Sex differences and survival in adults with bicuspid aortic valves : verification in 3 contemporary echocardiographic cohorts

Background-—Sex-related differences in morbidity and survival in bicuspid aortic valve (BAV) adults are fundamentally unknown. Contemporary studies portend excellent survival for BAV patients identified at early echocardiographic-clinical stages. Whether BAV adults incur a survival disadvantage throughout subsequent echocardiographic-clinical stages remains undetermined. Methods and Results-—Analysis was done of 3 different cohorts of consecutive patients with echocardiographic diagnosis of BAV identified retrospectively: (1) a community cohort of 416 patients with first BAV diagnosis (age 35 21 years, follow-up 16 7 years), (2) a tertiary clinical referral cohort of 2824 BAV adults (age 51 16 years, follow-up 9 6 years), and (3) a surgical referral cohort of 2242 BAV adults referred for aortic valve replacement (AVR) (age 62 14 years, follow-up 6 5 years). For the community cohort, 20-year risks of aortic regurgitation (AR), AVR, and infective endocarditis were higher in men (all P=0.04); for a total BAV-related morbidity risk of 52 4% vs 35 6% in women (P=0.01). The cohort’s 25-year survival was identical to that in the general population (P=0.98). AR independently predicted mortality in women (P=0.001). Baseline AR was more common in men (P=0.02) in the tertiary cohort, with 20-year survival lower than that in the general population (P<0.0001); age-adjusted relative death risk was 1.16 (95% confidence interval [CI] 1.05-1.29) for men versus 1.67 (95% CI 1.38-2.03) for women (P=0.001). AR independently predicted mortality in women (P=0.01). Baseline AR and infective endocarditis were higher in men (both =0.001) for the surgical referral cohort, with 15-year survival lower than that in the general population (P<0.0001); age-adjusted relative death risk was 1.34 (95% CI 1.22-1.47) for men versus 1.63 (95% CI 1.40-1.89) for women (P=0.026). AR and NYHA class independently predicted mortality in women (both P=0.04). Conclusions-—Within evolving echocardiographic-clinical stages, the long-term survival of adults with BAV is not benign, as both men and women incur excess mortality. Although BAV-related morbidity is higher in men in the community, and AR and infective endocarditis are more prevalent in men, women exhibit a significantly higher relative risk of death in tertiary and surgical referral cohorts, which is independently associated with A

High Prevalence of Abnormal Nocturnal Oximetry in Patients With Hypertrophic Cardiomyopathy

ObjectivesWe sought to determine the prevalence of nocturnal oxygen desaturation and obstructive sleep apnea (OSA) in a population of patients with hypertrophic cardiomyopathy (HCM).BackgroundThe coexistence of sleep apnea and HCM, 2 common cardiovascular conditions, has been largely unrecognized in the treatment of patients with HCM. The nocturnal hypoxia-induced hyperadrenergic state in OSA is expected to worsen hemodynamics and outcomes in HCM.MethodsOne hundred subjects with HCM between June 1, 2006, and July 14, 2008, were screened with nocturnal oximetry. Clinical variables were collected for statistical analysis. Oximetry was classified abnormal (suspicion of sleep-disordered breathing) in the presence of repetitive desaturation (≥5 events/h) followed by a rapid return to baseline oxygen saturation (SaO2) level with a decrease of ≥4% and threshold of 90%.ResultsSeventy-one (71%) patients with HCM had abnormal nocturnal oximetry (71 ± 9%, 95% confidence interval: 62% to 80%). Subjects with abnormal oximetry were older (age 59.5 ± 15.3 years) and more were hypertensive (n = 39 [55%]) than those with normal oximetry (age 45.8 ± 18.5 years, n = 9 [31%], p < 0.001, p = 0.03). Patients with HCM were more symptomatic in the presence of abnormal oximetry (New York Heart Association functional class II to III) (62% vs. 83%, p = 0.023). HCM patients had a higher prevalence of abnormal nocturnal oximetry (n = 71, 71%) compared with a control group of similar age and sex distribution (n = 49, 49%) (p = 0.001).ConclusionsAbnormal nocturnal oximetry is common in patients with HCM, suggesting that OSA is prevalent. OSA may impact hemodynamics and symptoms in HCM. Further studies are needed to determine the long-term benefit of OSA treatment on hemodynamics and disease progression in HCM

Epigenetic and metabolic reprogramming of fibroblasts in Crohn's disease strictures reveals histone deacetylases as therapeutic targets.

BACKGROUND & AIMS: No effective therapeutic intervention exists for intestinal fibrosis in Crohn's disease [CD]. We characterised fibroblast subtypes, epigenetic and metabolic changes, and signalling pathways in CD fibrosis to inform future therapeutic strategies. METHODS: We undertook immunohistochemistry, metabolic, signalling pathway and Epigenetic [Transposase-Accessible Chromatin using sequencing] analyses associated with collagen production in CCD-18Co intestinal fibroblasts and primary fibroblasts isolated from stricturing [SCD] and non-stricturing [NSCD] CD small intestine. SCD/ NSCD fibroblasts were cultured with TGFβ and valproic acid [VPA]. RESULTS: Stricturing CD was characterised by distinct histone deacetylase [HDAC] expression profiles, particularly HDAC1, HDAC2, and HDAC7. As a proxy for HDAC activity, reduced numbers of H3K27ac+ cells were found in SCD compared to NSCD sections. Primary fibroblasts had increased extracellular lactate [increased glycolytic activity] and intracellular hydroxyproline [increased collagen production] in SCD compared to NSCD cultures. The metabolic effect of TGFβ-stimulation was reversed by the HDAC inhibitor VPA. SCD fibroblasts appear "metabolically primed" and responded more strongly to both TGFβ and VPA. Treatment with VPA revealed TGFβ-dependent and independent Collagen-I production in CCD-18Co cells and primary fibroblasts. VPA altered the epigenetic landscape with reduced chromatin accessibility at the COL1A1 and COL1A2 promoters. CONCLUSIONS: Increased HDAC expression profiles, H3K27ac hypoacetylation, a significant glycolytic phenotype, and metabolic priming, characterise SCD-derived as compared to NSCD fibroblasts. Our results reveal a novel epigenetic component to Collagen-I regulation and TGFβ-mediated CD fibrosis. HDAC inhibitor therapy may 'reset' the epigenetic changes associated with fibrosis

Prospective Evaluation of Transseptal TMVR for Failed Surgical Bioprostheses: MITRAL Trial Valve-in-Valve Arm 1-Year Outcomes

OBJECTIVES: The aim of this study was to assess 1-year clinical outcomes among high-risk patients with failed surgical mitral bioprostheses who underwent transseptal mitral valve-in-valve (MViV) with the SAPIEN 3 aortic transcatheter heart valve (THV) in the MITRAL (Mitral Implantation of Transcatheter Valves) trial. BACKGROUND: The MITRAL trial is the first prospective study evaluating transseptal MViV with the SAPIEN 3 aortic THV in high-risk patients with failed surgical mitral bioprostheses. METHODS: High-risk patients with symptomatic moderate to severe or severe mitral regurgitation (MR) or severe mitral stenosis due to failed surgical mitral bioprostheses were prospectively enrolled. The primary safety endpoint was technical success. The primary THV performance endpoint was absence of MR grade ≥2+ or mean mitral valve gradient ≥10 mm Hg (30 days and 1 year). Secondary endpoints included procedural success and all-cause mortality (30 days and 1 year). RESULTS: Thirty patients were enrolled between July 2016 and October 2017 (median age 77.5 years [interquartile range (IQR): 70.3 to 82.8 years], 63.3% women, median Society of Thoracic Surgeons score 9.4% [IQR: 5.8% to 12.0%], 80% in New York Heart Association functional class III or IV). The technical success rate was 100%. The primary performance endpoint in survivors was achieved in 96.6% (28 of 29) at 30 days and 82.8% (24 of 29) at 1 year. Thirty-day all-cause mortality was 3.3% and was unchanged at 1 year. The only death was due to airway obstruction after swallowing several pills simultaneously 29 days post-MViV. At 1-year follow-up, 89.3% of patients were in New York Heart Association functional class I or II, the median mean mitral valve gradient was 6.6 mm Hg (interquartile range: 5.5 to 8.9 mm Hg), and all patients had MR grade ≤1+. CONCLUSIONS: Transseptal MViV in high-risk patients was associated with 100% technical success, low procedural complication rates, and very low mortality at 1 year. The vast majority of patients experienced significant symptom alleviation, and THV performance remained stable at 1 year

Prospective Evaluation of TMVR for Failed Surgical Annuloplasty Rings: MITRAL Trial Valve-in-Ring Arm 1-Year Outcomes

OBJECTIVES: The authors report 1-year outcomes of high-risk patients with failed surgical annuloplasty rings undergoing transseptal mitral valve-in-ring (MViR) with the SAPIEN 3 aortic transcatheter heart valve (THV). BACKGROUND: The MITRAL (Mitral Implantation of Transcatheter Valves) trial is the first prospective study evaluating transseptal MViR with the SAPIEN 3 aortic THV in high-risk patients with failed surgical annuloplasty rings. METHODS: Prospective enrollment of high-risk patients with symptomatic moderate to severe or severe mitral regurgitation (MR) or severe mitral stenosis and failed annuloplasty rings at 13 U.S. sites. The primary safety endpoint was technical success. The primary THV performance endpoint was absence of MR grade ≥2+ or mean mitral valve gradient ≥10 mm Hg (30 days and 1 year). Secondary endpoints included procedural success and all-cause mortality (30 days and 1 year). RESULTS: Thirty patients were enrolled between January 2016 and October 2017 (median age 71.5 years [interquartile range: 67.0 to 76.8 years], 36.7% women, median Society of Thoracic Surgeons score 7.6% [interquartile range: 5.1% to 11.8%], 76.7% in New York Heart Association functional class III or IV). Technical success was 66.7% (driven primarily by need for a second valve in 6 patients). There was no intraprocedural mortality or conversion to surgery. The primary performance endpoint was achieved in 85.7% of survivors at 30 days (24 of 28) and 89.5% of patients alive at 1 year with echocardiographic data available (17 of 19). All-cause mortality at 30 days was 6.7% and at 1 year was 23.3%. Among survivors at 1-year follow-up, 84.2% were in New York Heart Association functional class I or II, the median mean mitral valve gradient was 6.0 mm Hg (interquartile range: 4.7 to 7.3 mm Hg), and all had ≤1+ MR. CONCLUSIONS: Transseptal MViR was associated with a 30-day mortality rate lower than predicted by the Society of Thoracic Surgeons score. At 1 year, transseptal MViR was associated with symptom improvement and stable THV performance

Prospective Study of TMVR Using Balloon-Expandable Aortic Transcatheter Valves in MAC: MITRAL Trial 1-Year Outcomes

OBJECTIVES: The aim of this study was to evaluate 1-year outcomes of valve-in-mitral annular calcification (ViMAC) in the MITRAL (Mitral Implantation of Transcatheter Valves) trial. BACKGROUND: The MITRAL trial is the first prospective study evaluating the feasibility of ViMAC using balloon-expandable aortic transcatheter heart valves. METHODS: A multicenter prospective study was conducted, enrolling high-risk surgical patients with severe mitral annular calcification and symptomatic severe mitral valve dysfunction at 13 U.S. sites. RESULTS: Between February 2015 and December 2017, 31 patients were enrolled (median age 74.5 years [interquartile range (IQR): 71.3 to 81.0 years], 71% women, median Society of Thoracic Surgeons score 6.3% [IQR: 5.0% to 8.8%], 87.1% in New York Heart Association functional class III or IV). Access was transatrial (48.4%), transseptal (48.4%), or transapical (3.2%). Technical success was 74.2%. Left ventricular outflow tract obstruction (LVOTO) with hemodynamic compromise occurred in 3 patients (transatrial, n = 1; transseptal, n = 1; transapical, n = 1). After LVOTO occurred in the first 2 patients, pre-emptive alcohol septal ablation was implemented to decrease risk in high-risk patients. No intraprocedural deaths or conversions to open heart surgery occurred during the index procedures. All-cause mortality at 30 days was 16.7% (transatrial, 21.4%; transseptal, 6.7%; transapical, 100% [n = 1]; p = 0.33) and at 1 year was 34.5% (transatrial, 38.5%; transseptal, 26.7%; p = 0.69). At 1-year follow-up, 83.3% of patients were in New York Heart Association functional class I or II, the median mean mitral valve gradient was 6.1 mm Hg (IQR: 5.6 to 7.1 mm Hg), and all patients had ≤1+ mitral regurgitation. CONCLUSIONS: At 1 year, ViMAC was associated with symptom improvement and stable transcatheter heart valve performance. Pre-emptive alcohol septal ablation may prevent transcatheter mitral valve replacement-induced LVOTO in patients at risk. Thirty-day mortality of patients treated via transseptal access was lower than predicted by the Society of Thoracic Surgeons score. Further studies are needed to evaluate safety and efficacy of ViMAC

Design, Analysis and Testing of a Novel Mitral Valve for Transcatheter Implantation

Mitral regurgitation is a common mitral valve dysfunction which may lead to heart failure. Because of the rapid aging of the population, conventional surgical repair and replacement of the pathological valve are often unsuitable for about half of symptomatic patients, who are judged high-risk. Transcatheter valve implantation could represent an effective solution. However, currently available aortic valve devices are inapt for the mitral position. This paper presents the design, development and hydrodynamic assessment of a novel bi-leaflet mitral valve suitable for transcatheter implantation. The device consists of two leaflets and a sealing component made from bovine pericardium, supported by a self-expanding wireframe made from superelastic NiTi alloy. A parametric design procedure based on numerical simulations was implemented to identify design parameters providing acceptable stress levels and maximum coaptation area for the leaflets. The wireframe was designed to host the leaflets and was optimised numerically to minimise the stresses for crimping in an 8 mm sheath for percutaneous delivery. Prototypes were built and their hydrodynamic performances were tested on a cardiac pulse duplicator, in compliance with the ISO5840-3:2013 standard. The numerical results and hydrodynamic tests show the feasibility of the device to be adopted as a transcatheter valve implant for treating mitral regurgitation