Formula: see text]= 1.00 than those without a PFO. These data suggest that hyperoxia-induced decreases in QIPAVA during exercise occur when [Formula: see text] ≥ 0.80 and is not a result of altered in vivo microbubble dynamics supporting the idea that hyperoxia closes QIPAVA.

Quantification of shunt fraction using contrast ultrasound and indicator dilution in an in vitro model

Transthoracic saline contrast echocardiography is commonly used to assess intrathoracic shunt flow in vivo. Though the technique has many advantages (safe, simple, repeatable), the measurement technique lacks specificity, and the contrast agent has limited stability. This study sought to determine if the indicator dilution modeling technique could be applied to ultrasound contrast data to quantify shunt fraction and to determine if buoyant force has a significant effect on microbubble pathway determination at a “vascular” bifurcation. A model of the pulmonary circuit was perfused with blood at three distinct flow rates (low, medium and high) over shunt fractions ranging from ∼2–10 %. The buoyancy effect on contrast was quantified using a simplified in vitro model of a vascular bifurcation that had an upper and lower outflow tract where saline contrast formed from carbon monoxide (CO) gas passed through the bifurcation, was collected and quantified. The indicator dilution model was found to have a mean bias of − 3.2 % for the low flow stage, − 2.6 % for the medium flow stage and − 1.4 % for the high flow stage compared to volumetric measurements, suggesting agreement increases with increasing flow rate. Investigations of the buoyant effects revealed that at lower flow rates, contrast bubbles that encounter a bifurcation will favor the upper outflow tract over the lower. However, this effect is reduced by increasing the flow rate two-fold. These data identify that application of indicator dilution theory to contrast ultrasound data and the pathway ultrasound contrast travels in a network of tubules is flow dependent.

High prevalence of patent foramen ovale in recreational to elite breath hold divers

ObjectivesDuring apnea diving, a patent foramen ovale may function as a pressure relief valve under conditions of high pulmonary pressure, preserving left-ventricular output. Patent foramen ovale prevalence in apneic divers has not been previously reported. We aimed to determine the prevalence of patent foramen ovale in apneic divers compared to non-divers. DesignCross sectional. MethodsApnea divers were recruited from a training camp in Cavtat, Croatia and the diving community of Split, Croatia. Controls were recruited from the population of Split, Croatia and Eugene, Oregon, USA. Participants were instrumented with an intravenous catheter and underwent patent foramen ovale screening utilizing transthoracic saline contrast echocardiography. Appearance of microbubbles in the left heart within 3 cardiac cycles indicated the presence of patent foramen ovale. Lung function was measured with spirometry. Comparison of patent foramen ovale prevalence was conducted using chi-square analysis, p < .05. ResultsApnea divers had a significantly higher prevalence of patent foramen ovale (19 of 36, 53%) compared to controls (9 of 36, 25%) (X2 (1, N = 72) = 5.844, p = .0156). ConclusionsWhy patent foramen ovale prevalence is greater in apnea divers remains unknown, though hyperbaria during an apnea dive results in a translocation of blood volume centrally with a concomitant reduction in lung volume and alveolar hypoxia during ascent results in hypoxic pulmonary vasoconstriction. These conditions increase pulmonary arterial pressure, increasing right-atrial pressure allowing for right-to-left blood flow through a patent foramen ovale which may be beneficial for preserving cardiac output and reducing capillary hydrostatic forces.

Party Balloon Inflation Maneuver During Saline Contrast Transthoracic Echocardiography to Detect Patent Foramen Ovale

Saline contrast echocardiography requires an adequate provocation method for the detection of patent foramen ovale. The party balloon inflation maneuver during saline contrast transthoracic echocardiography is easy to explain to patients and objectively assesses the performance of provocative maneuvers by a clinician by watching balloon inflation. (Level of Difficulty: Intermediate.)

Importance of saline contrast transthoracic echocardiography for evaluating large right-to-left shunt in patent foramen ovale associated with cryptogenic stroke

Transcatheter closure of patent foramen ovale (PFO) is an effective therapy for preventing recurrent stroke in very specific patient cohorts, such as cryptogenic stroke (CS). The identification of high-risk PFO, which is more likely to be linked to CS, is essential. This study aimed to assess the accuracy of saline contrast transthoracic echocardiography (TTE) for evaluating large right-to-left (RL) shunt. We enrolled 119 patients with or without CS who were confirmed to have PFO by transesophageal echocardiography (TEE) or catheterization. The severity of RL shunt evaluated by TTE and TEE was classified as follows: small (< 10 microbubbles), moderate (10–20 microbubbles), and large (> 20 microbubbles). With TTE, large RL shunt was observed in 94 (79%) of 119 patients, including 66 of 74 with CS and 28 of 45 without CS. With TEE, large RL shunt was observed in 33 (28 %) patients, including 26 with CS and 7 without CS. TTE showed large RL shunt more frequently than TEE (p < 0.01). Large RL shunt evaluated by TTE had a sensitivity of 89 % and an accuracy of 70 % for the association with CS, whereas large RL shunt evaluated by TEE had a sensitivity of 35% and an accuracy of 56 %. Accuracy was significantly greater in TTE than in TEE (p = 0.02). In conclusion, TTE identified large RL shunt associated with CS with higher sensitivity and accuracy compared to TEE. Our findings suggest that the decision for device closure should be made based on the severity of RL shunt by TTE.

Reduction in Pulmonary Arterial Pressure at Rest and During Exercise and Improvement in Gas Exchange Efficiency Following Percutaneous Closure of Patent Foramen Ovale

PURPOSE The patent foramen ovale (PFO) is a source of intracardiac right-to-left shunt and is present in ~1/3rd of the adult population. Deficits in pulmonary gas exchange efficiency associated with PFO have been well-documented (Lovering et al, J Appl Physiol 2016). However, changes in pulmonary artery pressure and total pulmonary resistance (TPR) following closure have not previously been reported. METHODS Four candidates (3F, 1M) for closure of PFO were identified by local cardiologists and referred to our laboratory as subjects. 3 subjects (3F) received physician clearance to participate in the exercise trials. 1 subject (1M) was not cleared for exercise so only resting measures were taken. Presence and size of PFO was confirmed utilizing transthoracic saline contrast echocardiography (TTSCE). A radial arterial catheter was placed utilizing aseptic technique. Subjects exercised at 4 sub-maximal workloads (25%, 50%, 75% and 90% of pre-closure VO2Max), with arterial blood drawn anaerobically during the last 30 seconds of each workload and immediately analyzed in duplicate for gas content. Transthoracic ultrasound measures of cardiac output (QT) and pulmonary arterial systolic pressure (PASP) were taken prior to exercise and during the final minute of each workload. TPR was calculated as PASP/ QT. Subjects then underwent percutaneous closure of PFO utilizing a commercially available closure device (Amplatzer PFO Occluder, Abbott, Illinois; Cardioform Septal Occluder, GORE, Arizona). All measures were repeated in the laboratory 3-6 months after closure of PFO following confirmation of endothelialization of the closure device with TTSCE. RESULTS Data were analyzed by a 2-way (Closure x Workload) RMANOVA. There was a main effect of closure on PASP F(1, 11) = 21.05, p = 0.0008, and a main effect of closure on TPR F(1, 11) = 9.899, p = 0.0093, with reductions in both following closure. There was a main effect of workload, but not closure, on cardiac output F(4, 11) = 60.18, p < 0.0001. There were main effects of both workload F(4,11) = 73665, p = .0033 and closure F(1,11) = 28.31, p = .0002 on pulmonary gas exchange efficiency. CONCLUSION Improvements in pulmonary gas exchange efficiency are expected with removal of the intracardiac right-to-left shunt. However, our results demonstrating a significantly reduced pulmonary artery pressure, due to a significantly reduced TPR, are intriguing and deserve more attention to better understand the contributing factors of a PFO to exercise-induced pulmonary hypertension.

Impact of Patent Foramen Ovale Anatomic Features on Right-to-Left Shunt in Patients with Cryptogenic Stroke

The purpose of this study was to investigate the impact of the morphologic characteristics of patent foramen ovale (PFO) on right-to-left shunt (RLS) in patients with PFO and cryptogenic stroke using transesophageal echocardiography and saline contrast transthoracic echocardiography (c-TTE). Of the 165 patients with PFO stroke, both the height and the length of PFO in the provoked RLS group were smaller than those in the constant RLS group. PFO height, interatrial septum mobility and proportion of atrial septal aneurysms were greater in the severe RLS group than in the mild and moderate RLS groups. Multivariate analysis revealed that PFO height and interatrial septum mobility were independent predictors of severe RLS. Multiple territorial ischemic lesions were more common in the severe RLS or constant RLS group. Our findings indicated that the severity of RLS was related to the anatomic features in PFO, inducing different cerebral ischemia lesion patterns in cryptogenic stroke patients with PFO.

Efficacy of Saline Contrast Transthoracic Echocardiography for Identifying High-Risk Patent Foramen Ovale

Because transcatheter closure of patent foramen ovale (PFO) is an effective therapy for cryptogenic stroke (CS),1-3 identifying high-risk PFO, which is most likely to be linked to CS, has become important. This study aimed to evaluate the efficacy of saline contrast transthoracic echocardiography (TTE) for identifying high-risk PFO.

Abstract No. 700 Diagnostic accuracy of saline contrast transthoracic echocardiogram in detecting pulmonary arteriovenous malformation in hereditary hemorrhagic telangiectasia: a comparison of saline contrast transthoracic echocardiography versus computed tomography angiography of the chest

Abstract No. 700 Diagnostic accuracy of saline contrast transthoracic echocardiogram in detecting pulmonary arteriovenous malformation in hereditary hemorrhagic telangiectasia: a comparison of saline contrast transthoracic echocardiography versus computed tomography angiography of the chest

Lower Diffusing Capacity of the Lungs for Carbon Monoxide in Women with a Patent Foramen Ovale

The test of diffusing capacity of the lungs for carbon monoxide (DLco) assumes that all of the cardiac output flows through the pulmonary circuit. Right to left blood flow across a patent foramen ovale (PFO) allows blood to bypass the pulmonary circuit. The shunted red blood cells are not exposed to alveolar gas and thus, would not bind any carbon monoxide with a DLco test. This may result in a lower carbon monoxide uptake and therefore a lower measured DLco. Consequently, we hypothesized that subjects with a PFO (PFO+) would have a lower DLco than subjects without a PFO (PFO−). We retrospectively analyzed historical data from our lab that included 77 PFO+ subjects (Ages:18–35; 31 Female) and 55 PFO− subjects (Ages 18–38; 24 Female). DLco was measured using the single‐breath, breath‐hold technique and ATS/ERS standards. We compared DLco absolute, DLco% predicted and DLco/Alveolar volume (VA) absolute and DLco/VA %predicted. There were no significant differences between PFO+ and PFO− subjects as a group. There were no significant differences between PFO+ and PFOmen. However, PFO+ women had DLco and DLco/VA % predicted values that were 10% lower than PFO− women, though these values were still &gt;100% predicted. Median and mean degree of resting PFO shunt scored with transthoracic saline contrast echocardiography were identical between men and women. In conclusion, these data suggest the degree of blood flow through the PFO under resting conditions may not explain the reason for the lower DLco observed in PFO+ women.Support or Funding InformationDepartment of Defense Grant W81XWH‐10‐2‐0114American Heart Association Scientist Development grant 2280238American Physiological Society's Giles F. Filley Memorial Award for Excellence in Respiratory Physiology and MedicineAmerican Lung Association in Oregon and administered through American Thoracic Society Grant C‐10‐014This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

AltitudeOmics: effect of reduced barometric pressure on detection of intrapulmonary shunt, pulmonary gas exchange efficiency, and total pulmonary resistance.

Blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA) occurs in healthy humans at rest and during exercise when breathing hypoxic gas mixtures at sea level and may be a source of right-to-left shunt. However, at high altitudes, QIPAVA is reduced compared with sea level, as detected using transthoracic saline contrast echocardiography (TTSCE). It remains unknown whether the reduction in QIPAVA (i.e., lower bubble scores) at high altitude is due to a reduction in bubble stability resulting from the lower barometric pressure (PB) or represents an actual reduction in QIPAVA. To this end, QIPAVA, pulmonary artery systolic pressure (PASP), cardiac output (QT), and the alveolar-to-arterial oxygen difference (AaDO2) were assessed at rest and during exercise (70-190 W) in the field (5,260 m) and in the laboratory (1,668 m) during four conditions: normobaric normoxia (NN; [Formula: see text] = 121 mmHg, PB = 625 mmHg; n = 8), normobaric hypoxia (NH; [Formula: see text] = 76 mmHg, PB = 625 mmHg; n = 7), hypobaric normoxia (HN; [Formula: see text] = 121 mmHg, PB = 410 mmHg; n = 8), and hypobaric hypoxia (HH; [Formula: see text] = 75 mmHg, PB = 410 mmHg; n = 7). We hypothesized QIPAVA would be reduced during exercise in isooxic hypobaria compared with normobaria and that the AaDO2 would be reduced in isooxic hypobaria compared with normobaria. Bubble scores were greater in normobaric conditions, but the AaDO2 was similar in both isooxic hypobaria and normobaria. Total pulmonary resistance (PASP/QT) was elevated in HN and HH. Using mathematical modeling, we found no effect of hypobaria on bubble dissolution time within the pulmonary transit times under consideration (<5 s). Consequently, our data suggest an effect of hypobaria alone on pulmonary blood flow. NEW & NOTEWORTHY Blood flow through intrapulmonary arteriovenous anastomoses, detected by transthoracic saline contrast echocardiography, was reduced during exercise in acute hypobaria compared with normobaria, independent of oxygen tension, whereas pulmonary gas exchange efficiency was unaffected. Modeling the effect(s) of reduced air density on contrast bubble lifetime did not result in a significantly reduced contrast stability. Interestingly, total pulmonary resistance was increased by hypobaria, independent of oxygen tension, suggesting that pulmonary blood flow may be changed by hypobaria.

Bubble and macroaggregate methods differ in detection of blood flow through intrapulmonary arteriovenous anastomoses in upright and supine hypoxia in humans

Blood flow through intrapulmonary arteriovenous anastomoses (Q̇IPAVA) increases in healthy humans breathing hypoxic gas and is potentially dependent on body position. Previous work in subjects breathing room air has shown an effect of body position when Q̇IPAVA is detected with transthoracic saline contrast echocardiography (TTSCE). However, the potential effect of body position on Q̇IPAVA has not been investigated when subjects are breathing hypoxic gas or with a technique capable of quantifying Q̇IPAVA. Thus the purpose of this study was to quantify the effect of body position on Q̇IPAVA when breathing normoxic and hypoxic gas at rest. We studied Q̇IPAVA with TTSCE and quantified Q̇IPAVA with filtered technetium-99m-labeled macroaggregates of albumin (99mTc-MAA) in seven healthy men breathing normoxic and hypoxic (12% O2) gas at rest while supine and upright. On the basis of previous work using TTSCE, we hypothesized that the quantified Q̇IPAVA would be greatest with hypoxia in the supine position. We found that Q̇IPAVA quantified with 99mTc-MAA significantly increased while subjects breathed hypoxic gas in both supine and upright body positions (ΔQ̇IPAVA = 0.7 ± 0.4 vs. 2.5 ± 1.1% of cardiac output, respectively). Q̇IPAVA detected with TTSCE increased from normoxia in supine hypoxia but not in upright hypoxia (median hypoxia bubble score of 2 vs. 0, respectively). Surprisingly, Q̇IPAVA magnitude was greatest in upright hypoxia, when Q̇IPAVA was undetectable with TTSCE. These findings suggest that the relationship between TTSCE and 99mTc-MAA is more complex than previously appreciated, perhaps because of the different physical properties of bubbles and MAA in solution. NEW & NOTEWORTHY Using saline contrast bubbles and radiolabeled macroaggregrates (MAA), we detected and quantified, respectively, hypoxia-induced blood flow through intrapulmonary arteriovenous anastomoses (Q̇IPAVA) in supine and upright body positions in healthy men. Upright hypoxia resulted in the largest magnitude of Q̇IPAVA quantified with MAA but the lowest Q̇IPAVA detected with saline contrast bubbles. These surprising results suggest that the differences in physical properties between saline contrast bubbles and MAA in blood may affect their behavior in vivo.

Relationship between quantitative and descriptive methods of studying blood flow through intrapulmonary arteriovenous anastomoses during exercise

Several methods exist to study intrapulmonary arteriovenous anastomoses (IPAVA) in humans. Transthoracic saline contrast echocardiography (TTSCE), i.e., bubble scores, is minimally-invasive, but cannot be used to quantify the magnitude of blood flow through IPAVA (QIPAVA). Radiolabeled macroaggregates of albumin (99mTc-MAA) have been used to quantify QIPAVA in humans, but this requires injection of radioactive particles. Previous work has shown agreement between 99mTc-MAA and TTSCE, but this has not been tested simultaneously in the same group of subjects. Thus, the purpose of this study was to determine if there was a relationship between QIPAVA quantified with 99mTc-MAA and bubble scores obtained with TTSCE. To test this, we used 99mTc-MAA and TTSCE to quantify and detect QIPAVA at rest and during exercise in humans. QIPAVA significantly increased from rest to exercise using 99mTc-MAA and TTSCE and there was a moderately-strong, but significant relationship between methods. Our data suggest that high bubble scores generally correspond with large QIPAVA quantified with 99mTc-MAA during exercise.

Characterization of blood flow through intrapulmonary arteriovenous anastomoses and patent foramen ovale at rest and during exercise in stroke and transient ischemic attack patients.

We determined whether stroke and/or TIA subjects have exercise-induced blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA ) and/or patent foramen ovale (QPFO ) and a genetic predisposition for ischemic stroke. Twenty-eight stroke and/or TIA subjects (33-63years old) underwent transthoracic saline contrast echocardiography concomitant with transcranial Doppler to detect QIPAVA and QPFO at rest and during supine exercise with and without breathing 100% O2 . We also examined genetic polymorphisms in FV Leiden (G1691A; rs6025), factor II (FII) prothrombin (G20210A; rs1799963), methylene tetrahydfropholate reductase (C677T, rs1801133), and plasminogen-activator inhibitor-1 (PAI-1) (4G/5G; rs1799889) and angiotensin-converting enzyme (ACE; I/D, rs4646994) in 24/28 subjects. No subject without PFO had QIPAVA at rest (n=17), but 12/17 did with exercise. All PFO subjects had QPFO at rest (n=11) and 7/11 had either QIPAVA or QPFO with exercise. Breathing 100% O2 during exercise reduced or eliminated left heart contrast in all subjects. Gene analyses revealed that 15/24 patients were either heterozygous or homozygous for methylenetetrahydrofolate reductase gene polymorphism; 4G/4G and 4G/5G genotypes of plasminogen-activator inhibitor-1 were present in 7/24 and 13/24 patients, respectively; polymorphisms of ACE D/D genotype were present in 6/24 and I/D in 14/24 patients. Having both I/D and 4G/4G genotypes was more prevalent in PFO+ subjects (P=.03), and there was a trend (P=.06) for PFO- subjects to have a greater D/D genotype prevalence. Novel genetic predispositions reported here in PFO subjects should be investigated further in larger stroke and/or TIA patient datasets.

Decreased arterial PO2, not O2 content, increases blood flow through intrapulmonary arteriovenous anastomoses at rest.

The mechanism(s) that regulate hypoxia-induced blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA ) are currently unknown. Our previous work has demonstrated that the mechanism of hypoxia-induced QIPAVA is not simply increased cardiac output, pulmonary artery systolic pressure or sympathetic nervous system activity and, instead, it may be a result of hypoxaemia directly. To determine whether it is reduced arterial PO2 (PaO2) or O2 content (CaO2) that causes hypoxia-induced QIPAVA , individuals were instructed to breathe room air and three levels of hypoxic gas at rest before (control) and after CaO2 was reduced by 10% by lowering the haemoglobin concentration (isovolaemic haemodilution; Low [Hb]). QIPAVA , assessed by transthoracic saline contrast echocardiography, significantly increased as PaO2 decreased and, despite reduced CaO2 (via isovolaemic haemodilution), was similar at iso-PaO2. These data suggest that, with alveolar hypoxia, low PaO2 causes the hypoxia-induced increase in QIPAVA , although where and how this is detected remains unknown. Alveolar hypoxia causes increased blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA ) in healthy humans at rest. However, it is unknown whether the stimulus regulating hypoxia-induced QIPAVA is decreased arterial PO2 (PaO2) or O2 content (CaO2). CaO2 is known to regulate blood flow in the systemic circulation and it is suggested that IPAVA may be regulated similar to the systemic vasculature. Thus, we hypothesized that reduced CaO2 would be the stimulus for hypoxia-induced QIPAVA . Blood volume (BV) was measured using the optimized carbon monoxide rebreathing method in 10 individuals. Less than 5days later, subjects breathed room air, as well as 18%, 14% and 12.5% O2 , for 30min each, in a randomized order, before (CON) and after isovolaemic haemodilution (10% of BV withdrawn and replaced with an equal volume of 5% human serum albumin-saline mixture) to reduce [Hb] (Low [Hb]). PaO2 was measured at the end of each condition and QIPAVA was assessed using transthoracic saline contrast echocardiography. [Hb] was reduced from 14.2±0.8 to 12.8±0.7gdl(-1) (10±2% reduction) from CON to Low [Hb] conditions. PaO2 was no different between CON and Low [Hb], although CaO2 was 10.4%, 9.2% and 9.8% lower at 18%, 14% and 12.5% O2 , respectively. QIPAVA significantly increased as PaO2 decreased and, despite reduced CaO2, was similar at iso-PaO2. These data suggest that, with alveolar hypoxia, low PaO2 causes the hypoxia-induced increase in QIPAVA . Whether the low PO2 is detected at the carotid body, airway and/or the vasculature remains unknown.

Resting arterial hypoxaemia in subjects with chronic heart failure, pulmonary hypertension and patent foramen ovale.

What is the central question of this study? Does a patent foramen ovale contribute to resting arterial hypoxaemia, defined as arterial oxygen saturation <95%, in subjects with chronic heart failure with or without pulmonary arterial hypertension? What is the main finding and its importance? The presence of a patent foramen ovale contributed to resting arterial hypoxaemia only in subjects with chronic heart failure with pulmonary arterial hypertension. These data suggest that the presence of a patent foramen ovale should be considered in chronic heart failure patients with arterial hypoxaemia and pulmonary hypertension. The roles of intrapulmonary and intracardiac shunt in contributing to arterial hypoxaemia at rest in subjects with chronic heart failure (CHF) have not been well investigated. We hypothesized that blood flow through intrapulmonary arteriovenous anastomoses (Q̇ IPAVA ) and/or patent foramen ovale (Q̇ PFO ) could potentially contribute to arterial hypoxaemia and, with pulmonary hypertension (PH) secondary to CHF, this contribution may be exacerbated. Fifty-six subjects with CHF (New York Heart Association Classes I-III), with (+) or without (-) PH [defined as peak tricuspid regurgitation velocity ≥2.9ms(-1) (CHF PH+, n=32) and peak tricuspid regurgitation velocity ≤2.8ms(-1) (CHF PH-, n=24)], underwent arterial blood gas analysis and transthoracic saline contrast echocardiography concomitant with transcranial Doppler to detect Q̇ IPAVA and Q̇ PFO . Seventeen of 56 subjects with CHF (30%) had Q̇ PFO , but only four of 56 subjects with CHF had Q̇ IPAVA (7%), both similar to age- and sex-matched control subjects. Mean arterial oxygen saturation (SaO2) was lower in subjects with Q̇ PFO . Only CHF PH+ subjects with Q̇ PFO had arterial hypoxaemia (mean SaO2 <95%). Bubble scores assessed using transthoracic saline contrast echocardiography were correlated with microembolic signals detected with transcranial Doppler in subjects with Q̇ PFO . Significant Q̇ IPAVA was not present in either CHF PH+ or PH- subjects, suggesting that Q̇ IPAVA is not dependent on increased pulmonary pressure and does not contribute significantly to arterial hypoxaemia in older subjects with CHF. Given that SaO2 was lower in all subjects with CHF who had Q̇ PFO compared with those without Q̇ PFO , a patent foramen ovale should be considered when determining potential causes of arterial hypoxaemia, because Q̇ PFO was present in 30% of these subjects.

Aggravation of hepatopulmonary syndrome after sildenafil treatment in a patient with coexisting portopulmonary hypertension.

Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPHTN) are complications of portal hypertension and cirrhosis. Their pathophysiological mechanisms clearly differ. HPS is characterized by a defect in arterial oxygenation induced by pulmonary vascular dilatation. In contrast, PPHTN is predominantly due to excessive pulmonary vasoconstriction and vascular remodeling, but is rarely associated with hypoxia. We report a case of a patient who had both HPS and PPHTN at the time of presentation. HPS was aggravated after sildenafil administration for the treatment of PPHTN. We demonstrated increased amount of intrapulmonay shunt after sildenafil challenge by using agitated saline contrast transthoracic echocardiography.

Sildenafil, nifedipine and acetazolamide do not allow for blood flow through intrapulmonary arteriovenous anastomoses during exercise while breathing 100% oxygen.

Blood flow through intrapulmonary arteriovenous anastomoses (IPAVAs) is known to increase in healthy humans during exercise while breathing room air, but is prevented or significantly reduced during exercise while breathing 100% O2, potentially due to vasoconstriction of IPAVAs. Thus, pharmacological interventions that target known pathways regulating the cardiopulmonary circulation may be able to prevent the hyperoxia-induced reduction in IPAVA blood flow (Q̇ IPAVA ) during exercise. In nine healthy human subjects, we investigated the effects of sildenafil (100mg p.o.), nifedipine (20mg p.o.) and acetazolamide (250mg p.o. three times a day for 3days) on Q̇ IPAVA at rest and during cycle ergometer exercise at 50, 100, 150, 200 and 250W, while breathing room air (normoxia) and 100% O2 (hyperoxia). Transthoracic saline contrast echocardiography and a 0-5 bubble scoring system were used to detect and assess Q̇ IPAVA qualitatively; ultrasound was used to assess the blood flow velocity oftricuspid regurgitation and the left ventricular outflow tract blood flow to calculate pulmonary artery systolic pressure (PASP) and cardiac output, respectively. Without drugs, bubble scores increased significantly to ≥2 at 150W in normoxia and to ≤2 at 200W in hyperoxia. Only nifedipine consistently increased cardiac output at rest and during low-intensity exercise in normoxia and hyperoxia. However, there was no detectable effect of any drug on Q̇ IPAVA ; specifically, bubble scores were the same during exercise in either normoxia or hyperoxia. Accordingly, the reduction in Q̇ IPAVA during exercise while breathing 100% O2 is likely not to be due to the independent pharmacological mechanisms of action associated with sildenafil, nifedipine or acetazolamide.