The Genetic Landscape of Patent Foramen Ovale: A Systematic Review.

Patent Foramen Ovale (PFO) is a common postnatal defect of cardiac atrial septation. A certain degree of familial aggregation has been reported. Animal studies suggest the involvement of the Notch pathway and other cardiac transcription factors (GATA4, TBX20, NKX2-5) in Foramen Ovale closure. This review evaluates the contribution of genetic alterations in PFO development. We systematically reviewed studies that assessed rare and common variants in subjects with PFO. The protocol was registered with PROSPERO and followed MOOSE guidelines. We systematically searched English studies reporting rates of variants in PFO subjects until the 30th of June 2021. Among 1231 studies, we included four studies: two of them assessed the NKX2-5 gene, the remaining reported variants of chromosome 4q25 and the GATA4 S377G variant, respectively. We did not find any variant associated with PFO, except for the rs2200733 variant of chromosome 4q25 in atrial fibrillation patients. Despite the scarceness of evidence so far, animal studies and other studies that did not fulfil the criteria to be included in the review indicate a robust genetic background in PFO. More research is needed on the genetic determinants of PFO.

Percutaneous Closure of PFO in Patients with Reduced Oxygen Saturation at Rest and during Exercise: Short- and Long-Term Results.

BACKGROUND: A patent foramen ovale (PFO) is a rare cause of hypoxemia and clinical symptoms of dyspnea. Due to a right-to-left shunt, desaturated blood enters the systemic circulation in a subset of patients resulting in dyspnea and a subsequent reduction in quality of life (QoL). Percutaneous closure of PFO is the treatment of choice. OBJECTIVES: This retrospective multicentre study evaluates short- and long-term results of percutaneous closure of PFO in patients with dyspnea and/or reduced oxygen saturation. METHODS: Patients with respiratory symptoms were selected from databases containing all patients percutaneously closed between January 2000 and September 2018. Improvement in dyspnea, oxygenation, and QoL was investigated using pre- and postprocedural lung function parameters and two postprocedural questionnaires (SF-36 and PFSDQ-M). RESULTS: The average follow-up period was 36 [12-43] months, ranging from 0 months to 14 years. Percutaneous closure was successful in 15 of the 16 patients. All patients reported subjective improvement in dyspnea immediately after device deployment, consistent with their improvement in oxygen saturation (from 90 ± 6% to 94 [92-97%] on room air and in upright position) (p < 0.05). Both questionnaires also indicated an improvement of dyspnea and QoL after closure. The two early and two late deaths were unrelated to the procedure. CONCLUSION: PFO-related dyspnea and/or hypoxemia can be treated successfully with a percutaneous intervention with long-lasting benefits on oxygen saturation, dyspnea, and QoL.

Ventilatory responses to acute hypoxia and hypercapnia in humans with a patent foramen ovale.

Subjects with a patent foramen ovale (PFO) have blunted ventilatory acclimatization to high altitude compared with subjects without PFO. The blunted response observed could be because of differences in central and/or peripheral respiratory chemoreflexes. We hypothesized that compared with subjects without a PFO (PFO-), subjects with a PFO (PFO+) would have blunted ventilatory responses to acute hypoxia and hypercapnia. Sixteen PFO+ subjects (9 female) and 15 PFO- subjects (8 female) completed four 20-min trials on the same day: 1) normoxic hypercapnia (NH), 2) hyperoxic hypercapnia (HH), 3) isocapnic hypoxia (IH), and 4) poikilocapnic hypoxia (PH). Hypercapnic trials were completed before the hypoxic trials, the order of the hypercapnic (NH & HH) and hypoxic (IH & PH) trials were randomized, and trials were separated by ≥40 min. During the NH trials but not the HH trials subjects who were PFO+ had a blunted hypercapnic ventilatory response compared with subjects who were PFO- (1.41 ± 0.46 l·min-1·mmHg-1 vs. 1.98 ± 0.71 l·min-1·mmHg-1, P = 0.02). There were no differences between the PFO+ and PFO- subjects with respect to the acute hypoxic ventilatory response during IH and PH trials. Hypoxic ventilatory depression was similar between subjects who were PFO+ and PFO- during IH. These data suggest that compared with subjects who were PFO-, subjects who were PFO+ have normal ventilatory chemosensitivity to acute hypoxia but blunted ventilatory chemosensitivity to carbon dioxide, possibly because of reduced carbon dioxide sensitivity of either the central and/or the peripheral chemoreceptors. NEW & NOTEWORTHY Patent foramen ovale (PFO) is found in ~25%-40% of the population. The presence of a PFO appears to be associated with blunted ventilatory responses during acute exposure to normoxic hypercapnia. The reason for this blunted ventilatory response during acute exposure to normoxic hypercapnia is unknown but may suggest differences in either central and/or peripheral chemoreflex contribution to hypercapnia.

Platypnea-Orthodeoxia Syndrome After Complicated Cholecystectomy: An Unsuspected Diagnosis.

A 65-year-old woman with no significant prior medical history presented, in the postoperative course of a complicated cholecystectomy, several episodes of arterial desaturation. Pulmonary embolism was repeatedly suspected, but there was no evidence of pulmonary thrombus on the chest computed tomography angiographies obtained. As these episodes were mainly induced by postural changes, a platypnea-orthodeoxia syndrome was suspected. A transthoracic echocardiogram was performed and revealed a patent foramen ovale. A transesophageal echocardiography confirmed the presence of a significant right-to-left shunt exacerbated by the Valsalva manouver. The defect was repaired using a percutaneous transcatheter technique with complete resolution of the condition.

Doente do sexo feminino, 65 anos de idade, sem antecedentes pessoais relevantes, apresentou no pós-operatório de uma colecistectomia complicada diversos episódios de dessaturação arterial. Suspeitou-se repetidamente de tromboembolismo pulmonar, no entanto as diversas angio-tomografias computorizadas obtidas nunca revelaram a presença de trombos no leito vascular pulmonar. Atendendo a que os episódios de dessaturação eram maioritariamente despoletados por alterações posturais, foi levantada a hipótese de se tratar de uma síndrome de platipneia-ortodeoxia. Foi realizado ecocardiograma transtorácico, que revelou um foramen oval patente; o ecocardiograma transesofágico confirmou a presença de um shunt direito-esquerdo significativo, exacerbado pela manobra de Valsalva. O defeito foi reparado através de uma técnica transcatéter, com resolução completa do quadro clínico.

Effectiveness of the critical congenital heart disease screening program for early diagnosis of cardiac abnormalities in newborn infants.

OBJECTIVES: To evaluate the effectiveness of critical congenital heart disease (CCHD) screening program for early diagnosis of cardiac anomalies in newborn infants.  Methods: This is a hospital-based prospective cross-sectional study conducted in the Pediatric and Neonatology Department, King Fahad Hospital at  Albaha, Saudi Arabia, between February 2016 and February 2017. Results: We screened 2961 (95.4%) of 3103 patients in a nursery unit; 142 (4.6%) patients were not screened. The test was positive in 114 (3.9%) patients and negative in 2847 (96.1%). There were 94 (3.2%) false positives and 20 (0.7%) true positives. Critical cardiac defects were diagnosed in 7 (0.2%) patients of all screened infants, and severe pulmonary hypertension was diagnosed in 13 (0.4%) patients. True negative results were found in 2841(96%) patients, and no cardiac defect was diagnosed, whereas false negative results were seen in 6 (0.2%) patients diagnosed with ventricular septal defect. The sensitivity was 77%, and the specificity was very high at 97%, with a positive predictive value of 18%, and a negative predictive value of 99.8% (95% confidence interval 13.78-19.18, p=0.0001). Conclusion: Pulse oximetry was found to be easy, safe, sensitive, and highly specific for diagnosis of CCHD.

Impaired endothelial function in patients with cryptogenic stroke and patent foramen ovale is not affected by closure.

INTRODUCTION: Patent foramen ovale (PFO) is associated with cryptogenic stroke (CS) and migraine with aura (MA). Endothelial dysfunction (ED) is a risk factor for development of cardiovascular disease, but might also be involved in migraine pathophysiology. Short-term worsening of migraine has been described after closure of PFO. We evaluated endothelial function in patients with CS and PFO, before and after closure of PFO, and in patients with migraine, whether changes in endothelial function was related to a change in migraine frequency. MATERIAL AND METHODS: Patients with CS and PFO were included; 20 with planned closure of PFO and seven controls on medical treatment only. Endothelial function was assessed by peripheral arterial tonometry (EndoPatR ) and biomarkers of endothelial activation. Patients were followed longitudinally at baseline, day 1, 1 month, and 6 months. A headache diary was used to assess migraine frequency. RESULT: Mean age of the cohort was 45.4 years, and migraine prevalence was 50% whereof 84.6% had MA. Median EndoPatR index (RHI) at baseline was 1.60 (IQR 1.41-2.00). There was no change in RHI over time, either in closure patients (P = 0.66), nor in controls (P = 0.31), and there was no change in biomarkers of endothelial activation. Three migraine patients experienced worsening of migraine frequency directly after closure. DISCUSSION: Endothelial function did not change after closure of PFO. Although patients were lacking cardiovascular risk factors, a high proportion had impaired endothelial function. Whether ED can have predictive value, identifying PFO at higher risk for recurrent stroke warrants further investigations.

Hypoxemia in the setting of right to left shunting through patent foramen ovale without pulmonary hypertension.

Patent foramen ovale is often seen in the population but rarely observed with right to left shunting in the absence of pulmonary hypertension. Our report describes such a case where a patient with progressive shortness of breath had resolution of symptoms upon percutaneous closure. A discussion of the case and relation to similar cases is presented. A literature review along with explanation of possible contributing mechanisms in our patient's situation is explained. We also discuss several implications for practice and suggest that percutaneous closure is effective in our case and in similar situations.

Exercise after SCUBA diving increases the incidence of arterial gas embolism.

Arterialization of gas bubbles after decompression from scuba diving has traditionally been associated with pulmonary barotraumas or cardiac defects, such as the patent foramen ovale. Recent studies have demonstrated the right-to-left passage of bubbles through intrapulmonary arterial-venous anastamoses (IPAVA) that allow blood to bypass the pulmonary microcirculation. These passages open up during exercise, and the aim of this study is to see if exercise in a postdiving period increases the incidence of arterialization. After completing a dive to 18 m for 47 min, patent foramen ovale-negative subjects were monitored via transthoracic echocardiography, within 10 min after surfacing, for bubble score at rest. Subjects then completed an incremental cycle ergometry test to exhaustion under continuous transthoracic echocardiography observation. Exercise was suspended if arterialization was observed and resumed when the arterialization cleared. If arterialization was observed a second time, exercise was terminated, and oxygen was administered. Out of 23 subjects, 3 arterialized at rest, 12 arterialized with exercise, and 8 did not arterialize at all even during maximal exercise. The time for arterialization to clear with oxygen was significantly shorter than without. Exercise after diving increased the incidence of arterialization from 13% at rest to 52%. This study shows that individuals are capable of arterializing through IPAVA, and that the intensity at which these open varies by individual. Basic activities associated with SCUBA diving, such as surface swimming or walking with heavy equipment, may be enough to allow the passage of venous gas emboli through IPAVA.

Prevalence of patent foramen ovale and its impact on oxygen desaturation in obstructive sleep apnea.

BACKGROUND: A possible association between patent foramen ovale (PFO) and obstructive sleep apnea has been suggested (OSA), whereby right-to-left shunting may exacerbate the severity of nocturnal oxygen desaturation. However, the interaction between these two conditions has not been well characterised. METHODS: A case-control study was conducted to evaluate the epidemiological association between PFO and OSA. Subjects were recruited prospectively from a sleep laboratory population, and 102 OSA subjects (mean age 51.5 ± 13 years) were compared to 50 controls without OSA (mean age 49.9 ± 12.4). The presence and size of right-to-left shunting were determined by contrast transcranial Doppler ultrasonography with Valsalva provocation. Using the 21,749 obstructive breathing events recorded at polysomnography from the OSA group, a mixed-effects linear regression model was developed to evaluate the impact of right-to-left shunting on nocturnal oxygen desaturation (ΔSpO2). RESULTS: A higher prevalence of PFO was present in the OSA group compared to the control group (47.1% vs. 26.0%, OR 2.53, CI 1.20 to 5.31, p=0.014). From the regression model, right-to-left shunt size did not exert a significant influence on the severity of ΔSpO2 (coefficient 0.85, CI -0.62 to 2.32, p=0.254); whereas sleep state, event type, body position, event duration, awake oxygen saturation, apnea-hypopnea index and body mass index were all independent predictors of ΔSpO2. CONCLUSION: A higher prevalence of PFO is found in OSA subjects. However, the degree of right-to-left shunting, characterised by Valsalva provocation, is not associated with an increased severity of nocturnal oxygen desaturation.

[Threshold rat neonatal cardiomyocyte response to gradual cryptosporidial infection severity increase].

Infectious gastroenteritis is one of the common causes of tachyarrythmia, malabsorbtion and growth retardation in children. Our recent studies have indicated that neonatal.cryptosporidial gastroenteritis is associated with long-term cardiomyocyte abnormalities. The aim of the present study was to find out how neonatal cryptosporidiosis of various severities affects cardiac anatomy and cardiomyocyte polyploidization, remodeling and HIF-1α expression. Using real-time PCR, cytometry, immunohistochemistry, image analysis and interatrial septum visual examination, we revealed that gradual increase in cryptosporidial invasion was associated with threshold changes. At weak parasitic infection, interatrial septum was entire and there was no statistically significant change in cardiomyocytes. At moderate and severe infection, all changes in cardiac anatomy and cardiomyocytes were statistically significant and demonstrated approximately similar degree. Compared to control, heart were atrophied and elongated, interatrial septum contained a small window (patentforamrn ovale), and cardiomyocytes lost protein, became elongated, thin and accumulated additional genomes. Also we found HIF-1α mRNA hyperexpression. Notable, the threshold response to gradual stimulus is an important criterion of development programming since such a response is commonly a consequence of abnormal anatomic structure formation and cell differentiation failure. Our results can be interesting for physicians because they indicate that even moderate cryptosporidiosis can be dangerous for neonatal heart and can trigger neonatal programming of cardiovascular pathology. Also, our results for the first time demonstrate the association between gastroenteritis, patent foramen ovale and cardiomyocyte malfunction.

Catecholamine-induced opening of intrapulmonary arteriovenous anastomoses in healthy humans at rest.

The mechanism or mechanisms that cause intrapulmonary arteriovenous anastomoses (IPAVA) to either open during exercise in subjects breathing room air and at rest when breathing hypoxic gas mixtures, or to close during exercise while breathing 100% oxygen, remain unknown. During conditions when IPAVA are open, plasma epinephrine (EPI) and dopamine (DA) concentrations both increase, potentially representing a common mechanism. The purpose of this study was to determine whether EPI or DA infusions open IPAVA in resting subjects breathing room air and, subsequently, 100% oxygen. We hypothesized that these catecholamine infusions would open IPAVA. We performed saline-contrast echocardiography in nine subjects without a patent foramen ovale before and during serial EPI and DA infusions while breathing room air and then while breathing 100% oxygen. Bubble scores (0-5) were assigned based on the number and spatial distribution of bubbles in the left ventricle. Pulmonary artery systolic pressure (PASP) was estimated using Doppler ultrasound, while cardiac output (Q(C)) was measured using echocardiography. Bubble scores were significantly greater during EPI infusions of 80-320 ng·kg(-1)·min(-1) compared with baseline when subjects breathed room air; however, bubble scores did not increase when they breathed 100% oxygen. At comparable Q(C) and PASP, intravenous DA (16 µg·kg(-1)·min(-1)) and EPI (40 ng·kg(-1)·min(-1)) resulted in identical bubble scores. Subsequent studies revealed that ß-blockade did not prevent hypoxia-induced opening of IPAVA. We suggest that increases in Q(C) or PASP (or both) secondary to EPI or DA infusions open IPAVA in normoxia. The closing mechanism associated with breathing 100% oxygen is independent from the opening mechanisms.

QTL mapping of complex binary traits in an advanced intercross line.

An advanced intercross line (AIL) is an easier and more cost-effective approach compared to recombinant inbred lines for fine mapping of quantitative trait loci (QTL) identified by F(2) designs. In an AIL, a complex binary trait can be mapped through analysis of either continuously distributed proxy traits for the liability of the binary trait or the liability itself, the latter presenting the greater statistical challenge. In another work, we successfully applied both approaches in an AIL to fine map previously identified QTL underlying anatomical parameters of the cardiac inter-atrial septum including patent foramen ovale. Here, we describe the statistical methods that we used to analyse complex binary traits in our AIL design. This is achieved using a likelihood-based method, with the expectation-maximisation algorithm allowing use of standard logistic regression methods for model fitting.

A gain-of-function TBX20 mutation causes congenital atrial septal defects, patent foramen ovale and cardiac valve defects.

BACKGROUND: Ostium secundum atrial septal defects (ASDII) account for approximately 10% of all congenital heart defects (CHD), and mutations in cardiac transcription factors, including TBX20, were identified as an underlying cause for ASDII. However, very little is known about disease penetrance in families and functional consequences of inherited TBX20 mutations. METHODS: The coding region of TBX20 was directly sequenced in 170 ASDII patients. Functional consequences of one novel mutation were investigated by surface plasmon resonance, CD spectropolarymetry, fluorescence spectrophotometry, luciferase assay and chromatin immunoprecipitation. RESULTS: We found a novel mutation in a highly conserved residue in the T-box DNA binding domain (I121M) segregating with CHD in a three generation kindred. Four mutation carriers revealed cardiac phenotypes in terms of cribriform ASDII, large patent foramen ovale or cardiac valve defects. Interestingly, tertiary hydrophobic interactions within the mutant TBX20 T-box were significantly altered leading to a more dynamic structure of the protein. Moreover, Tbx20-I121M resulted in a significantly enhanced transcriptional activity, which was further increased in the presence of co-transcription factors GATA4/5 and NKX2-5. Occupancy of DNA binding sites on target genes was also increased. CONCLUSIONS: We suggest that TBX20-I121M adopts a more fluid tertiary structure leading to enhanced interactions with cofactors and more stable transcriptional complexes on target DNA sequences. Our data, combined with that of others, suggest that human ASDII may be related to loss-of-function as well as gain-of-function TBX20 mutations.

Right-to-left shunt in CADASIL patients: prevalence and correlation with clinical and MRI findings.

BACKGROUND AND PURPOSE: A high prevalence of right-to-left shunt (RLS) was described in a family of patients with CADASIL, a rare cerebral arteriopathy attributable to Notch3 gene mutations. The aim of this study was to determine the prevalence of RLS in patients with CADASIL and possible relation to clinical phenotype and cerebral MRI lesion load. METHODS: Twenty-three CADASIL patients underwent Transcranial Doppler with gaseous contrast to asses RLS. Correlations between RLS, clinical features, and MRI lesion volume (LV) were determined. RESULTS: Large RLS was diagnosed in 47% of patients. No significant clinical or MRI differences were found between patients with and without RLS. CONCLUSIONS: We found a high prevalence of RLS in our group of CADASIL patients. This may not be a coincidence, but can be rather related to the role of the Notch receptor family in the development of cardiovascular system.