AIMS: Bicuspid aortic valve (BAV), where two valve leaflets are found instead of the usual three, affects 1-2% of the general population and is associated with significant morbidity and mortality. Despite its frequency, the majority of cases remain unexplained. This is, at least in part, because there are two types of valve leaflet primordia: endocardial cushions and intercalated valve swellings (ICVS). Moreover, multiple progenitors make distinct contributions to the formation of these primordia. Genomic studies in mouse and human have suggested a correlation between BAV and malfunctional primary cilia. However, the precise requirement for cilia during early embryonic valvulogenesis remains unknown. METHODS AND RESULTS: Here, we disrupted primary cilia by deleting the ciliary gene Ift88 in the main progenitor cells forming the aortic valve using specific Cre drivers: Wnt1-Cre for neural crest cells, Isl1-Cre for second heart field (SHF) cells, Tie2-Cre for endocardial-derived cells, and Tnnt2-Cre for direct-differentiating SHF in the ICVS. Loss of Ift88, and thus primary cilia, from neural crest cells and endocardium did not impact aortic valve formation. However, primary cilia were essential in SHF cells for aortic valve leaflet formation, with over half of Ift88f/f;Isl1-Cre mutants presenting with BAV. As the valve leaflets were forming, 50% of the Ift88f/f;Isl1-Cre mutants had two small leaflets in the position of the usual posterior leaflet, meaning that at this stage, the aortic valve was quadricuspid, which then remodelled to BAV by E15.5. Mechanistic studies demonstrated premature differentiation of SHF cells as the ICVS formed, leading to the formation of a broadened ICVS that formed two posterior leaflet precursors. This abnormality in the formation of the ICVS was associated with disruption of Notch-Jag1 signalling pathway, with Jag1f/f;Isl1-Cre mutants presenting with a similar phenotype. CONCLUSION: These data show that primary cilia, via the Notch-Jag1 signalling pathway, regulate differentiation of SHF cells in the aortic valve primordia. Additionally, we identify a mechanistic link between the developmental basis of quadricuspid and bicuspid arterial valve leaflets.

• Klíčová slova
• Aortic valve, Cilia, Ift88, bicuspid aortic valve, intercalated valve swelling, second heart field,
• MeSH
• aortální chlopeň * abnormality   metabolismus   embryologie   patologie   MeSH
• bikuspidální aortální chlopeň MeSH
• buněčná diferenciace MeSH
• cilie * metabolismus   patologie   MeSH
• crista neuralis metabolismus   MeSH
• endokardové polštáře metabolismus   embryologie   patologie   MeSH
• fenotyp MeSH
• modely nemocí na zvířatech MeSH
• myši knockoutované MeSH
• myši transgenní MeSH
• nádorové supresorové proteiny MeSH
• nemoci srdečních chlopní * metabolismus   genetika   patologie   embryologie   MeSH
• protein Wnt1 genetika   metabolismus   MeSH
• receptory Notch metabolismus   MeSH
• signální transdukce MeSH
• vývojová regulace genové exprese MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• nádorové supresorové proteiny MeSH
• protein Wnt1 MeSH
• receptory Notch MeSH
• Tg737Rpw protein, mouse MeSH Prohlížeč

In developed countries, calcific aortic stenosis (CAS) has become the most common acquired valvular disease and cause for valve replacement. The prevalence of the disease increases with age, reaching over 5 % in adults over 75 years of age. The cases of CAS are classified as either of a previously normal (tricuspid) aortic valve (senile, syn. age - related, "sclerotic" type), or based on a congenitally malformed, usually bicuspid aortic valve. This paper is a brief summary of our 5 previous publications from the years 2007 - 2021, devoted to histopathology of CAS, namely to vascularization, inflammatory infiltrate and metaplastic ossification of the valve, and also to topography of these lesions in individual valve cusps. We conclude that calcification of the aortic valve is not a passive degenerative lesion, but an active multifactorial inflammatory process driven by cells native to the aortic valve. Pathogenesis of CAS is similar to that of atherosclerosis.

• Klíčová slova
• Aortic valve, Pathogenesis, aortic valve, calcific aortic stenosis, inflammation, pathogenesis, probiotics,
• MeSH
• aortální chlopeň * patologie   abnormality   MeSH
• aortální stenóza * patologie   etiologie   MeSH
• kalcinóza * patologie   MeSH
• lidé MeSH
• zánět patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

OBJECTIVE: We investigated long-term outcomes of bicuspid aortic valve (BAV) repair, with external annuloplasty, according to aorta phenotype. METHODS: Between 2003 and 2020, all patients with BAV operated on for aortic insufficiency (AI) and/or aneurysm were included. Repairs included isolated AI repair with subvalvular with or without sinotubular junction (STJ) (single or double) annuloplasty, supracoronary aorta replacement (with or without hemiroot remodeling), and root remodeling with external subvalvular ring annuloplasty. RESULTS: Among 343 patients operated, reparability rate was 81.3% (n = 279; age 46 ± 13.3 years). At 10 years (median follow-up: 3.42 years; interquartile range, 1.1, 5.8), survival was 93.9% (n = 8 deaths, similar to general population), cumulative incidence of reoperation was 6.2% (n = 10), AI grade >2 was 5.8% (n = 9), and grade >1 was 23.0% (n = 30). BAV repair stabilizing both the annulus and STJ with annuloplasty, compared with nonstabilized STJ repair (single annuloplasty), had lower incidence of reoperation (2.6% vs 22.5%, P = .0018) and AI grade >2 (1.2% vs 23.6%, P < .001) at 9 years. Initial commissural angle <160° was not a risk factor for reoperation, compared with angle ≥160° if symmetrical repair was achieved (2.7% and 4.1%, respectively, at 6 years, P = .85). Multivariable model showed that absence of STJ stabilization (odds ratio, 6.7; 95% confidence interval, 2.1-20, P = .001) increased recurrent AI, but not initial commissural angle <160° (odds ratio, 1.01; 95% confidence interval, 0.39-2.63, P = .98). Commissures adjusted symmetrically led to lower transvalvular gradient, compared with nonsymmetrical repair (8.7 mm Hg vs 10.2 mm Hg, P = .029). CONCLUSIONS: BAV repair, tailored to aorta phenotype, is associated with excellent durable outcomes if both annulus and STJ are reduced and stabilized with external ring annuloplasty. Commissural angle <160° is not associated with reoperation if symmetrical repair is achieved.

• Klíčová slova
• annuloplasty, aortic aneurysm, aortic insufficiency, aortic valve repair, bicuspid aortic valve,
• MeSH
• anuloplastika srdeční chlopně * škodlivé účinky   mortalita   metody   MeSH
• aortální aneurysma chirurgie   diagnostické zobrazování   mortalita   MeSH
• aortální chlopeň chirurgie   abnormality   diagnostické zobrazování   patofyziologie   MeSH
• aortální insuficience * chirurgie   patofyziologie   diagnostické zobrazování   mortalita   MeSH
• bikuspidální aortální chlopeň * chirurgie   patofyziologie   MeSH
• časové faktory MeSH
• chirurgická náhrada chlopně škodlivé účinky   přístrojové vybavení   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• pooperační komplikace etiologie   MeSH
• reoperace statistika a číselné údaje   MeSH
• retrospektivní studie MeSH
• rizikové faktory MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Calcific aortic valve stenosis (CAVS) is the most frequent acquired heart valve disease in the developed world and the most common cause of heart valve replacement, particularly in older adults. It is considered a form of atherosclerosis and, like the latter, of inflammatory pathogenesis. METHODS: The incidence and severity of features of chronic inflammation (vascularization, cellular infiltration, bone metaplasia, calcification) in surgically resected semilunar cusps of a tricuspid aortic valve in 100 patients with CAVS were assessed. A novel method of placing metal clips during the operation by the surgeon to distinguish individual cusps was implemented, allowing the pathologist to associate lesions to particular cusps. The findings were evaluated statistically. RESULTS: The median age of the cohort was 73 years. There was a male predominance of 3.5:1. Almost all the patients had a medical history of risk factors - hypertension (92x), diabetes (51x), and dyslipidaemia (85x). Statistical evaluation of the pathological findings showed that the left cusp was least affected by calcification, vascularization, and chronic inflammation, compared to both the right and non-coronary cusps. On the other hand, the left cusp was the most common site of bone metaplasia. The reason for these differences is unknown. We speculate about mechanobiological effects of abnormal hemodynamics. CONCLUSIONS: Chronic inflammation plays a significant role in pathogenesis of CAVS. Distinguishing the resected aortic valve cusps by placing metal clips is a useful method to study potential differences (topography) in the pathology of individual cusps.

• Klíčová slova
• Aortic valve cusps, Calcific aortic valve stenosis, Inflammation, Pathogenesis,
• MeSH
• aortální chlopeň abnormality   patologie   chirurgie   MeSH
• aortální stenóza epidemiologie   patologie   chirurgie   MeSH
• endokarditida epidemiologie   patologie   chirurgie   MeSH
• hodnocení rizik MeSH
• incidence MeSH
• kalcinóza epidemiologie   patologie   chirurgie   MeSH
• kardiochirurgické výkony MeSH
• lidé středního věku MeSH
• lidé MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH

Patients with a bicuspid aortic valve (BAV) frequently require surgical intervention for aortic regurgitation (AR) and/or aneurysm. Valve-preserving surgery and repair of regurgitant BAVs have evolved into an increasingly used alternative to replacement. Anatomic predictors of possible repair failures have been identified and solutions developed. Using current techniques most non-calcified BAVs can be preserved or repaired. Excellent repair durability and freedom from valve-related complications can be achieved if all pathologic components of aortic valve and root including annular dilatation are corrected. Anatomic variations must be addressed using tailored approaches.

• Klíčová slova
• Aortic regurgitation, Aortic valve repair, Aortic valve replacement, Bicuspid aortic valve,
• MeSH
• anuloplastika srdeční chlopně MeSH
• aorta patologie   MeSH
• aortální chlopeň abnormality   chirurgie   MeSH
• bikuspidální aortální chlopeň MeSH
• lidé MeSH
• nemoci srdečních chlopní komplikace   diagnóza   chirurgie   MeSH
• výběr pacientů MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Current guidelines recommend root replacement when diameter of the sinuses of Valsalva are superior to 45 mm particularly for bicuspid valve. However, in case of tubular aorta aneurysms with moderate root dilatation (40-45 mm diameter), the approach is still debated regarding the increased risk of coronary reimplantation. We present a modified hemi-remodeling aortic repair technique that includes the replacement of the noncoronary sinus, ascending aorta, and valve repair with external ring annuloplasty in patients with bicuspid aortic valve (BAV) and moderately dilated aortic root. METHODS: Between 2003 and 2017, 18 patients presenting with left-right BAV and an aortic root diameter at 42.3+/-3.3 mm underwent hemi-root and ascending aorta replacement and aortic valve repair with external annuloplasty. RESULTS: Postoperatively, 16 (88.9%) had no aortic insufficiency (AI) and 2 (11.1%) had grade I AI, no patients had grade III or grade IV AI. Overall survival and freedom from grade II AI at 4 years and freedom from aortic valve-related reoperation were 100%. CONCLUSION: The standardized modified hemi-remodeling technique we present is a safe and reproducible procedure, with satisfactory durability at follow-up. This technique represents an interesting alternative to full valve sparing root replacement, as it avoids the operative risk of coronary reimplantation, allows shorter cross-clamping time and a better exposition on the valve for a symmetrical repair, placing the commissure at 180°, compared with valve sparing root replacement.

• Klíčová slova
• aneurysm of the ascending aorta, annuloplasty, aortic valve repair, bicuspid aortic valve, valve sparing root replacement,
• MeSH
• anuloplastika srdeční chlopně metody   MeSH
• aortální chlopeň abnormality   chirurgie   MeSH
• bikuspidální aortální chlopeň MeSH
• nemoci srdečních chlopní chirurgie   MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• anuloplastika srdeční chlopně výchova   MeSH
• aorta thoracica chirurgie   MeSH
• aortální chlopeň abnormality   chirurgie   MeSH
• bikuspidální aortální chlopeň MeSH
• kardiologie výchova   MeSH
• lidé MeSH
• nemoci srdečních chlopní chirurgie   MeSH
• šicí techniky výchova   MeSH
• studium lékařství specializační postgraduální metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• audiovizuální média MeSH
• práce podpořená grantem MeSH
• úvodníky MeSH

• MeSH
• anuloplastika srdeční chlopně výchova   MeSH
• aortální chlopeň abnormality   chirurgie   MeSH
• bikuspidální aortální chlopeň MeSH
• hrudní chirurgie výchova   MeSH
• lidé MeSH
• nemoci srdečních chlopní chirurgie   MeSH
• studium lékařství specializační postgraduální metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• audiovizuální média MeSH
• práce podpořená grantem MeSH
• úvodníky MeSH

• MeSH
• aortální chlopeň abnormality   diagnostické zobrazování   chirurgie   MeSH
• aortální insuficience diagnostické zobrazování   etiologie   chirurgie   MeSH
• dospělí MeSH
• lidé MeSH
• vrozené srdeční vady komplikace   diagnostické zobrazování   chirurgie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

Polyamines are cationic molecules synthesized via a highly regulated pathway, obtained from the diet or produced by the gut microbiota. They are involved in general molecular and cellular phenomena that play a role also in vascular disease. Bicuspid aortic valve (BAV) is a congenital malformation associated to a greater risk of thoracic ascending aorta (TAA) aneurysm, whose pathogenesis is not yet well understood. We focused on differential analysis of key members of polyamine pathway and on polyamine concentration in non-dilated TAA samples from patients with either stenotic tricuspid aortic valve (TAV) or BAV (diameter ≤ 45 mm), vs. normal aortas from organ donors, with the aim of revealing a potential involvement of polyamines in early aortopathy. Changes of gene expression in TAA samples were evaluated by RT-PCR. Changes of ornithine decarboxylase 1 (ODC1), a key enzyme in polyamine formation, and cationic amino acid transporter 1 (SLC7A1/CAT-1) expression were analyzed also by Western blot. ODC1 subcellular localization was assessed by immunohistochemistry. Polyamine concentration in TAA samples was evaluated by HPLC. BAV TAA samples showed an increased concentration of putrescine and spermidine vs. TAV and donor samples, together with a decreased mRNA level of polyamine anabolic enzymes and of the putative polyamine transporter SLC7A1/CAT-1. The catabolic enzyme spermidine/spermine N1-acetyltransferase 1 showed a significant mRNA increase in TAV samples only, together with a decreased concentration of spermine. The decreased expression of SLC7A1/CAT-1 and ODC1 mRNAs in BAV corresponded to increased or unchanged expression of the respective proteins. ODC was located mainly in smooth muscle cell (SMC) nucleus in TAV and donor samples, while it was present also in SMC cytoplasm in BAV samples, suggesting its activation. In conclusion, BAV, but not TAV non-dilated samples show increased polyamine concentration, accompanied by the activation of a regulatory negative feedback mechanism.

• Klíčová slova
• Aneurysm, Aortopathy, Bicuspid aortic valve, Ornithine decarboxylase, Polyamines, Thoracic ascending aorta,
• MeSH
• aorta thoracica MeSH
• aorta metabolismus   MeSH
• aortální chlopeň abnormality   metabolismus   MeSH
• bikuspidální aortální chlopeň MeSH
• biologické markery metabolismus   MeSH
• dopplerovská echokardiografie MeSH
• dospělí MeSH
• imunohistochemie MeSH
• lidé středního věku MeSH
• lidé MeSH
• nemoci srdečních chlopní diagnóza   metabolismus   MeSH
• polyaminy metabolismus   MeSH
• progrese nemoci MeSH
• senioři MeSH
• stupeň závažnosti nemoci MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biologické markery MeSH
• polyaminy MeSH