Fibrosis and expression of extracellular matrix proteins in human interventricular septum in aortic valve stenosis and regurgitation.

Valvular heart disease leads to ventricular pressure and/or volume overload. Pressure overload leads to fibrosis, which might regress with its resolution, but the limits and details of this reverse remodeling are not known. To gain more insight into the extent and nature of cardiac fibrosis in valve disease, we analyzed needle biopsies taken from the interventricular septum of patients undergoing surgery for valve replacement focusing on the expression and distribution of major extracellular matrix protein involved in this process. Proteomic analysis performed using mass spectrometry revealed an excellent correlation between the expression of collagen type I and III, but there was little correlation with the immunohistochemical staining performed on sister sections, which included antibodies against collagen I, III, fibronectin, sarcomeric actin, and histochemistry for wheat germ agglutinin. Surprisingly, the immunofluorescence intensity did not correlate significantly with the gold standard for fibrosis quantification, which was performed using Picrosirius Red (PSR) staining, unless multiplexed on the same tissue section. There was also little correlation between the immunohistochemical markers and pressure gradient severity. It appears that at least in humans, the immunohistochemical pattern of fibrosis is not clearly correlated with standard Picrosirius Red staining on sister sections or quantitative proteomic data, possibly due to tissue heterogeneity at microscale, comorbidities, or other patient-specific factors. For precise correlation of different types of staining, multiplexing on the same section is the best approach.

Surgical aortic valve replacement etiologies, hemodynamics, and outcomes in 1346 patients from the Malaysian heart centre.

BACKGROUND: This study examined the characteristics and outcomes of surgical aortic valve replacement (SAVR) both isolated and in combination with other cardiac surgery in Malaysia from 2015 to 2021. METHODS: This was a retrospective study of 1346 patients analyzed on the basis of medical records, echocardiograms and surgical reports. The overall sample was both considered as a whole and divided into aortic stenosis (AS)/aortic regurgitation (AR)-predominant and similar-severity subgroups. RESULTS: The most common diagnosis was severe AS (34.6%), with the 3 most common etiologies being bicuspid valve degeneration (45.3%), trileaflet valve degeneration (36.3%) and rheumatic valve disease (12.2%). The second most common diagnosis was severe AR (25.5%), with the most common etiologies being root dilatation (21.0%), infective endocarditis (IE) (16.6%) and fused prolapse (12.2%). Rheumatic valve disease was the most common mixed disease. A total of 54.5% had AS-predominant pathology (3 most common etiologies: bicuspid valve degeneration valve, degenerative trileaflet valve and rheumatic valve disease), 36.9% had AR-predominant pathology (top etiologies: root dilatation, rheumatic valve disease and IE), and 8.6% had similar severity of AS and AR. Overall, 62.9% of patients had trileaflet valve morphology, 33.3% bicuspid, 0.6% unicuspid and 0.3% quadricuspid. For AS, the majority were high-gradient severe AS (49.9%), followed by normal-flow low-gradient (LG) severe AS (10.0%), paradoxical low-flow (LF)-LG severe AS (6.4%) and classical LF-LG severe AS (6.1%). The overall in-hospital and total 1-year mortality rates were 6.4% and 14.8%, respectively. Pure severe AS had the highest mortality. For AS-predominant pathology, the etiology with the highest mortality was trileaflet valve degeneration; for AR-predominant pathology, it was dissection. The overall survival probability at 5 years was 79.5% in all patients, 75.7% in the AS-predominant subgroup, 83.3% in the AR-predominant subgroup, and 87.3% in the similar-severity subgroup. CONCLUSIONS: The 3 most common causes of AS- predominant patients undergoing SAVR is bicuspid valve degeneration, degenerative trileaflet valve and rheumatic and for AR-predominant is root dilatation, rheumatic and IE. Rheumatic valve disease is an important etiology in our SAVR patients especially in mixed aortic valve disease. Study registration IJNREC/562/2022.

Aortic Regurgitation: Review of the Diagnostic Criteria and the Management Guidelines.

PURPOSE OF REVIEW: The evaluation of aortic regurgitation (AR) has advanced from physical examination and angiography towards evidence based non-invasive quantitative methods, primarily with echocardiography and more recently with cardiac magnetic resonance (CMR). This review highlights the guidelines and recent evidence in the diagnosis and management of AR; and outlines future areas of research. RECENT FINDINGS: Contemporary large cohorts of AR patients studied with echocardiography and CMR suggest that the left ventricular remodeling and systolic function triggers for intervention may be lower than previously recommended in the guidelines and emphasize the importance of LV volumes in risk stratification. Important gaps of knowledge in the quantitation of AR severity and patient risk stratification were fulfilled recently. Potential thresholds for intervention using ventricular volumes and CMR quantitative findings were recently described. The criteria for what constitutes hemodynamically significant AR and the optimal timing of intervention AR deserve further study.

Postoperative myocardial fibrosis assessment in aortic valvular heart diseases-a cardiovascular magnetic resonance study.

AIMS: Left ventricular remodelling occurs during the chronic course of aortic regurgitation (AR) and aortic stenosis (AS), leading to myocardial hypertrophy and fibrosis. Several studies have shown that extracellular volume fraction (ECV) and indexed extracellular volume (iECV) are important surrogate markers of diffuse myocardial fibrosis (MF). Postoperative data on these cardiovascular magnetic resonance (CMR) extracellular expansion parameters for either AS or AR are scarce. This study aimed to demonstrate the postoperative changes that occur in diffuse MF, and the influence of preoperative MF on the reversal of LV remodelling, in patients with AR or AS. METHODS AND RESULTS: Patients with severe AR or AS and indications for surgery were prospectively enrolled. Patients underwent pre- and postoperative CMR, and ECV and iECV were quantified. Data from 99 patients were analysed (32 with AR and 67 with AS). After surgery, the left ventricle mass index decreased in both groups (AR: 110 vs. 91 g/m2; AS: 86 vs. 68 g/m2, both P < 0.001). The late gadolinium enhancement fraction (AR: preoperative 1.9% vs. postoperative 1.7%, P = 0.575; AS: preoperative 2.4% vs. postoperative 2.4%, P = 0.615) and late gadolinium enhancement mass (AR: preoperative 3.8 g vs. postoperative 2.5 g, P = 0.635; AS: preoperative 3.4 g vs. postoperative 3.5 g, P = 0.575) remained stable in both groups. Preoperative iECV and ECV were greater in the AR group (iECV: 30 mL/m2 vs. 22 mL/m2, P = 0.001; ECV: 28.4% vs. 27.2%, P = 0.048). Indexed extracellular volume decreased after surgery in both groups (AR: 30-26.5 mL/m2, AS: 22-18.2 mL/m2, both P < 0.001); it was still greater in the AR group (AR: 26.5 mL/m2 vs. AS: 18.2 mL/m2, P < 0.001). Postoperative ECV remained stable in the AR group (preoperative 28.4% vs. postoperative 29.9%; P = 0.617) and increased in the AS group (preoperative 27.2% vs. postoperative 28.6%; P = 0.033). CONCLUSION: Patients with both AR or AS presented reduction in iECV after surgery, unfolding the reversible nature of diffuse MF. In contrast to patients with AS, those with AR developed postoperative iECV regression with stable ECV, suggesting a balanced reduction in both intracellular and extracellular myocardial components.

The role of the bicuspid aortic valve in sudden cardiac death-findings at cardiac autopsy.

BACKGROUND: Bicuspid aortic valve (BAV) is the most common congenital cardiac defect in the adult population, with a prevalence of 0.5%-2%. It is well recognized that aortic stenosis (AS), aortic regurgitation (AR) and aertopathy may develop by the fifth or sixth decade of life. There is a paucity of autopsy studies evaluating the hearts of subjects with BAV. The aim of this study is to ascertain the role of BAV in cases of sudden cardiac death. METHODS: A database of 6325 whole hearts referred to a specialist cardiac pathology center between 2004 and 2021 was reviewed to identify a subgroup of 91 subjects with a BAV reported. All cases had a negative full body autopsy and toxicology before being referred and subsequently underwent detailed cardiac evaluation including histological analysis by expert cardiac pathologists. RESULTS: The mean age of death was 37 ± 16 years (84% male). Death was attributed to aortic valve or aortic disease in 57% (n = 52) of cases; AS 30% (n = 27), endocarditis 11% (n = 10), aortic dissection (AD) 9% (n = 8) and AR 8% (n = 7). In the remaining 43% of cases, BAV was an incidental finding. CONCLUSION: The majority of deaths in young individuals with BAV were attributed to complications related to the aortic valve or aorta indicating that BAV is not a benign condition. When a BAV is identified, individuals should be appropriately follow-up with imaging to inform the optimal timing of intervention before a complication develops that may predispose the individual to a premature death.

Long-term outcomes after aortic root repair using selective sinus replacement.

OBJECTIVES: The study aim was to evaluate long-term results after anatomic restoration of the aortic root. METHODS: During an 18-year period, a total of 669 patients underwent valve-sparing root repair (aneurysm 554, dissection 115) using selective sinus replacement. None/trivial, mild, moderate, and severe (grades 3+ and 4+) insufficiency were present in 57, 146, 204, and 262 patients, respectively. RESULTS: The anatomic repair was adjusted to the existing aortic annulus diameter, which was 27.0 ± 3.0 mm on average. Replacement of 1, 2, or 3 sinuses of Valsalva was performed in 209, 234, and 226 patients, respectively. Altogether, 454 additional procedures on the cusps were performed, mostly as cusp patch plasty with pericardium (210). Thirty-day mortality was 0.6%. The mean follow-up duration was 7.1 ± 4.1 years (range, 0.01-19.1 years). The estimated freedom from relevant aortic insufficiency grade 3+ or greater (15 events) was 98% ± 1%, 97% ± 1%, and 94% ± 3% at 5, 10, and 15 years, respectively. On echocardiogram, no patient revealed a considerable change of the form or size of the repaired root, which was confirmed radiologically in 160 patients who received computed tomography angiography for any reason. Multivariate logistic regression analysis identified cusp prolapse/pseudo-prolapse as the only independent risk factor for the development of recurrent insufficiency grade 2+ or greater (41 occurrences), with a hazard ratio of 3.258 (95% confidence interval, 1.658-6.403; P = .001). An association between aortic annulus size and functional results could not be demonstrated. CONCLUSIONS: Patient-tailored root repair using isolated sinus replacement offers excellent functional long-term results regardless of underlying root pathology or annulus size. Aortic cusp pathology was decisive for long-term valve function.

Novel bicuspid aortic valve model with aortic regurgitation for hemodynamic status analysis using an ex vivo simulator.

OBJECTIVE: The objective was to design and evaluate a clinically relevant, novel ex vivo bicuspid aortic valve model that mimics the most common human phenotype with associated aortic regurgitation. METHODS: Three bovine aortic valves were mounted asymmetrically in a previously validated 3-dimensional-printed left heart simulator. The non-right commissure and the non-left commissure were both shifted slightly toward the left-right commissure, and the left and right coronary cusps were sewn together. The left-right commissure was then detached and reimplanted 10 mm lower than its native height. Free margin shortening was used for valve repair. Hemodynamic status, high-speed videography, and echocardiography data were collected before and after the repair. RESULTS: The bicuspid aortic valve model was successfully produced and repaired. High-speed videography confirmed prolapse of the fused cusp of the baseline bicuspid aortic valve models in diastole. Hemodynamic and pressure data confirmed accurate simulation of diseased conditions with aortic regurgitation and the subsequent repair. Regurgitant fraction postrepair was significantly reduced compared with that at baseline (14.5 ± 4.4% vs 28.6% ± 3.4%; P = .037). There was no change in peak velocity, peak gradient, or mean gradient across the valve pre- versus postrepair: 293.3 ± 18.3 cm/sec versus 325.3 ± 58.2 cm/sec (P = .29), 34.3 ± 4.2 mm Hg versus 43.3 ± 15.4 mm Hg (P = .30), and 11 ± 1 mm Hg versus 9.3 ± 2.5 mm Hg (P = .34), respectively. CONCLUSIONS: An ex vivo bicuspid aortic valve model was designed that recapitulated the most common human phenotype with aortic regurgitation. These valves were successfully repaired, validating its potential for evaluating valve hemodynamics and optimizing surgical repair for bicuspid aortic valves.

Relationship between the aortic root Z-score and degree of translamellar mucoid extracellular matrix accumulation.

PURPOSES: A retrospective analysis was performed to compare the pathological findings and aortic root Z-score in patients with and without connective tissue disease (CTD). METHODS: Twenty-two patients {47.5 [15-85] years old, 18 males} underwent surgery for aortic root dilatation without aortic dissection: 10 {40 [16-59] years old} with CTD and 12 {57.5 [15-85] years old} without CTD (non-CTD; p = 0.049). Systemic hypertension (p = 0.043) and the degree of preoperative aortic regurgitation (p = 0.017) were higher in the non-CTD patients than in the CTD patients. RESULTS: The diameters of the sinotubular junction (STJ) (p = 0.048) and ascending aorta (Asc.Ao.) (p = 0.020) and the Z-scores of the STJ (p = 0.027) and Asc.Ao. (p = 0.009) were significantly higher in the non-CTD patients than in the CTD patients. The degree of translamellar mucoid extracellular matrix accumulation (T-MEMA) of the Asc.Ao. was significantly higher in the non-CTD patients than in the CTD patients (p = 0.037) and was significantly correlated with the Z-scores of the aorta (R = 0.746, p < 0.01 in the sinus of Valsalva and R = 0.382, p = 0.031 in the Asc.Ao.), although there was no significant correlation between the diameter of the STJ and that of Asc.Ao. CONCLUSIONS: In non-CTD patients, not only the aortic root but also Asc.Ao. tended to dilate with age, and a significant correlation between the Z-scores of the aorta root and the Asc.Ao. and the degrees of T-MEMA was observed.

Hypoxic Culture Maintains Cell Growth of the Primary Human Valve Interstitial Cells with Stemness.

The characterization of aortic valve interstitial cells (VICs) cultured under optimal conditions is essential for understanding the molecular mechanisms underlying aortic valve stenosis. Here, we propose 2% hypoxia as an optimum VIC culture condition. Leaflets harvested from patients with aortic valve regurgitation were digested using collagenase and VICs were cultured under the 2% hypoxic condition. A significant increase in VIC growth was observed in 2% hypoxia (hypo-VICs), compared to normoxia (normo-VICs). RNA-sequencing revealed that downregulation of oxidative stress-marker genes (such as superoxide dismutase) and upregulation of cell cycle accelerators (such as cyclins) occurred in hypo-VICs. Accumulation of reactive oxygen species was observed in normo-VICs, indicating that low oxygen tension can avoid oxidative stress with cell-cycle arrest. Further mRNA quantifications revealed significant upregulation of several mesenchymal and hematopoietic progenitor markers, including CD34, in hypo-VICs. The stemness of hypo-VICs was confirmed using osteoblast differentiation assays, indicating that hypoxic culture is beneficial for maintaining growth and stemness, as well as for avoiding senescence via oxidative stress. The availability of hypoxic culture was also demonstrated in the molecular screening using proteomics. Therefore, hypoxic culture can be helpful for the identification of therapeutic targets and the evaluation of VIC molecular functions in vitro.

A Role for Peroxisome Proliferator-Activated Receptor Gamma Agonists in Counteracting the Degeneration of Cardiovascular Grafts.

ABSTRACT: Aortic valve replacement for severe stenosis is a standard procedure in cardiovascular medicine. However, the use of biological prostheses has limitations especially in young patients because of calcifying degeneration, resulting in implant failure. Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist, was shown to decrease the degeneration of native aortic valves. In this study, we aim to examine the impact of pioglitazone on inflammation and calcification of aortic valve conduits (AoC) in a rat model. Cryopreserved AoC (n = 40) were infrarenally implanted into Wistar rats treated with pioglitazone (75 mg/kg chow; n = 20, PIO) or untreated (n = 20, controls). After 4 or 12 weeks, AoC were explanted and analyzed by histology, immunohistology, and polymerase chain reaction. Pioglitazone significantly decreased the expression of inflammatory markers and reduced the macrophage-mediated inflammation in PIO compared with controls after 4 (P = 0.03) and 12 weeks (P = 0.012). Chondrogenic transformation was significantly decreased in PIO after 12 weeks (P = 0.001). Calcification of the intima and media was significantly reduced after 12 weeks in PIO versus controls (intima: P = 0.008; media: P = 0.025). Moreover, echocardiography revealed significantly better functional outcome of the AoC in PIO after 12 weeks compared with control. Interestingly, significantly increased intima hyperplasia could be observed in PIO compared with controls after 12 weeks (P = 0.017). Systemic PPAR-gamma activation prevents inflammation as well as intima and media calcification in AoC and seems to inhibit functional impairment of the implanted aortic valve. To further elucidate the therapeutic role of PPAR-gamma regulation for graft durability, translational studies and long-term follow-up data should be striven for.

Aortic Regurgitation Is Associated With Ascending Aortic Remodeling in the Nondilated Aorta.

OBJECTIVE: The probability of aortic complications in patients with bicuspid aortic valve is higher in association with aortic regurgitation (AR) compared with aortic stenosis (AS) or normally functioning valves. The objective of this study was to determine whether this is related to the specific characteristics of aneurysmatic dilatation that includes AR or whether AR itself has a negative impact on the aortic wall, independent of aneurysmatic dilatation. Approach and Results: Nondilated aortic specimens were harvested intraoperatively from individuals with tricuspid aortic valves and either AS (n=10) or AR (n=16). For controls, nondilated aortas were harvested during autopsies from individuals with tricuspid aortic valves and no evidence of aortic valve disease (n=10). Histological and immunohistochemical analyses revealed that compared with control aortas, overall medial degeneration was more severe in AR-aortas (P=0.005) but not AS-aortas (P=0.23). This pathological remodeling included mucoid extracellular matrix accumulation (P=0.005), elastin loss (P=0.003), elastin fragmentation (P=0.008), and decreased expression of fibrillin (P=0.003) and collagen (P=0.008). Furthermore, eNOS (endothelial nitric oxide synthase) expression was decreased in the intima (P=0.0008) and in vasa vasorum (P=0.004) of AR-aortas but not AS-aortas (all P>0.05). Likewise, subendothelial apoptosis was increased in AR-aortas (P=0.03) but not AS-aortas (P=0.50). CONCLUSIONS: AR has a negative effect on the nondilated ascending aortic wall. Accordingly, our results support the need for more detailed studies of the aortic wall in relation to aortic valve disease and may ultimately lead to more aggressive clinical monitoring and/or surgical criteria for patients with relevant AR. Graphic Abstract: A graphic abstract is available for this article.

Aortic root geometry following valve-sparing root replacement with reimplantation or remodeling: experimental investigation under static continuous pressure.

The differences in aortic root geometry associated with various valve-sparing root replacement (VSRR) techniques have not fully been understood. We evaluated the root configuration of current VSRR techniques by developing in vitro test apparatus. Six fresh porcine hearts were used for each model. The aortic root remodeling control group involved replacement of the ascending aorta with diameter reduction of sino-tubular junction (STJ) (C1). The aortic valve reimplantation control group involved replacement of the ascending aorta alone (C2). VSRR included remodeling without (RM) or with annuloplasty (RM + A) and reimplantation with a tube (RI) or a handmade neo-Valsalva graft (RI + V). The root geometry of each model in response to closing hydraulic pressures of 80 and 120 mmHg was investigated using echocardiography. Among the VSRR models, RM yielded the largest aorto-ventricular junction (AVJ), which was similar to those in non-VSRR models [mean AVJ diameter (mm) at 80 mmHg; RM = 25.1 ± 1.5, RM + A = 20.9 ± 0.7, RI = 20.7 ± 0.9, RI + V = 20.8 ± 0.4]. RI + V yielded the largest Valsalva size and largest ratio of Valsalva/AVJ, which was similar to the control group [mean Valsalva diameter (mm) at 80 mmHg; RM = 28.4 ± 1.4, RM + A = 25.8 ± 1.3, RI = 23.6 ± 1.0, RI + V = 30.5 ± 0.8, ratio of Valsalva/AVJ at 80 mmHg; RM = 1.14 ± 0.06, RM + A = 1.24 ± 0.06, RI = 1.15 ± 0.06, RI + V = 1.47 ± 0.05]. The STJ diameter at 80 mmHg was numerically smaller with RM + A (22.4 ± 1.2 mm) than with RM (24.8 ± 2.3 mm, p = 0.11). There were no significant differences in AVJ, Valsalva, or STJ distensibility or ellipticity between procedures. Current modifications, including annuloplasty for remodeling or reimplantation in the setting of neo-Valsalva graft, yield near-physiological root geometries.

Comparison of microstructural alterations in the proximal aorta between aortic stenosis and regurgitation.

OBJECTIVE: We aimed to analyze the association among flow patterns, gene expression, and histologic alterations of the proximal aorta in patients with aortic valve disease. METHODS: A total of 131 patients referred for aortic valve replacement were grouped by valve dysfunction (aortic stenosis vs aortic regurgitation) and valve morphology (bicuspid vs tricuspid). On the basis of magnetic resonance imaging, aortic tissue from outer and inner curvature was collected for gene expression and histologic analysis. To identify differences in aortic remodeling, age- and sex-adjusted data for inflammation (CCL2, VCAM1, inflammation and atherosclerosis) and medial degeneration (COL1A1, ELN, fibrosis, elastin fragmentation, and cystic medial necrosis) were compared. RESULTS: First, we compared all patients with aortic regurgitation (n = 64) and patients with aortic stenosis (n = 67). In patients with aortic regurgitation, COL1A1 expression and all histologic markers were significantly increased. With respect to aortic diameter, all subsequent analyses were refined by considering only individuals with aortic diameter 40 mm or greater. Second, patients with bicuspid aortic valve were compared, resulting in a similar aortic diameter. Although patients with aortic regurgitation were younger, no differences were found in gene expression or histologic level. Third, valve morphology was compared in patients with aortic regurgitation. Although aortic diameter was similar, patients with regurgitant bicuspid aortic valve were younger than patients with regurgitant tricuspid aortic valve. Inflammatory markers were similar, whereas markers for medial degeneration were increased in patients with regurgitant tricuspid aortic valve. CONCLUSIONS: Our results indicate that the proximal aorta in patients with aortic regurgitation showed an increased inflammation and medial degeneration compared with patients with aortic stenosis. Refining both groups by valve morphology, in patients with bicuspid aortic valve, no difference except age was detected between aortic regurgitation and aortic stenosis. In patients with aortic regurgitation, tricuspid aortic valve revealed increased markers for medial degeneration but no differences regarding inflammatory markers.

Inter-operative determination of the aortic root and cusp geometry associated with the aortic regurgitation grade.

PURPOSES: To perform successful aortic valve plasty (AVP) and valve-sparing root replacement (VSRR), a sufficient understanding of the aortic root and cusp geometry is required. Several key parameters of the aortic root and cusp geometry were, therefore, measured intraoperatively. METHODS: Forty-nine patients (63.1 ± 16.6 y.o., 40 males) were measured during the surgeries. The patients were divided into 3 groups; including patients with no or mild aortic valve regurgitation (AR) (n = 13), moderate AR (n = 18), and severe AR (n = 18). RESULTS: There were no significant differences in the body surface area (1.72 ± 0.19 m2) among the 3 groups (p = 0.858). The effective height (EH) and geometric height (GH) of right coronary cusp were smaller than those of the others (EH: p = 0.068, GH: p < 0.01). The insertion line length (ILL) and free margin length (FML) of each leaflet tended to be significantly longer according to the AR grade(ILL: p < 0.01, FML: p < 0.01). The FML/AVJ ratios were significantly different (p < 0.01). The FML/ILL ratios were constant with the ratio of 0.88 ± 0.1(p = 0.624). CONCLUSIONS: Although the ILL and FML tended to increase with the AR grade, the FML/ILL ratio remained constant. For successful AVP and VSRR, adequately maintaining the FML/ILL ratio is necessary to prevent remarkable cusp prolapse while also preserving its favorable cusp motion.

A nonsense variant in FBN1 caused autosomal dominant Marfan syndrome in a Chinese family: a case report.

BACKGROUND: Marfan syndrome (MFS) is a common autosomal dominant inherited disease, and the occurrence rate is around 0.1-0.2‰. The causative variant of FNB1 gene accounts for approximately 70-80% of all MFS cases. In this study, we found a heterozygous c.3217G > T (p.Glu1073*) nonsense variant in the FBN1 gene. This finding extended the variant spectrum of the FBN1 gene and will provide a solution for patients to bear healthy offspring by preimplantation genetic testing or prenatal diagnosis. CASE PRESENTATION: The patient was treated due to tachycardia during excitement in a hospital. Echocardiography showed dilatation of the ascending aorta and main pulmonary artery, mitral regurgitation (mild), tricuspid regurgitation (mild), and abnormal left ventricular filling. Electrocardiograph showed sinus rhythm. In addition, flutters of shadows in front of his eyes and vitreous opacity were present in the patient. Genomic DNA was extracted from peripheral blood samples from members of the family and 100 unrelated controls. Potential variants were screened out by next-generation sequencing and confirmed by MLPA & Sanger sequencing. Real-time fluorescence quantitative PCR (RT-qPCR) was performed to detect the relative mRNA quantitation in the patient. A heterozygous nonsense variant c.3217G > T of the FBN1 gene, which resulted in p. Glu1073Term, was identified in both patients. Only wild type bases were found in the cDNA sequence of the patient. Real-time fluorogenic quantitative PCR results showed that the relative expression level of FBN1 cDNA in the patient was only about 21% compared to that of normal individuals. This variant c.3217G > T of the FBN1 gene introduces a Stop codon in the cb-EGF12 domain. We speculated that a premature translational-termination codon (PTC) was located in the mRNA and the target mRNA was disintegrated through a process known as nonsense-mediated mRNA decay (NMD), which led to a significant decrease of the fibrillin-1 protein, eventually causing clinical symptoms in the patient. CONCLUSIONS: In this study, we found a heterozygous c.3217G > T (p.Glu1073*) nonsense variant in the FBN1 gene, which eventually led to Marfan syndrome in a Chinese family.

Giant cell aortitis.

Inflammatory aortic diseases are broadly classified into three categories according to the degree of inflammation: atherosclerosis, atherosclerosis with excessive inflammation, and aortitis/periaortitis. This paper presents a case of a 39-year old man with aneurysmal dilatation of thoracic aorta and aortic valve insufficiency. The aortic wall showed thickening and wrinkled "tree bark" appearance as well as apparent scarring of the intima. Histological examination revealed intimal hyperplasia, a granulomatous/giant cell pattern in the inner tunica media, a few epithelioid macrophages, abundant chronic lymphoplasmacytic and histiocytic inflammation and discrete fibrinoid necrosis. The histological findings were indicative of Horton's disease, but no typical clinical features were present. The case illustrates the difficulties involved in diagnosing inflammatory aortic diseases where it may be challenging to arrive at a specific diagnosis despite the knowledge of medical history, and available macroscopic and histological findings.

Modified Ozaki Procedure Including Annular Enlargement for Small Aortic Annuli in Young Patients.

BACKGROUND: Aortic valve neocuspidization (AVNeo) (Ozaki procedure) has excellent midterm results in adults. Outcomes in patients with a small native aortic annulus are unknown. We report early outcomes in young patients with small native aortic valve annuli. METHODS: Retrospective data of patients undergoing AVNeo between 2015 and 2019 were reviewed. Patients with native aortic annulus less than 21 mm undergoing 3-leaflet AVNeo were included. RESULTS: A total of 51 patients were identified (median age 7.9 years; median weight 21 kg), and 80% patients were less than or equal to 12 years age. Preoperative indication was aortic regurgitation (AR) (n = 23), aortic stenosis (AS) (n = 22), or mixed AS and AR (n = 6). Baseline anatomy was quadricuspid (n = 1), tricuspid (n = 23), bicuspid (n = 15), or unicuspid (n = 12) valve. Preoperative peak gradient for AS and mixed AS and AR patients was 55.36 mm Hg. Median native annulus diameter was 17 mm; sinus and annular enlargements were required in 22 patients and 9 patients, respectively. Median intensive care unit and hospital length of stay were 2.0 days and 7.2 days, respectively. There were no reinterventions, and there was 1 hospital mortality unrelated to aortic valve. At discharge, 94% of patients had less than or equal to mild AR, and the median peak gradient was 18 mm Hg. At mean follow-up of 11.9 months, 80% and 82% of patients had less than moderate AR and AS, respectively. Three patients required surgical reintervention. In annular enlargement patients, mean annulus Z score remained greater than 0 at follow-up. CONCLUSIONS: The Ozaki procedure has acceptable short-term results in young patients with small aortic annuli. A larger aortic annulus can be achieved with surgical annular enlargement. Long-term follow-up is necessary to determine late valve function and potential continued annular growth.

Case report: early aortic valve degeneration associated with interstitial deletion of chromosome 2-46,XX,del (2)(q31.3; q32.2).

BACKGROUND: Interstitial deletions within the long arm of chromosome 2, involving the 2q31q33 region, are rare but are known to be associated with delays in development, behavioral problems, facial dysmorphism and various hand/foot anomalies. CASE PRESENTATION: Here, we describe a case with an interstitial 2q31.3.q32.2 deletion, presenting the previously described phenotype, exhibiting fibromyxoid degeneration of the aortic valve in addition to previously described clinical features. CONCLUSION: Interstitial deletion in chromosome 2q31.2q32.3 might be associated to a fibromyxoid degeneration of valvular leaflets generating regurgitation. Patients diagnosed with this mutation may require investigation to rule out a valvular disease.

Incidental detection of Corynebacterium jeikeium endocarditis via regular blood examination in an afebrile hemodialysis patient.

Herein, we describe a rare case of Corynebacterium jeikeium endocarditis that silently progressed in a 65-year-old man undergoing hemodialysis. Because routine monthly blood examination revealed high C-reactive protein levels, blood cultures were collected, although he had no symptom and was afebrile. After 2 days, a Gram-positive rod was detected in one set of the blood culture. Furthermore, transthoracic echocardiography revealed new aortic regurgitation (AR) and vegetations, and, therefore, infective endocarditis was suspected. Transesophageal echocardiography showed vegetations with a maximum diameter of 8 mm on his aortic valve, with some valve destruction. C. jeikeium was identified in three sets of blood cultures. Administration of daptomycin was started because he had vancomycin allergy. Judging from the high risk of embolization due to vegetations, emergency aortic valve replacement was performed on the second day. C. jeikeium was detected in a resected cardiac valve specimen and blood. This case emphasizes that physicians should always consider the possibility of infective endocarditis even in hemodialysis patients without any symptoms.

Preoperative Cardiac Computed Tomography Characteristics Associated with Recurrent Aortic Regurgitation after Aortic Valve Re-Implantation.

OBJECTIVE: To identify the preoperative cardiac computed tomography (CT) factors influencing postoperative recurrent aortic regurgitation (AR) in patients who underwent aortic valve repair with the re-implantation technique (David operation) due to AR. MATERIALS AND METHODS: A total of 117 patients (age, 49.4 ± 15.6 years; 83 males) who underwent the David operation for AR were included in this retrospective study. Aortic root profiles including the aortic regurgitant orifice area (ARO) and the aortic cusp asymmetry ratio of the areas (ASRarea), which is defined as the maximum/minimum areas among the three cusp areas at the level of the commissures, were measured on preoperative cardiac CT scans. Clinical and CT findings were compared between a group with recurrent AR grade < 3 (no, trivial, or mild AR) and recurrent ≥ 3 + AR. To determine the optimal cut-off values of ASR and ARO, the receiver operating characteristic (ROC) curve was used. Cox regression analysis was used for the analysis of the factors affecting recurrent 3 + AR. RESULTS: Postoperatively, recurrent 3 + AR developed in 17 (14.5%) patients and occurred within a median of 268 days (interquartile range: 78-582 days). The cut-off ARO value for discriminating the patients with recurrent 3 + AR was > 24 mm² (sensitivity, 76.5%; specificity 64.8%), and the area under the ROC curve (AUC) was 0.72. For ASRarea, the cut-off value was > 1.58 (sensitivity, 76.5%; specificity, 58.0%) and the AUC was 0.64. Multivariable Cox regression showed that ARO > 24 mm² (hazard ratio = 3.79, p = 0.020) was a potential independent parameter for recurrent 3 + AR. ROC for the linear regression model showed that the AUC for both ARO and ASRarea was 0.73 (95% confidence interval, 0.64-0.81, p < 0.001). CONCLUSION: ARO and ASRarea detected on preoperative cardiac CT would be potentially helpful for identifying AR patients who may benefit from the David operation.