Wnt Signaling Inhibition Prevents Postnatal Inflammation and Disease Progression in Mouse Congenital Myxomatous Valve Disease.

BACKGROUND: Myxomatous valve disease (MVD) is the most common cause of mitral regurgitation, leading to impaired cardiac function and heart failure. MVD in a mouse model of Marfan syndrome includes valve leaflet thickening and progressive valve degeneration. However, the underlying mechanisms by which the disease progresses remain undefined. METHODS: Mice with Fibrillin 1 gene variant Fbn1C1039G/+ recapitulate histopathologic features of Marfan syndrome, and Wnt (Wingless-related integration site) signaling activity was detected in TCF/Lef-lacZ (T-cell factor/lymphoid enhancer factor-ß-galactosidase) reporter mice. Single-cell RNA sequencing was performed from mitral valves of wild-type and Fbn1C1039G/+ mice at 1 month of age. Inhibition of Wnt signaling was achieved by conditional induction of the secreted Wnt inhibitor Dkk1 (Dickkopf-1) expression in periostin-expressing valve interstitial cells of Periostin-Cre; tetO-Dkk1; R26rtTA; TCF/Lef-lacZ; Fbn1C1039G/+ mice. Dietary doxycycline was administered for 1 month beginning with MVD initiation (1-month-old) or MVD progression (2-month-old). Histological evaluation and immunofluorescence for ECM (extracellular matrix) and immune cells were performed. RESULTS: Wnt signaling is activated early in mitral valve disease progression, before immune cell infiltration in Fbn1C1039G/+ mice. Single-cell transcriptomics revealed similar mitral valve cell heterogeneity between wild-type and Fbn1C1039G/+ mice at 1 month of age. Wnt pathway genes were predominantly expressed in valve interstitial cells and valve endothelial cells of Fbn1C1039G/+ mice. Inhibition of Wnt signaling in Fbn1C1039G/+ mice at 1 month of age prevented the initiation of MVD as indicated by improved ECM remodeling and reduced valve leaflet thickness with decreased infiltrating macrophages. However, later, Wnt inhibition starting at 2 months did not prevent the progression of MVD. CONCLUSIONS: Wnt signaling is involved in the initiation of mitral valve abnormalities and inflammation but is not responsible for later-stage valve disease progression once it has been initiated. Thus, Wnt signaling contributes to MVD progression in a time-dependent manner and provides a promising therapeutic target for the early treatment of congenital MVD in Marfan syndrome.

Significance of Fibrillin-1, Filamin A, MMP2 and SOX9 in Mitral Valve Pathology.

Genetic factors play a significant role in the pathogenesis of mitral valve diseases, including mitral valve prolapse (MVP) and mitral valve regurgitation. Genes like Fibrillin-1 (FBN1), Filamin A (FLNA), matrix metalloproteinase 2 (MMP2), and SRY-box transcription factor 9 (SOX9) are known to influence mitral valve pathology but knowledge of the exact mechanism is far from clear. Data regarding serum parameters, transesophageal echocardiography, and genetic and histopathologic parameters were investigated in 54 patients who underwent cardiovascular surgery for mitral valve regurgitation. The possible association between Fibrillin-1, Filamin A, MMP2, and SOX9 gene expressions was checked in relationship with the parameters of systemic inflammatory response. The mRNA expression levels (RQ-relative quantification) were categorized into three distinct groups: low (RQ < 1), medium/normal (RQ = 1-2), and high (RQ > 2). Severe fibrosis of the mitral valve was reflected by high expression of FBN1 and low expression of MMP2 (p < 0.05). The myxoid degeneration level was associated with the mRNA expression level for FBN1 and a low lymphocyte-monocyte ratio was associated with an increased mRNA expression of FBN1 (p < 0.05). A high number of monocytes was associated with high values of FBN1 whereas the increase in the number of lymphocytes was associated with high levels of MMP2. In addition, we observed that the risk of severe hyalinization was enhanced by a low mRNA expression of FLNA and/or SOX9. In conclusion, a lower FLNA mRNA expression can reflect the aging process that is highlighted in mitral valve pathology as a higher risk for hyalinization, especially in males, that might be prevented by upregulation of the SOX9 gene. FBN1 and MMP2 influence the inflammation-related fibrotic degeneration of the mitral valve. Understanding the genetic base of mitral valve pathology can provide insights into disease mechanisms, risk stratification, and potential therapeutic targets.

Cardiac reverse remodeling in primary mitral regurgitation: mitral valve replacement vs. mitral valve repair.

BACKGROUND: When feasible, guidelines recommend mitral valve repair (MVr) over mitral valve replacement (MVR) to treat primary mitral regurgitation (MR), based upon historic outcome studies and transthoracic echocardiography (TTE) reverse remodeling studies. Cardiovascular magnetic resonance (CMR) offers reference standard biventricular assessment with superior MR quantification compared to TTE. Using serial CMR in primary MR patients, we aimed to investigate cardiac reverse remodeling and residual MR post-MVr vs MVR with chordal preservation. METHODS: 83 patients with ≥ moderate-severe MR on TTE were prospectively recruited. 6-min walk tests (6MWT) and CMR imaging including cine imaging, aortic/pulmonary through-plane phase contrast imaging, T1 maps and late-gadolinium-enhanced (LGE) imaging were performed at baseline and 6 months after mitral surgery or watchful waiting (control group). RESULTS: 72 patients completed follow-up (Controls = 20, MVr = 30 and MVR = 22). Surgical groups demonstrated comparable baseline cardiac indices and co-morbidities. At 6-months, MVr and MVR groups demonstrated comparable improvements in 6MWT distances (+ 57 ± 54 m vs + 64 ± 76 m respectively, p = 1), reduced indexed left ventricular end-diastolic volumes (LVEDVi; - 29 ± 21 ml/m2 vs - 37 ± 22 ml/m2 respectively, p = 0.584) and left atrial volumes (- 23 ± 30 ml/m2 and - 39 ± 26 ml/m2 respectively, p = 0.545). At 6-months, compared with controls, right ventricular ejection fraction was poorer post-MVr (47 ± 6.1% vs 53 ± 8.0% respectively, p = 0.01) compared to post-MVR (50 ± 5.7% vs 53 ± 8.0% respectively, p = 0.698). MVR resulted in lower residual MR-regurgitant fraction (RF) than MVr (12 ± 8.0% vs 21 ± 11% respectively, p = 0.022). Baseline and follow-up indices of diffuse and focal myocardial fibrosis (Native T1 relaxation times, extra-cellular volume and quantified LGE respectively) were comparable between groups. Stepwise multiple linear regression of indexed variables in the surgical groups demonstrated baseline indexed mitral regurgitant volume as the sole multivariate predictor of left ventricular (LV) end-diastolic reverse remodelling, baseline LVEDVi as the most significant independent multivariate predictor of follow-up LVEDVi, baseline indexed LV end-systolic volume as the sole multivariate predictor of follow-up LV ejection fraction and undergoing MVR (vs MVr) as the most significant (p < 0.001) baseline multivariate predictor of lower residual MR. CONCLUSION: In primary MR, MVR with chordal preservation may offer comparable cardiac reverse remodeling and functional benefits at 6-months when compared to MVr. Larger, multicenter CMR studies are required, which if the findings are confirmed could impact future surgical practice.

Altered Responsiveness to TGFß and BMP and Increased CD45+ Cell Presence in Mitral Valves Are Unique Features of Ischemic Mitral Regurgitation.

[Figure: see text].

Accessory left atrial cords: A case report and literature review.

INTRODUCTION: Accessory left atrial cords are fibroelastic structures found in the left atrium. Left atrial cords may be associated with mitral valve disease, atrial fibrillation, stroke, and other congenital left-side anomalies. METHODS: We presented the case of a man with severe Mitral Regurgitation and two accessories left atrial cords attached to P2 scallop by a single tendon and performed a literature review using PUBMED/MEDLINE, Web of Science, and EMBASE databases on December 4, 2021. RESULTS: According to our review, accessory left atrial cords were found more frequently in women (36 patients, 62%), more frequently attached to the mitral valve (66% of reports) and mitral regurgitation was the most frequently reported pattern of mitral valve disease (64.2%). No other cases of double left atrial cords attached to P2 segment were found. CONCLUSION: Accessory left atrial chords may be related to mitral valve disease and other left-side congenital abnormalities. These structures were found more frequently in females and A2 insertion was the most frequently observed pattern in the review.

Mechanism of Eccentric Cardiomyocyte Hypertrophy Secondary to Severe Mitral Regurgitation.

BACKGROUND: Primary valvular heart disease is a prevalent cause of morbidity and mortality in both industrialized and developing countries. Although the primary consequence of valvular heart disease is myocardial dysfunction, treatment of valvular heart diseases centers around valve repair or replacement rather than prevention or reversal of myocardial dysfunction. This is particularly evident in primary mitral regurgitation (MR), which invariably results in eccentric hypertrophy and left ventricular (LV) failure in the absence of timely valve repair or replacement. The mechanism of LV dysfunction in primary severe MR is entirely unknown. METHODS: Here, we developed the first mouse model of severe MR. Valvular damage was achieved by severing the mitral valve leaflets and chords with iridectomy scissors, and MR was confirmed by echocardiography. Serial echocardiography was performed to follow up LV morphology and systolic function. Analysis of cardiac tissues was subsequently performed to evaluate valve deformation, cardiomyocyte morphology, LV fibrosis, and cell death. Finally, dysregulated pathways were assessed by RNA-sequencing analysis and immunofluorescence. RESULTS: In the ensuing 15 weeks after the induction of MR, gradual LV dilatation and dysfunction occurred, resulting in severe systolic dysfunction. Further analysis revealed that severe MR resulted in a marked increase in cardiac mass and increased cardiomyocyte length but not width, with electron microscopic evidence of sarcomere disarray and the development of sarcomere disruption. From a mechanistic standpoint, severe MR resulted in activation of multiple components of both the mammalian target of rapamycin and calcineurin pathways. Inhibition of mammalian target of rapamycin signaling preserved sarcomeric structure and prevented LV remodeling and systolic dysfunction. Immunohistochemical analysis uncovered a differential pattern of expression of the cell polarity regulator Crb2 (crumbs homolog 2) along the longitudinal axis of cardiomyocytes and close to the intercalated disks in the MR hearts. Electron microscopy images demonstrated a significant increase in polysome localization in close proximity to the intercalated disks and some areas along the longitudinal axis in the MR hearts. CONCLUSIONS: These results indicate that LV dysfunction in response to severe MR is a form of maladaptive eccentric cardiomyocyte hypertrophy and outline the link between cell polarity regulation and spatial localization protein synthesis as a pathway for directional cardiomyocyte growth.

Tenascin C promotes valvular remodeling in two large animal models of ischemic mitral regurgitation.

Ischemic mitral regurgitation (MR) is a frequent complication of myocardial infarction (MI) characterized by adverse remodeling both at the myocardial and valvular levels. Persistent activation of valvular endothelial cells leads to leaflet fibrosis through endothelial-to-mesenchymal transition (EMT). Tenascin C (TNC), an extracellular matrix glycoprotein involved in cardiovascular remodeling and fibrosis, was also identified in inducing epithelial-to-mesenchymal transition. In this study, we hypothesized that TNC also plays a role in the valvular remodeling observed in ischemic MR by contributing to valvular excess EMT. Moderate ischemic MR was induced by creating a posterior papillary muscle infarct (7 pigs and 7 sheep). Additional animals (7 pigs and 4 sheep) served as controls. Pigs and sheep were sacrificed after 6 weeks and 6 months, respectively. TNC expression was upregulated in the pig and sheep experiments at 6 weeks and 6 months, respectively, and correlated well with leaflet thickness (R = 0.68; p < 0.001 at 6 weeks, R = 0.84; p < 0.001 at 6 months). To confirm the translational potential of our findings, we obtained mitral valves from patients with ischemic cardiomyopathy presenting MR (n = 5). Indeed, TNC was also expressed in the mitral leaflets of these. Furthermore, TNC induced EMT in isolated porcine mitral valve endothelial cells (MVEC). Interestingly, Toll-like receptor 4 (TLR4) inhibition prevented TNC-mediated EMT in MVEC. We identified here for the first time a new contributor to valvular remodeling in ischemic MR, namely TNC, which induced EMT through TLR4. Our findings might set the path for novel therapeutic targets for preventing or limiting ischemic MR.

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.

Myocardial fibrosis in asymptomatic and symptomatic chronic severe primary mitral regurgitation and relationship to tissue characterisation and left ventricular function on cardiovascular magnetic resonance.

BACKGROUND: Myocardial fibrosis occurs in end-stage heart failure secondary to mitral regurgitation (MR), but it is not known whether this is present before onset of symptoms or myocardial dysfunction. This study aimed to characterise myocardial fibrosis in chronic severe primary MR on histology, compare this to tissue characterisation on cardiovascular magnetic resonance (CMR) imaging, and investigate associations with symptoms, left ventricular (LV) function, and exercise capacity. METHODS: Patients with class I or IIa indications for surgery underwent CMR and cardiopulmonary exercise testing. LV biopsies were taken at surgery and the extent of fibrosis was quantified on histology using collagen volume fraction (CVFmean) compared to autopsy controls without cardiac pathology. RESULTS: 120 consecutive patients (64 ± 13 years; 71% male) were recruited; 105 patients underwent MV repair while 15 chose conservative management. LV biopsies were obtained in 86 patients (234 biopsy samples in total). MR patients had more fibrosis compared to 8 autopsy controls (median: 14.6% [interquartile range 7.4-20.3] vs. 3.3% [2.6-6.1], P < 0.001); this difference persisted in the asymptomatic patients (CVFmean 13.6% [6.3-18.8], P < 0.001), but severity of fibrosis was not significantly higher in NYHA II-III symptomatic MR (CVFmean 15.7% [9.9-23.1] (P = 0.083). Fibrosis was patchy across biopsy sites (intraclass correlation 0.23, 95% CI 0.08-0.39, P = 0.001). No significant relationships were identified between CVFmean and CMR tissue characterisation [native T1, extracellular volume (ECV) or late gadolinium enhancement] or measures of LV function [LV ejection fraction (LVEF), global longitudinal strain (GLS)]. Although the range of ECV was small (27.3 ± 3.2%), ECV correlated with multiple measures of LV function (LVEF: Rho = - 0.22, P = 0.029, GLS: Rho = 0.29, P = 0.003), as well as NTproBNP (Rho = 0.54, P < 0.001) and exercise capacity (%PredVO2max: R = - 0.22, P = 0.030). CONCLUSIONS: Patients with chronic primary MR have increased fibrosis before the onset of symptoms. Due to the patchy nature of fibrosis, CMR derived ECV may be a better marker of global myocardial status. Clinical trial registration Mitral FINDER study; Clinical Trials NCT02355418, Registered 4 February 2015, https://clinicaltrials.gov/ct2/show/NCT02355418.

Meta-analysis of results of subvalvular repair for severe ischemic mitral regurgitation.

BACKGROUND AND AIM OF THE STUDY: The aim of this meta-analysis was to compare short- and long-term outcomes of patients undergoing mitral annuloplasty (MA) with or without papillary muscle surgery (PMS) for the treatment of ischemic mitral regurgitation (IMR). METHODS: A systematic review and meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement were performed. RESULTS: Nine studies met the inclusion criteria. This meta-analysis identified 478 patients: 228 patients underwent MA alone and 250 patients underwent concomitant PMS. Early mortality was similar between two groups (odds ratio [OR] 1.14, 95% confidence interval [CI], 0.51-2.53; P = .75). PMS was associated at follow-up with a higher freedom from cardiac-related events (P = .050); moreover, although both surgical techniques had a positive impact on ventricular remodeling, the PMS group showed a significant higher reduction of left ventricle end-diastolic diameter (OR, 4.89, 95% CI, 2.77-7.01; P < .001) and left ventricle end-systolic diameter values (OR, 4.11, 95% CI, 1.98-6.24; P < .001). Finally, PMS compared with MA alone was associated with a significant reduction of recurrent mitral regurgitation at follow-up (OR, 3.25, 95% CI, 1.60-6.59; P = .001). CONCLUSIONS: This meta-analysis demonstrated superiority in terms of ventricular remodeling of a combined approach encompassing PMS and MA over MA alone in IMR. Moreover, the association of subvalvular surgery with restrictive MA decreases the incidence of mitral regurgitation recurrence and cardiac-related events at follow-up.

Prognostic Implications of Magnetic Resonance-Derived Quantification in Asymptomatic Patients With Organic Mitral Regurgitation: Comparison With Doppler Echocardiography-Derived Integrative Approach.

BACKGROUND: Magnetic resonance imaging (MRI) is an accurate method for the quantitative assessment of organic mitral regurgitation (OMR). The aim of the present study was to compare the discriminative power of MRI quantification and the recommended Doppler echocardiography (ECHO)-derived integrative approach to identify asymptomatic patients with OMR and adverse outcome. METHODS: The study population consisted of 258 asymptomatic patients (63±14 years, 60% men) with preserved left ventricular ejection fraction (>60%) and chronic moderate and severe OMR (flail 25%, prolapse 75%) defined by using the ECHO-derived integrative approach. All patients underwent MRI to quantify regurgitant volume (RV) of OMR by subtracting the aortic forward flow volume from the total left ventricular stroke volume. Severe OMR was defined as RV≥60 mL. RESULTS: Mean ECHO-derived RV was on average 17.1 mL larger than the MRI-derived RV (P<0.05). Concordant grading of OMR severity with both techniques was observed in 197 (76%) individuals with 62 (31%) patients having severe OMR (MRI SEV-ECHO SEV) and 135 (69%) patients having moderate OMR (MRI MOD-ECHO MOD). The remaining 61 (24%) individuals had discordant findings (MRI SEV-ECHO MOD or MRI MOD-ECHO SEV) between the 2 techniques. The majority of these differences in OMR classification were observed in patients with late systolic or multiple jets (both κ<0.2). Patients with eccentric jets showed moderate agreement (κ=0.53; 95% confidence interval, 0.41-0.64). In contrast, a very good agreement (κ=0.90; 95% confidence interval, 0.82-0.98) was observed in a combination of holosystolic, central, and single jet. During a median follow-up of 5.0 years (interquartile range, 3.5-6.0 years), 38 (15%) patients died and 106 (41%) either died or developed indication for mitral valve surgery. In separate Cox regression analyses, the MRI-derived left ventricular end-systolic volume index, RV, and OMR category (severe versus moderate), and the ECHO-derived OMR category were independent predictors of all-cause mortality (all P<0.05). The MRI-derived RV showed the largest area under the curve to predict mortality (0.72) or its combination with the development of indication for mitral valve surgery (0.83). CONCLUSIONS: The findings of the present study suggest that the MRI-derived assessment of OMR can better identify patients with severe OMR and adverse outcome than ECHO-derived integrative approach warranting close follow-up and perhaps, early mitral valve surgery.

Myocardial fibrosis predicts adverse outcome after MitraClip implantation.

BACKGROUND: High-risk patients with mitral regurgitation (MR) may be treated by a percutaneous mitral valve repair with the MitraClip, but identification of patients who may benefit remains difficult. We aimed to determine whether myocardial fibrosis predicts outcome in MR patients undergoing MitraClip implantation and is beneficial in clinical decision making. METHODS: Preprocedural to the MitraClip implantation, myocardial fibrosis was analyzed with cardiovascular magnetic resonance (CMR) through late gadolinium enhancement. The CMR data were core-lab adjudicated measured before the MitraClip implantation. Adverse outcome was defined as New York Heart Association (NYHA) class III or IV after 1 month or death within 1 month after the MitraClip implantation. RESULTS: In total, 23 patients underwent preprocedural CMR, mean age 80 ± 9 years, 45% male, 64% atrial fibrillation and 73% NYHA class III or IV at baseline. Myocardial fibrosis was present in 55% of the patients with degenerative MR and in 64% of the patients with functional MR. An adverse outcome occurred in 69% of the patients with myocardial fibrosis and in 11% of the patients without myocardial fibrosis (P = 0.01). CONCLUSIONS: Our hypothesis-generating study showed that the presence of myocardial fibrosis predicts adverse outcome in patients undergoing MitraClip implantation. After confirmation with larger sample size, identification of myocardial fibrosis might contribute to assess prognosis and to clinical decision making.

Extended Posterior Leaflet Augmentation for Ischemic Mitral Regurgitation　- Augmented Posterior Leaflet Snuggling up to Anterior Leaflet.

BACKGROUND: The ideal surgical technique for ischemic mitral regurgitation (MR) is controversial. We introduced an extended posterior mitral leaflet (PML) augmentation technique for functional MR with severe tethering, which detached the PML from the annulus almost completely and augmented it with a large 3×6-cm oval pericardial patch. Methods and Results: A total of 17 mitral repairs using the new technique were performed for ischemic MR with no 30-day mortality and 2 hospital deaths. The NYHA class was III in 47% and IV in 13%. The EuroSCORE II was 9.7±4.9. The ring size was 32±1.4 mm. Concomitant coronary bypass was performed in 67% and left ventricular repair in 28%. The mechanism of leaflet closure was evaluated using transthoracic echocardiography in 15 survivors. MR decreased to none or trivial with a significant increase in coaptation length (Pre: 4.6±0.8 mm vs. Post: 9.8±2.5 mm; P<0.001). The PML flexibly moved forward and tightly contacted as if "snuggling up" to the anterior leaflet. There were no late deaths, heart failure readmissions or MR recurrences during follow-up (850±181 days). All patients remained in NYHA I or II. CONCLUSIONS: Extended PML augmentation for ischemic MR showed excellent early results with deep leaflet coaptation through a "snuggling up" phenomenon, which would help prevent late MR recurrence.

Mitral Valve Pathology.

PURPOSE OF REVIEW: This review describes numerous pathologic entities that cause structural abnormalities of the mitral valve. Different pathologic entities involve different components of the so-called mitral apparatus: atrial wall, annulus, leaflets, chordae, papillary muscles, and/or left ventricular free wall. These abnormalities can cause valvular stenosis, regurgitation, or both. RECENT FINDINGS: Currently, in addition to open-chest surgery to replace or repair the damaged mitral valve, there are less invasive percutaneous approaches to address mitral valve dysfunction. These include narrowing the orifice, clipping the leaflets, and inserting bioprostheses percutaneously. Understanding the structural abnormalities discussed in this review is essential for choosing the optimal therapeutic intervention for mitral valve disease.

Black aortic valve: Minocycline pigmentation complicating treatment of pyoderma gangrenosum.

We describe the case of a 75-year-old male with pyoderma gangrenosum (PG) who had severe aortic insufficiency and moderate mitral regurgitation. He had been taking minocycline for 15 years to treat PG. He underwent aortic valve replacement and mitral valve repair. Aortotomy revealed a black discoloration of the aortic valve and sinus of Valsalve.

A Multi Center Experience: Is Valve Replacement Safe for Patients with Hugely Dilated Left Ventricle?

BACKGROUND: Dilated left ventricle occurs in chronic aortic and mitral regurgitations. We describe the early outcome of mitral and aortic valve replacement for patients with severely dilated left ventricle in different surgical interventions. METHODS: From March 2014 to December 2018, 620 patients with left ventricular end-diastolic diameter (LVEDD) of ≥ 70 mm underwent valve replacement procedures in 8 cardiac surgery centers in Egypt. One hundred ninety four cases (31.3%) underwent aortic valve replacement, 173 cases (27.9%) underwent mitral valve replacement, 123 cases (19.9%) underwent double valve replacement, 59 cases (9.5%) underwent double valve replacement with either tricuspid valve repair or replacement, 33 cases (5.3%) underwent mitral valve replacement with either tricuspid valve repair or replacement, 20 cases (3.2%) underwent mitral valve replacement with CABG, 10 cases (1.6%) underwent aortic valve replacement with CABG, while 8 cases (1.3%) underwent aortic valve replacement with ascending aortic aneurysm repair. RESULTS: Four patients (0.6%) developed new postoperative renal failure, which required dialysis. Twenty-nine patients (4.7%) required reoperation for bleeding. One patient (0.2 %) developed sternal dehiscence. Five patients (0.8%) postoperatively developed stroke. Twenty-five patients (4%) died, and the main causes of death were low cardiac output and sepsis with eventual multi-organ failure. CONCLUSION: Valve replacement in patients with hugely dilated left ventricle are safe operations with satisfactory outcomes even if combined with other procedures, especially with proper preoperative preparation, intraoperative preservation of posterior mitral leaflet, and meticulous postoperative follow up in the surgical ICU.

Development of a fluid-structure interaction model to simulate mitral valve malcoaptation.

OBJECT: Mitral regurgitation (MR) is a condition in which the mitral valve does not prevent the reversal of blood flow from the left ventricle into the left atrium. This study aimed at numerically developing a model to mimic MR and poor leaflet coaptation and also comparing the performance of a normal mitral valve to that of the MR conditions at different gap junctions of 1, 3 and 5 mm between the anterior and posterior leaflets. RESULTS: The results revealed no blood flow to the left ventricle when a gap between the leaflets was 0 mm. However, MR increased this blood flow, with increases in the velocity and pressure within the atrium. However, the pressure within the aorta did not vary meaningfully (ranging from 22 kPa for a 'healthy' model to 25 kPa for severe MR). CONCLUSIONS: The findings from this study have implications not only for understanding the changes in pressure and velocity as a result of MR in the ventricle, atrium or aorta, but also for the development of a computational model suitable for clinical translation when diagnosing and determining treatment for MR.

Serotonin receptor 2B signaling with interstitial cell activation and leaflet remodeling in degenerative mitral regurgitation.

AIMS: Mitral valve interstitial cells (MVIC) play an important role in the pathogenesis of degenerative mitral regurgitation (MR) due to mitral valve prolapse (MVP). Numerous clinical studies have observed serotonin (5HT) dysregulation in cardiac valvulopathies; however, the impact of 5HT-mediated signaling on MVIC activation and leaflet remodeling in MVP have been investigated to a limited extent. Here we test the hypothesis that 5HT receptors (5HTRs) signaling contributes to MVP pathophysiology. METHODS AND RESULTS: Diseased human MV leaflets were obtained during cardiac surgery for MVP; normal MV leaflets were obtained from heart transplants. MV RNA was used for microarray analysis of MVP patients versus control, highlighting genes that indicate the involvement of 5HTR pathways and extracellular matrix remodeling in MVP. Human MV leaflets were also studied in vitro and ex vivo with biomechanical testing to assess remodeling in the presence of a 5HTR2B antagonist (LY272015). MVP leaflets from Cavalier King Charles Spaniels were used as a naturally acquired in vivo model of MVP. These canine MVP leaflets (N=5/group) showed 5HTR2B upregulation. This study also utilized CB57.1ML/6 mice in order to determine the effect of Angiotensin II infusion on MV remodeling. Histological analysis showed that MV thickening due to chronic Angiotensin II remodeling is mitigated by a 5HTR2B antagonist (LY272015) but not by 5HTR2A inhibitors. CONCLUSION: In humans, MVP is associated with an upregulation in 5HTR2B expression and increased 5HT receptor signaling in the leaflets. Antagonism of 5HTR2B mitigates MVIC activation in vitro and MV remodeling in vivo. These observations support the view that 5HTR signaling is involved not only in previously reported 5HT-related valvulopathies, but it is also involved in the pathological remodeling of MVP.

Cardiac MR Strain: A Noninvasive Biomarker of Fibrofatty Remodeling of the Left Atrial Myocardium.

Purpose To determine whether left atrial (LA) strain quantification with cardiac magnetic resonance (MR) imaging feature tracking is associated with the severity of LA fibrofatty myocardial remodeling at histologic analysis. Materials and Methods This prospective case-control study was approved by the institutional review board. LA strain was evaluated with cardiac MR feature tracking between January 2014 and March 2015 in 13 consecutive patients (mean age, 61 years ± 19; nine male) with mitral regurgitation in the 24 hours before mitral valve surgery and 13 age- and sex-matched healthy control subjects. LA strain parameters were compared first between control subjects and patients and then according to atrial fibrillation and mitral regurgitation status. Associations between LA strain and histology of preoperative biopsies were reported by using receiver operating characteristic curve analysis and Spearman correlation. Results Peak longitudinal atrial strain (PLAS) was significantly lower in patients with mitral regurgitation than in healthy control subjects (P < .001). Increased LA remodeling was significantly related to altered LA strain, and the strongest association was found between PLAS and the degree of fibrofatty myocardial replacement at histologic analysis (r = -0.75, P = .017). LA end-diastolic volume was increased in patients with mitral regurgitation when compared with that in healthy volunteers (P < .001) because of volume overload; however, volume did not correlate with the histologic degree of LA fibrofatty replacement (r = -0.35, P = .330). Conclusion LA strain, especially PLAS, correlates strongly with the degree of fibrofatty replacement at histologic analysis. Such functional imaging biomarker in combination with LA volumetry could help to guide clinical decisions, since myocardial structural remodeling is a known morphologic substrate of LA dysfunction leading to atrial fibrillation with adverse outcome. © RSNA, 2017 Online supplemental material is available for this article.

Natural history of echocardiographic abnormalities in mucopolysaccharidosis III.

BACKGROUND: Mucopolysaccharidosis (MPS) type III, Sanfilippo Syndrome, is an autosomal recessive lysosomal storage disorder. MPS I and II patients often develop cardiac involvement leading to early mortality, however there are limited data in MPS III. The objective of this study is to describe cardiac abnormalities in a large group of MPS III patients followed in a longitudinal natural history study designed to determine outcome measures for gene transfer trials. METHODS: A single center study of MPS III patients who were enrolled in the Nationwide Children's Hospital natural history study in 2014. Two cardiologists reviewed all patient echocardiograms for anatomic, valvular, and functional abnormalities. Valve abnormalities were defined as abnormal morphology, trivial mitral regurgitation (MR) with abnormal morphology or at least mild MR, and any aortic regurgitation (AR). Abnormal left ventricular (LV) function was defined as ejection fraction < 50%. Group comparisons were assessed using two-sample t-tests or Wilcoxon rank sum tests for continuous variables and chi-square or Fisher's exact tests for categorical variables. RESULTS: Twenty-five patients, 15 Type A and 10 Type B MPS III, underwent 45 echocardiograms. Fifteen patients (60%) demonstrated an abnormal echocardiographic finding with age at first abnormal echocardiogram within the study being 6.8 ±â€¯2.8 years. Left-sided valve abnormalities were common over time: 7 mitral valve thickening, 2 mitral valve prolapse, 16 MR (8 mild, 8 trivial), 3 aortic valve thickening, and 9 AR (7 mild, 2 trivial). Two patients had asymmetric LV septal hypertrophy. No valvular stenosis or ventricular function abnormalities were noted. Incidental findings included: mild aortic root dilation (2), bicommissural aortic valve (1), and mild tricuspid regurgitation (3). CONCLUSIONS: Individuals with Sanfilippo A and B demonstrate a natural history of cardiac involvement with valvular abnormalities most common. In short-term follow up, patients demonstrated only mild progression of abnormalities, none requiring intervention. Valvular disease prevalence is similar to MPS I and II, but appears less severe. These findings raise no specific concerns for gene transfer trials in patients in this age range.