A germline chimeric KANK1-DMRT1 transcript derived from a complex structural variant is associated with a congenital heart defect segregating across five generations.

Structural variants (SVs) pose a challenge to detect and interpret, but their study provides novel biological insights and molecular diagnosis underlying rare diseases. The aim of this study was to resolve a 9p24 rearrangement segregating in a family through five generations with a congenital heart defect (congenital pulmonary and aortic valvular stenosis and pulmonary artery stenosis), by applying a combined genomic analysis. The analysis involved multiple techniques, including karyotype, chromosomal microarray analysis (CMA), FISH, genome sequencing (GS), RNA-seq, and optical genome mapping (OGM). A complex 9p24 SV was hinted at by CMA results, showing three interspersed duplicated segments. Combined GS and OGM analyses revealed that the 9p24 duplications constitute a complex SV, on which a set of breakpoints matches the boundaries of the CMA duplicated sequences. The proposed structure for this complex rearrangement implies three duplications associated with an inversion of ~ 2 Mb region on chromosome 9 and a SINE element insertion at the more distal breakpoint. Interestingly, this genomic structure of rearrangement forms a chimeric transcript of the KANK1/DMRT1 loci, which was confirmed by both RNA-seq and Sanger sequencing on blood samples from 9p24 rearrangement carriers. Altogether with breakpoint amplification and FISH analysis, this combined approach allowed a deep characterization of this complex rearrangement. Although the genotype-phenotype correlation remains elusive from the molecular mechanism point of view, this study identified a large genomic rearrangement at 9p24 segregating with a familial congenital heart defect, revealing a genetic biomarker that was successfully applied for embryo selection, changing the reproductive perspective of affected individuals.

A germline chimeric KANK1-DMRT1 transcript derived from a complex structural variant is associated with a congenital heart defect segregating across five generations.

Structural variants (SVs) pose a challenge to detect and interpret, but their study provides novel biological insights and molecular diagnosis underlying rare diseases. The aim of this study was to resolve a 9p24 rearrangement segregating in a family through five generations with a congenital heart defect (congenital pulmonary and aortic valvular stenosis, and pulmonary artery stenosis), by applying a combined genomic analysis. The analysis involved multiple techniques, including karyotype, chromosomal microarray analysis (CMA), FISH, whole-genome sequencing (WGS), RNA-seq and optical genome mapping (OGM). A complex 9p24 SV was hinted at by CMA results, showing three interspersed duplicated segments. Combined WGS and OGM analyses revealed that the 9p24 duplications constitute a complex SV, on which a set of breakpoints match the boundaries of the CMA duplicated sequences. The proposed structure for this complex rearrangement implies three duplications associated with an inversion of ~ 2Mb region on chromosome 9 with a SINE element insertion at the more distal breakpoint. Interestingly, this hypothesized genomic structure of rearrangement forms a chimeric transcript of the KANK1/DMRT1 loci, which was confirmed by RNA-seq on blood from 9p24 rearrangement carriers. Altogether with breakpoint amplification and FISH analysis, this combined approach allowed a deep characterization of this complex rearrangement. Although the genotype-phenotype correlation remains elusive from the molecular mechanism point of view, this study identified a large genomic rearrangement at 9p segregating with a familial congenital clinical trait, revealing a genetic biomarker that was successfully applied for embryo selection, changing the reproductive perspective of affected individuals.

Cardiac sympathetic dysfunction in left ventricular hypertrophy caused by arterial hypertension and degenerative aortic stenosis.

BACKGROUND: To evaluate cardiac sympathetic innervation in hypertensive patients with left ventricular (LV) hypertrophy (H) and aortic stenosis (AS) submitted to transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS: Twenty-two hypertensive elders (82 ± 5 years) with severe AS and significant LVH (> 122 g·m-2 in women and > 149 g·m-2 in men) were compared with 14 patients with uncomplicated essential hypertension (HT) with similar degree of LVH and 10 controls. 123I-metaiodobenzylguanidine (MIBG) and 99mTc-tetrofosmin SPECT acquisitions were obtained to assess sympathetic innervation and LV perfusion. The innervation/perfusion mismatch score was taken as an indicator of cardiac sympathetic dysfunction. The imaging protocol was repeated 6 months after TAVI. Regional MIBG uptake was more heterogeneous in HT and AS patients than controls, and therefore, innervation/perfusion mismatch score was higher in both AS (9 ± 8) and HT (5 ± 2) than controls (1 ± 1, P < .001). On multivariate analysis, significant LVH was the major predictor of impaired LV sympathetic innervation (OR 19.45, 95% CI 1.87-201.92; P = .013). After TAVI, no differences in measures of LV sympathetic innervation were evident, although only a marginal LV mass reduction was observed (- 5.4 ± 2.4 g). CONCLUSIONS: Cardiac sympathetic innervation is impaired in patients with LVH, either with AS or not, and is not impacted significantly by TAVI procedure.

Echocardiographic Follow-Up of Congenital Aortic Valvular Stenosis II.

We evaluated the natural course of congenital aortic valvular stenosis (AVS) and factors affecting AVS progression during long-term follow-up with echocardiography. Medical records of 388 patients with AVS were reviewed; patients with concomitant lesions other than aortic regurgitation (AR) were excluded. Trivial AVS was defined as a transvalvular Doppler peak systolic instantaneous gradient of < 25 mmHg; mild stenosis, 25-49 mmHg; moderate stenosis, 50-75 mmHg; and severe stenosis, > 75 mmHg. Median age of the patients was 3 years (range 0 day to 21 years), and 287 (74%) were male. A total of 355 patients were followed with medical treatment alone for a median of 4.6 years (range 1 month to 20.6 years), and the degree of AVS increased in 75 (21%) patients. The risk of AVS progression was higher when AVS was diagnosed in neonates (OR 4.29, CI 1.81-10.18, p = 0.001) and infants (OR 3.79, CI 2.21-6.49, p = 0.001). After the infancy period, bicuspid valve morphology increased AVS progression risk (OR 2.4, CI 1.2-4.6, p = 0.034). Patients with moderate AVS were more likely to have AVS progression (OR 2.59, CI 1.3-5.1, p = 0.006). Bicuspid valve morphology increased risk of AR development/progression (OR 1.77, CI 1.1-2.7, p = 0.017). The patients with mild and moderate AVS were more likely to have AR development/progression (p = 0.001). The risk of AR development/progression was higher in patients with AVS progression (OR 2.25, CI 1.33-3.81, p = 0.002). Newborn babies and infants should be followed more frequently than older patients according to disease severity. Bicuspid aortic valve morphology and moderate stenosis are risk factors for the progression of AVS and AR.

Comparison of Balloon Dilatation and Surgical Valvuloplasty in Non-critical Congenital Aortic Valvular Stenosis at Long-Term Follow-Up.

The two main modalities used for congenital aortic valvular stenosis (AVS) treatment are balloon aortic valve dilatation (BAD) and surgical aortic valvuloplasty (SAV). This study evaluates residual and recurrent stenosis, aortic regurgitation (AR) development/progression, reintervention rates, and the risk factors associated with this end point in patients with non-critical congenital AVS who underwent BAD or SAV after up to 18 years of follow-up. From 1990 to 2017, 70 consecutive interventions were performed in patients with AVS, and 61 were included in this study (33 BADs and 28 SAVs). There were no significant differences in age, sex distribution, PSIG, and AR frequency between the BAD and SAV groups. Bicuspid valve morphology was more common in the BAD group than the SAV group. There was no statistically significant difference between PSIGs and AR development or progression after intervention at the immediate postoperative echocardiography of patients who underwent BAD or SAV (p = 0.82 vs. p = 0.29). Patients were followed 6.9 ± 5.1 years after intervention. The follow-up period in the SAV group was longer than that of the BAD group (9.5 ± 5.4 vs. 5.5 ± 4.4 years, p = 0.003). There was no statistically significant difference in the last echocardiographic PSIG between patients who underwent SAV or BAD (51.1 ± 33.5 vs. 57.3 ± 35.1, p = 0.659). Freedom from reintervention was 81.3% at 5 years and 57.5% at 10 years in the BAD group and 95.5% at 5 years and 81.8% at 10 years in the SAV group, respectively (p = 0.044). There was no difference in postprocedural immediate PSIG and last PSIG at follow-up and the development/progression of AR between patients who were treated with BAD versus SAV. However, long-term results of SAV were superior to those of BAD, with a somewhat prolonged reintervention interval.

The "Madness" of Friedrich Hölderlin: an iatrogenic intoxication.

The German poet Hölderlin, assumed to have suffered from schizophrenia, in fact has been the victim of a combined calomel and cantharidine intoxication administered by his physician Autenrieth. This new theory explains much better his behavioural changes and also his neurological and other concomitant symptoms; it can be tested by analysing a very few of his hairs for the presence of these compounds.

Calcific Aortic Valve Disease: Part 2-Morphomechanical Abnormalities, Gene Reexpression, and Gender Effects on Ventricular Hypertrophy and Its Reversibility.

In part 1, we considered cytomolecular mechanisms underlying calcific aortic valve disease (CAVD), hemodynamics, and adaptive feedbacks controlling pathological left ventricular hypertrophy provoked by ensuing aortic valvular stenosis (AVS). In part 2, we survey diverse signal transduction pathways that precede cellular/molecular mechanisms controlling hypertrophic gene expression by activation of specific transcription factors that induce sarcomere replication in-parallel. Such signaling pathways represent potential targets for therapeutic intervention and prevention of decompensation/failure. Hypertrophy provoking signals, in the form of dynamic stresses and ligand/effector molecules that bind to specific receptors to initiate the hypertrophy, are transcribed across the sarcolemma by several second messengers. They comprise intricate feedback mechanisms involving gene network cascades, specific signaling molecules encompassing G protein-coupled receptors and mechanotransducers, and myocardial stresses. Future multidisciplinary studies will characterize the adaptive/maladaptive nature of the AVS-induced hypertrophy, its gender- and individual patient-dependent peculiarities, and its response to surgical/medical interventions. They will herald more effective, precision medicine treatments.

Calcific Aortic Valve Disease: Part 1--Molecular Pathogenetic Aspects, Hemodynamics, and Adaptive Feedbacks.

Aortic valvular stenosis (AVS), produced by calcific aortic valve disease (CAVD) causing reduced cusp opening, afflicts mostly older persons eventually requiring valve replacement. CAVD had been considered "degenerative," but newer investigations implicate active mechanisms similar to atherogenesis--genetic predisposition and signaling pathways, lipoprotein deposits, chronic inflammation, and calcification/osteogenesis. Consequently, CAVD may eventually be controlled/reversed by lifestyle and pharmacogenomics remedies. Its management should be comprehensive, embracing not only the valve but also the left ventricle and the arterial system with their interdependent morphomechanics/hemodynamics, which underlie the ensuing diastolic and systolic LV dysfunction. Compared to even a couple of decades ago, we now have an increased appreciation of genomic and cytomolecular pathogenetic mechanisms underlying CAVD. Future pluridisciplinary studies will characterize better and more completely its pathobiology, evolution, and overall dynamics, encompassing intricate feedback processes involving specific signaling molecules and gene network cascades. They will herald more effective, personalized medicine treatments of CAVD/AVS.

Clinical impact of paravalvular leaks on biomarkers and survival after transcatheter aortic valve implantation.

BACKGROUND: There is accumulating evidence that up to 20% of the implanted devices after TAVI are associated with a significant degree of paravalvular leaks, which appear to be associated with a negative clinical outcome. METHODS: A total of 355 patients with severe aortic valvular stenosis (AVS) were treated by TAVI (Corevalve n = 222, Edwards Sapien n = 133). Survival, NT-proBNP and the grade of PVL were quantified up to 12 months after implantation. RESULTS: Technical success rate was 97.8%. Thirty-day mortality was 9.6%. Post-procedural transvalvular aortic regurgitation was seen only in a minority of cases (5%), whereas PVL were frequently observed (grade: <1+ in 58.2%, ≥1-<2 in 33.9%, and ≥2 in 7.9%). There was a clear relation-ship between PVL and adverse outcome (P < 0.001). After a transient increase, NT-proBNP showed a significant decline. Interestingly, a PVL ≥2+ was associated with a much higher rise in NT-proBNP compared to the other groups (P < 0.01), and a post-procedural increase in NT-proBNP by more than 1640 ng L(-1) within 5 days was associated with a significant increase in rate of death (P < 0.01). CONCLUSIONS: TAVI is an efficient treatment option for high-risk patients with severe AVS. The incidence of PVL is an inacceptable clinical problem. Serial measurement of NT-proBNP can be used for risk-stratification in patients with a significant PVL. In general, PVL graded ≥2+ is associated with a dramatically increased 6-month mortality. Therefore, any action to reduce paraprosthetical regurgitation is highly recommended.

A Case of Aortic Valve Replacement after Long-Term Antifungal Treatment of Candidemia / 日本心臓血管外科学会雑誌

We report a patient with candidemia, and remote organ infection, who underwent surgical treatment of aortic valvular stenosis. The patient was a 77-year-old man. <i>Candida glabrata </i>was detected in a blood culture during pharmacological treatment for pyelonephritis associated with vesicoureteral transition stenosis. A ureteral stent had been placed to preserve urine outflow, and vesicoureteral surgery had been scheduled. However, the urological surgery had to be performed first because of severe aortic valvular stenosis. After long-term (5 months) of antifungal treatment, <i>Candida </i>was no longer detected in the urine or blood cultures, but the serum <i>β</i>-D-glucan level did not fall below the reference value (21.6 pg/ml at the last measurement). It was difficult to control the infection further, and we decided to perform aortic valve replacement. There was no evidence of endocarditis at surgery, but pathological examination revealed traces of the fungus in the tissue of the aortic valve. The post-operative course was uneventful, and urological surgery was carried out 45 days later. Infection recurred when the antifungal medication was temporarily discontinued. The infection was then controlled by resumption of the antifungal medication. The patient has been free of recurrence for the past year since the aortic valve replacement. In the present case, in which a mycosis from a remote source was not readily eradicated prior to valve replacement, we were able to obtain good results by first administering long-term antifungal medication to quell the inflammation as much as possible.

N-terminal pro-B-type natriuretic peptide and its relationship with cardiac function in adults with congenital heart disease.

OBJECTIVES: The aim of this study was to determine the value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in adults with congenital heart disease (CHD) and investigate its relationship with ventricular function and exercise capacity. BACKGROUND: NT-proBNP may detect early deterioration in cardiac function. METHODS: In this cross-sectional study, extensive echocardiography, exercise testing, and NT-proBNP measurements were performed on the same day in consecutive adult patients with CHD. RESULTS: In total, 475 patients were included in this study (mean age of 34 ± 12 years, 57% male, 90% New York Heart Association class I). The median NT-proBNP level was 15.1 pmol/l (interquartile range [IQR]: 7.1 to 31.3 pmol/l), and the NT-proBNP level was >14 pmol/l in 53% of patients. The highest NT-proBNP levels were observed in patients with Fontan circulation (36.1 pmol/l [IQR: 14.4 to 103.8 pmol/l]) and a systemic right ventricle (RV) (31.1 pmol/l [IQR: 21.8 to 56.0 pmol/l]), and the lowest values were seen in patients with aortic coarctation (7.3 pmol/l [IQR: 2.8 to 19.5 pmol/l]). NT-proBNP levels correlated with age (r = 0.39, p < 0.001) and were higher in women (median of 21.7 vs. 10.4 pmol/l; p < 0.001). In patients with aortic stenosis or aortic coarctation, NT-proBNP levels correlated with diastolic function parameters of E/E' ratio (r = 0.40, p < 0.001) and left atrial dimension (r = 0.36, p < 0.001). In patients with a systemic RV, NT-proBNP levels correlated with RV annulus diameter (r = 0.31, p = 0.024). In patients with tetralogy of Fallot, the strongest correlations were observed with left atrial dimension (r = 0.46, p < 0.001) and left ventricular ejection fraction (r = 0.37, p < 0.001). NT-proBNP levels were associated with exercise capacity (n = 198) (maximum workload: ß = -0.08, p = 0.021) and peak oxygen uptake (ß = -0.012, p = 0.011) in a multivariable regression model adjusted for age and sex. CONCLUSIONS: NT-proBNP levels in adults with CHD clearly differ by diagnosis and are related to echocardiographic parameters and exercise capacity. Disease-specific correlations contribute to the understanding of the main hemodynamic problems per diagnosis. Follow-up data are needed to elucidate the additional prognostic value.

Balloon Valvuloplasty of Aortic Valve Stenosis in Childhood: Midterm Results in a Children's Hospital, Mansoura University, Egypt.

BACKGROUND: Balloon valvuloplasty was established as an alternative to surgery for treatment of aortic valve stenosis in childhood. Acute complications after balloon dilatation including aortic insufficiency or early death were described. AIM OF WORK: To analyze early outcome and midterm results of balloon aortic valvuloplasty (BAV) in Children's Hospital, Mansoura University, Egypt. SUBJECTS AND METHODS: Between April 2005-June 2008, all consecutive patients of age <18 years treated for aortic valve stenosis (AVS) with BAV were analyzed retrospectively. The study included 21 patients; 17 males, and 4 females. Their age ranged from the neonatal period to 10 years (mean age 5.6 ± 3.7 years). Patients with gradient ≥50 mmHg and aortic valve insufficiency (AI) up to grade I were included. All patients had isolated aortic valve stenosis except 3 patients (14.3%) had associated aortic coarctation. Six patients (28.6%) had bicuspid aortic valve. All patients had normal myocardial function except one (4.8%) had FS 15%. The duration of follow up was (mean ± SD: 18.5 ± 11.7 months). RESULTS: Femoral artery approach was used in 20 patients (95.2%) and carotid artery in one neonate (4.8%). Balloon/annulus ratio was 0.83 ± 0.04. Significant reduction in pressure gradient was achieved (mean 66.7 ± 9.8 mmHg to 20.65 ± 2.99 mmHg) (P < 0.001). Nine patients (42.8%) developed grade I AI, 2 patients (9.5%) developed grade II AI and 1 patient (4.8%) developed grade III AI. Two early deaths (9.5%); one died due to heart failure caused by grade IV AI and a neonate died because of severely compromised LV function. One patient (4.8%) had femoral artery occlusion necessitating anticoagulation. Patients remained free from re-intervention during follow up. CONCLUSION: Balloon valvuloplasty of aortic valve stenosis significantly reduces gradient with low morbidity and mortality in children.

A Case of Redo Aortic Valve Replacement by Right Minithoracotomy Approach with Port Access for Aortic Valve Stenosis after Coronary Artery Bypass Grafting / 日本心臓血管外科学会雑誌

We report a case of redo aortic valve replacement by right minithoracotomy approach for aortic stenosis after coronary artery bypass grafting (CABG). An 81-year-old man was followed-up once a year for 9 years after CABG. He complained of increasing respiratory distress, showed narrowing of the aortic valve area, elevation of the aortic valve pressure gradient, and tricuspid valve regurgitation by echocardiography. He was admitted for surgery. We considered minimally invasive operation would be better for him and performed aortic valve replacement (Carpentier-Edwards Perimaunt valve 19 mm) by a right minithoracotomy approach because graft injury could occur by median sternotomy after CABG, and he had the risks of advanced age, low activities of daily living, and mild dementia. His postoperative course was uneventful. On echocardiography performed at postoperative days 9, the ejection fraction recovered to 75% from 53% before surgery and the mean aortic valve pressure gradient was 8 mmHg. He was discharged on postoperative day 12. Right minithoracotomy approach with port access is a good option for redo operation for aortic valve stenosis after CABG.

Progression rate of aortic valve stenosis in korean patients.

BACKGROUND: Although there were studies about ethnic differences in aortic valve thickness and calcification that they may play a role in aortic valvular stenosis (AVS) progression, few studies about the progression rate of AVS in Asian population have been reported. The purpose of this study was to evaluate the progression rate of AVS in Korean patients. METHODS: We retrospectively analyzed 325 patients (181 men, age: 67 ± 13 years) with AVS who had 2 or more echocardiograms at least 6 months apart from 2003 to 2008. The patients with other significant valvular diseases or history of cardiac surgery were excluded. The progression rate of AVS was expressed in terms of increase in maximum aortic jet velocity per year (meter/second/year). RESULTS: Baseline AVS was mild in 207 (64%), moderate in 81 (25%), and severe in 37 (11%). There were no significant differences among the three groups in terms of age, gender, hypertension, smoking, and hypercholesterolemia. The mean progression rate was 0.12 ± 0.23 m/s/yr and more rapid in severe AVS (0.28 ± 0.36 m/s/yr) when compared to moderate (0.14 ± 0.26 m/s/yr) and mild AVS (0.09 ± 0.18 m/s/yr) (p < 0.001). The progression rate in bicuspid AVS was significantly higher than other AVS (0.23 ± 0.35 vs. 0.11 ± 0.20 m/s/yr, p = 0.002). By multivariate analysis, initial maximum aortic jet velocity (Beta = 0.175, p = 0.003), bicuspid aortic valve (Beta = 0.127, p = 0.029), and E velocity (Beta = -0.134, p = 0.018) were significantly associated with AVS progression. CONCLUSION: The progression rate of AVS in Korean patients is slower than that reported in Western population. Therefore, ethnic difference should be considered for the follow-up of the patients with AVS.

Progression Rate of Aortic Valve Stenosis in Korean Patients

BACKGROUND: Although there were studies about ethnic differences in aortic valve thickness and calcification that they may play a role in aortic valvular stenosis (AVS) progression, few studies about the progression rate of AVS in Asian population have been reported. The purpose of this study was to evaluate the progression rate of AVS in Korean patients. METHODS: We retrospectively analyzed 325 patients (181 men, age: 67 +/- 13 years) with AVS who had 2 or more echocardiograms at least 6 months apart from 2003 to 2008. The patients with other significant valvular diseases or history of cardiac surgery were excluded. The progression rate of AVS was expressed in terms of increase in maximum aortic jet velocity per year (meter/second/year). RESULTS: Baseline AVS was mild in 207 (64%), moderate in 81 (25%), and severe in 37 (11%). There were no significant differences among the three groups in terms of age, gender, hypertension, smoking, and hypercholesterolemia. The mean progression rate was 0.12 +/- 0.23 m/s/yr and more rapid in severe AVS (0.28 +/- 0.36 m/s/yr) when compared to moderate (0.14 +/- 0.26 m/s/yr) and mild AVS (0.09 +/- 0.18 m/s/yr) (p < 0.001). The progression rate in bicuspid AVS was significantly higher than other AVS (0.23 +/- 0.35 vs. 0.11 +/- 0.20 m/s/yr, p = 0.002). By multivariate analysis, initial maximum aortic jet velocity (Beta = 0.175, p = 0.003), bicuspid aortic valve (Beta = 0.127, p = 0.029), and E velocity (Beta = -0.134, p = 0.018) were significantly associated with AVS progression. CONCLUSION: The progression rate of AVS in Korean patients is slower than that reported in Western population. Therefore, ethnic difference should be considered for the follow-up of the patients with AVS.

Mechanism and Correlated Factors of SAM Phenomenon after Aortic Valve Replacement / 华中科技大学学报（医学）（英德文版）

To investigate the mechanism and correlated factors of systolic anterior motion (SAM) phenomenon after aortic valve replacement, 48 patients with severe aortic valvular stenosis were studied. Tested by echo-Doppler one week after aortic valve replacement, the patients were divided into two groups: SAM group and non-SAM group. The data of the left ventricular end-diastolic diameters, the left ventricular end-systolic diameters, the left ventricular outflow diameters, the thickness of the interventricular septum, the posterior wall of left ventricle, the blood velocities of left ventricular outflow and intra-cavitary gradients were recorded and compared. The results showed that no patients died during or after the operation. The blood velocities of left ventricular outflow was increased significantly in 9 patients (＞2.5 m/s), and 6 of them developed SAM phenomenon. There was significant difference in all indexes (P＜0.05 or P＜0.01) except the posterior wall of left ventricle (P＞0.05) between two groups. These indicated that the present of SAM phenomenon after aortic valve replacement may be directly related to the increase of blood velocities of left ventricular outflow and intra-cavitary gradients. It is also suggested that smaller left ventricular diastolic diameters, left ventricular systolic diameters, left ventricular outflow diameters and hypertrophy of interventricular septum may be the anatomy basis of SAM phenomenon.