A Randomized Control Study in Healthy Adult Smokers to Assess Reduced Exposure to Selected Cigarette Smoke Constituents in Switching to the Novel Heated Tobacco Product DT3.0a.

This was a randomized, controlled, open-label, confinement study to assess change in exposure to selected cigarette smoke constituents in healthy adult cigarette smokers who switched to using a novel heated tobacco product (direct heating tobacco system, platform 3, generation 3, version a [DT3.0a]). Sixty nonmenthol cigarette smokers were randomized into 1 of the 4 study groups in which subjects switched to a nonmenthol type of tobacco stick used with DT3.0a, switched to a nonmenthol tobacco stick used with an in-market heated tobacco product device (THS), continued to smoke nonmenthol cigarettes, or stopped smoking. Furthermore, 30 menthol cigarette smokers were randomized into 1 of the 2 study groups in which subjects switched to a menthol tobacco stick used with DT3.0a (mDT3.0a) or continued to smoke menthol cigarettes. Fifteen biomarkers of exposure to selected harmful and potentially harmful constituents (HPHCs) were measured during the 5-day exposure period, followed by assessment of nicotine pharmacokinetics with the assigned product. Results indicated that switching to DT3.0a, THS, and mDT3.0a showed significant exposure reductions in most of the selected HPHCs as compared to continuing smoking cigarettes, with reductions being similar in magnitude to reductions observed with smoking cessation. For DT3.0a and mDT3.0a, nicotine pharmacokinetic parameters were not remarkably different from those obtained for cigarettes and the THS except that a longer time to maximum concentration was obtained following use of the mDT3.0a. In conclusion, switching from smoking cigarettes to DT3.0a or THS use reduced exposure to most of the selected HPHCs, and no remarkable differences were observed for the measurements obtained from different flavors of DT3.0a stick.

Left ventricular fibrosis and CMR tissue characterization of papillary muscles in mitral valve prolapse patients.

PURPOSE: Mitral valve prolapse (MVP) is associated with left ventricle (LV) fibrosis, including the papillary muscles (PM), which is in turn linked to malignant arrhythmias. This study aims to evaluate comprehensive tissue characterization of the PM by cardiovascular magnetic resonance (CMR) imaging and its association with LV fibrosis observed by intraoperative biopsies. METHODS: MVP patients with indication for surgery due to severe mitral regurgitation (n = 19) underwent a preoperative CMR with characterization of the PM: dark-appearance on cine, T1 mapping, conventional bright blood (BB) and dark blood (DB) late gadolinium enhancement (LGE). CMR T1 mapping was performed on 21 healthy volunteers as controls. LV inferobasal myocardial biopsies were obtained in MVP patients and compared to CMR findings. RESULTS: MVP patients (54 ± 10 years old, 14 male) had a dark-appearance of the PM with higher native T1 and extracellular volume (ECV) values compared with healthy volunteers (1096 ± 78ms vs. 994 ± 54ms and 33.9 ± 5.6% vs. 25.9 ± 3.1%, respectively, p < 0.001). Seventeen MVP patients (89.5%) had fibrosis by biopsy. BB-LGE + in LV and PM was identified in 5 (26.3%) patients, while DB-LGE + was observed in LV in 9 (47.4%) and in PM in 15 (78.9%) patients. DB-LGE + in PM was the only technique that showed no difference with detection of LV fibrosis by biopsy. Posteromedial PM was more frequently affected than the anterolateral (73.7% vs. 36.8%, p = 0.039) and correlated with biopsy-proven LV fibrosis (Rho 0.529, p = 0.029). CONCLUSIONS: CMR imaging in MVP patients referred for surgery shows a dark-appearance of the PM with higher T1 and ECV values compared with healthy volunteers. The presence of a positive DB-LGE at the posteromedial PM by CMR may serve as a better predictor of biopsy-proven LV inferobasal fibrosis than conventional CMR techniques.

Prognostic value of the right ventricular ejection fraction using three-dimensional echocardiography: Systematic review and meta-analysis.

AIMS: Three-dimensional echocardiography (3DE) is a robust method for measuring the right ventricular (RV) ejection fraction (EF), which is closely associated with outcomes. We performed a systematic review and meta-analysis (1) to examine the prognostic value of RVEF and (2) to compare its prognostic value with that of left ventricular (LV) EF and LV global longitudinal strain (GLS). We also performed individual patient data analysis to validate the results. METHODS AND RESULTS: We searched articles reporting the prognostic value of RVEF. Hazard ratios (HR) were re-scaled using the within-study standard deviation (SD). To compare predictive values of RVEF and LVEF or LVGLS, the ratio of HR related to a 1-SD reduction of RVEF versus LVEF or LVGLS was calculated. Pooled HR of RVEF and pooled ratio of HR were analyzed in a random-effects model. Fifteen articles with 3,228 subjects were included. Pooled HR of a 1-SD reduction of RVEF was 2.54 (95% confidence interval (CI): 2.15-3.00). In subgroup analysis, RVEF was significantly associated with outcome in pulmonary arterial hypertension (PAH) (HR: 2.79, 95% CI: 2.04-3.82) and cardiovascular (CV) diseases (HR: 2.23, 95%CI: 1.76-2.83). In studies reporting HRs for both RVEF and LVEF or RVEF and LVGLS in the same cohort, RVEF had 1.8-fold greater prognostic power per 1-SD reduction than LVEF (ratio of HR: 1.81, 95%CI: 1.20-2.71), but had predictive value similar to that of LVGLS (ratio of HR: 1.10, 95%CI: 0.91-1.31) and to LVEF in patients with reduced LVEF (ratio of HR: 1.34, 95%CI: 0.94-1.91). In individual patient data analysis (n = 1,142), RVEF < 45% was significantly associated with worse CV outcome (HR: 4.95, 95% CI: 3.66-6.70), even in patients with reduced or preserved LVEF. CONCLUSIONS: The findings of this meta-analysis highlight and support the use of RVEF assessed by 3DE to predict CV outcomes in routine clinical practice in patients with CV diseases and in those with PAH.

Left Ventricular Fibrosis and CMR Tissue Characterization of Papillary Muscles in Mitral Valve Prolapse Patients.

Purpose: Mitral valve prolapse (MVP) is associated with left ventricle (LV) fibrosis, including the papillary muscles (PM), which is in turn linked to malignant arrhythmias. This study aims to evaluate comprehensive tissue characterization of the PM by cardiovascular magnetic resonance (CMR) imaging and its association with LV fibrosis observed by intraoperative biopsies. Methods: MVP patients with indication for surgery due to severe mitral regurgitation (n=19) underwent a preoperative CMR with characterization of the PM: dark-appearance on cine, T1 mapping, conventional bright blood (BB) and dark blood (DB) late gadolinium enhancement (LGE). CMR T1 mapping was performed on 21 healthy volunteers as controls. LV inferobasal myocardial biopsies were obtained in MVP patients and compared to CMR findings. Results: MVP patients (54±10 years old, 14 male) had a dark-appearance of the PM with higher native T1 and extracellular volume (ECV) values compared with healthy volunteers (1096±78ms vs 994±54ms and 33.9±5.6% vs 25.9±3.1%, respectively, p<0.001). Seventeen MVP patients (89.5%) had fibrosis by biopsy. BB-LGE+ in LV and PM was identified in 5 (26.3%) patients, while DB-LGE+ was observed in LV in 9 (47.4%) and in PM in 15 (78.9%) patients. DB-LGE+ in PM was the only technique that showed no difference with detection of LV fibrosis by biopsy. Posteromedial PM was more frequently affected than the anterolateral (73.7% vs 36.8%, p=0.039) and correlated with biopsy-proven LV fibrosis (Rho 0.529, p=0.029). Conclusions: CMR imaging in MVP patients referred for surgery shows a dark-appearance of the PM with higher T1 and ECV values compared with healthy volunteers. The presence of a positive DB-LGE at the posteromedial PM by CMR may serve as a better predictor of biopsy-proven LV inferobasal fibrosis than conventional CMR techniques.

Utilization of Engineering Advances for Detailed Biomechanical Characterization of the Mitral-Ventricular Relationship to Optimize Repair Strategies: A Comprehensive Review.

The geometrical details and biomechanical relationships of the mitral valve-left ventricular apparatus are very complex and have posed as an area of research interest for decades. These characteristics play a major role in identifying and perfecting the optimal approaches to treat diseases of this system when the restoration of biomechanical and mechano-biological conditions becomes the main target. Over the years, engineering approaches have helped to revolutionize the field in this regard. Furthermore, advanced modelling modalities have contributed greatly to the development of novel devices and less invasive strategies. This article provides an overview and narrative of the evolution of mitral valve therapy with special focus on two diseases frequently encountered by cardiac surgeons and interventional cardiologists: ischemic and degenerative mitral regurgitation.

Atrial Dysfunction in Significant Atrial Functional Mitral Regurgitation: Phenotypes and Prognostic Implications.

BACKGROUND: Atrial functional mitral regurgitation (AFMR) is associated with increased morbidity and mortality. Left atrial (LA) size and function in AFMR are poorly characterized. We aimed to assess LA function by reservoir strain (LASr) and estimated reservoir work (LAWr) and their impact on outcome in AFMR. METHODS: Consecutive patients at our institution between 2001 and 2019 and with significant (moderate or greater) AFMR were examined. LAWr was estimated as LASr×LA reservoir volume, and patients were grouped by median LASr and LAWr. Outcomes were all-cause death or heart failure hospitalizations. RESULTS: Five hundred fifteen AFMR patients were followed up for 5 (1-17) years. Patients had previously documented atrial fibrillation (AF; 37%), heart failure with preserved ejection fraction (HFpEF) without AF (24%), or both (HFpEF+AF, 39%). LA volume was largest in AF, while LA function parameters were most impaired in the combined HFpEF+AF group. During follow-up, patients with low LASr or LAWr had higher risk of death (P<0.001) and heart failure hospitalization (P<0.05). In Cox regression analyses, low LASr and LAWr, but not LA volume or left ventricular function, were associated with a higher risk of death (LASr: hazard ratio, 2.3 [95% CI, 1.6-3.5]; LAWr: hazard ratio, 3.4 [95% CI, 2.4-4.9]; both P<0.001) after adjustment for clinical and echocardiographic confounders. Low LASr and LAWr were strongest associated with death in HFpEF and HFpEF+AF. CONCLUSIONS: LA reservoir function but not LA size is a robust predictor of outcome in significant AFMR. This provides mechanistic insights into the interplay of functional versus geometric LA changes in AFMR.

Abnormal Mechanics Relate to Myocardial Fibrosis and Ventricular Arrhythmias in Patients With Mitral Valve Prolapse.

BACKGROUND: The relation between ventricular arrhythmia and fibrosis in mitral valve prolapse (MVP) is reported, but underlying valve-induced mechanisms remain unknown. We evaluated the association between abnormal MVP-related mechanics and myocardial fibrosis, and their association with arrhythmia. METHODS: We studied 113 patients with MVP with both echocardiogram and gadolinium cardiac magnetic resonance imaging for myocardial fibrosis. Two-dimensional and speckle-tracking echocardiography evaluated mitral regurgitation, superior leaflet and papillary muscle displacement with associated exaggerated basal myocardial systolic curling, and myocardial longitudinal strain. Follow-up assessed arrhythmic events (nonsustained or sustained ventricular tachycardia or ventricular fibrillation). RESULTS: Myocardial fibrosis was observed in 43 patients with MVP, predominantly in the basal-midventricular inferior-lateral wall and papillary muscles. Patients with MVP with fibrosis had greater mitral regurgitation, prolapse, and superior papillary muscle displacement with basal curling and more impaired inferior-posterior basal strain than those without fibrosis (P<0.001). An abnormal strain pattern with distinct peaks pre-end-systole and post-end-systole in inferior-lateral wall was frequent in patients with fibrosis (81 versus 26%, P<0.001) but absent in patients without MVP with basal inferior-lateral wall fibrosis (n=20). During median follow-up of 1008 days, 36 of 87 patients with MVP with >6-month follow-up developed ventricular arrhythmias associated (univariable) with fibrosis, greater prolapse, mitral annular disjunction, and double-peak strain. In multivariable analysis, double-peak strain showed incremental risk of arrhythmia over fibrosis. CONCLUSIONS: Basal inferior-posterior myocardial fibrosis in MVP is associated with abnormal MVP-related myocardial mechanics, which are potentially associated with ventricular arrhythmia. These associations suggest pathophysiological links between MVP-related mechanical abnormalities and myocardial fibrosis, which also may relate to ventricular arrhythmia and offer potential imaging markers of increased arrhythmic risk.

Sex Differences in Extensive Mitral Annular Calcification With Associated Mitral Valve Dysfunction.

Mitral annular calcification (MAC)-related mitral valve (MV) dysfunction is an increasingly recognized entity, which confers a high burden of morbidity and mortality. Although more common among women, there is a paucity of data regarding how the phenotype of MAC and the associated adverse clinical implications may differ between women and men. A total of 3,524 patients with extensive MAC and significant MAC-related MV dysfunction (i.e., transmitral gradient ≥3 mm Hg) were retrospectively analyzed from a large institutional database, with the goal of defining gender differences in clinical and echocardiographic characteristics and the prognostic importance of MAC-related MV dysfunction. We stratified patients into low- (3 to 5 mm Hg), moderate- (5 to 10 mm Hg), and high- (≥10 mm Hg) gradient groups and analyzed the gender differences in phenotype and outcome. The primary outcome was all-cause mortality, assessed using adjusted Cox regression models. Women represented the majority (67%) of subjects, were older (79.3 ± 10.4 vs 75.5 ± 10.9 years, p <0.001) and had a lower burden of cardiovascular co-morbidities than men. Women had higher transmitral gradients (5.7 ± 2.7 vs 5.3 ± 2.6 mm Hg, p <0.001), more concentric hypertrophy (49% vs 33%), and more mitral regurgitation. The median survival was 3.4 years (95% confidence interval 3.0 to 3.6) among women and 3.0 years (95% confidence interval 2.6 to 4.5) among men. The adjusted survival was worse among men, and the prognostic impact of the transmitral gradient did not differ overall by gender. In conclusion, we describe important gender differences among patients with MAC-related MV dysfunction and show worse adjusted survival among men; although, the adverse prognostic impact of the transmitral gradient was similar between men and women.

Left atrial function and not volume predicts mid-to-late atrial fibrillation after mitral valve repair.

OBJECTIVES: Patients undergoing surgical mitral valve repair (MVr) for degenerative mitral regurgitation are at risk of even late postoperative atrial fibrillation (AF). Left atrial (LA) function has been shown superior to LA volume in evaluating the risk of AF in diverse cardiac conditions. We therefore investigated the prognostic value of LA function and volume in predicting mid-to-late postoperative AF after MVr (>30 days postoperatively). METHODS: We retrospectively identified all patients who underwent MVr for degenerative mitral regurgitation between 2012 and 2019 at our institution. Exclusion criteria were preoperative AF, concomitant procedures, re-operations, missing or insufficiently processable preoperative echocardiograms and missing follow-up. LA function and volume measurements were conducted using speckle-tracking strain echocardiographic analysis. Postoperative LA function was measured in a subgroup with sufficient postoperative echocardiograms. RESULTS: We included 251 patients, of whom 39 (15.5%) experienced AF in the mid-to-late postoperative period. Reduced LA strain parameters and more than mild preoperative tricuspid regurgitation were independently associated with mid-to-late postoperative AF. LA volume index had no association with mid-to-late postoperative AF in univariable analysis and did not improve the performance of multivariable models. Patients with mid-to-late AF exhibited diminished improvement in LA function after surgery. CONCLUSIONS: In MVr patients, LA function (but not volume) showed independent predictive value for mid-to-late postoperative AF. Including LA function into surgical decision-making and approach may identify patients who will benefit from earlier intervention with the aim to prevent irreversible LA damage with consequent risk of postoperative AF.

Native and Post-Repair Residual Mitral Valve Prolapse Increases Forces Exerted on the Papillary Muscles: A Possible Mechanism for Localized Fibrosis?

BACKGROUND: Recent studies have linked mitral valve prolapse to localized myocardial fibrosis, ventricular arrhythmia, and even sudden cardiac death independent of mitral regurgitation or hemodynamic dysfunction. The primary mechanistic theory is rooted in increased papillary muscle traction and forces due to prolapse, yet no biomechanical evidence exists showing increased forces. Our objective was to evaluate the biomechanical relationship between prolapse and papillary muscle forces, leveraging advances in ex vivo modeling and technologies. We hypothesized that mitral valve prolapse with limited hemodynamic dysfunction leads to significantly higher papillary muscle forces, which could be a possible trigger for cellular and electrophysiological changes in the papillary muscles and adjacent myocardium. METHODS: We developed an ex vivo papillary muscle force transduction and novel neochord length adjustment system capable of modeling targeted prolapse. Using 3 unique ovine models of mitral valve prolapse (bileaflet or posterior leaflet prolapse), we directly measured hemodynamics and forces, comparing physiologic and prolapsing valves. RESULTS: We found that bileaflet prolapse significantly increases papillary muscle forces by 5% to 15% compared with an optimally coapting valve, which are correlated with statistically significant decreases in coaptation length. Moreover, we observed significant changes in the force profiles for prolapsing valves when compared with normal controls. CONCLUSIONS: We discovered that bileaflet prolapse with the absence of hemodynamic dysfunction results in significantly elevated forces and altered dynamics on the papillary muscles. Our work suggests that the sole reduction of mitral regurgitation without addressing reduced coaptation lengths and thus increased leaflet surface area exposed to ventricular pressure gradients (ie, billowing leaflets) is insufficient for an optimal repair.

Assessment of the exposure to selected smoke constituents in adult smokers using in-market heated tobacco products: a randomized, controlled study.

The objectives of this clinical study were to demonstrate a reduction in exposure to selected harmful and potentially harmful constituents (HPHCs) in Japanese healthy adult smokers who switched to four in-market heated tobacco products. Eighty-nine smokers were randomly assigned for five days to one of six study groups: four groups who switched to one of the commercially available heated tobacco products; a group who continued to smoke their own brand of combustible cigarettes (CC); or a group who stopped smoking (SS). Fifteen biomarkers of exposure (BoE) to 14 HPHCs and pyrene were measured at baseline, Day 3 and Day 5 in 24 h urine and breath, under clinical confinement. Product consumption, nicotine uptake and subjective effects were also measured before and after product switching. On Day 5, significant reductions in most BoE relative to the CC group were observed after switching to heated tobacco products. No changes in BoE were observed between baseline and Day 5 in the CC group. Significantly, the magnitude of the reduction in exposure to most of the selected HPHCs observed in the heated tobacco product groups was close to that observed in the SS group.

A soft robotic sleeve mimicking the haemodynamics and biomechanics of left ventricular pressure overload and aortic stenosis.

Preclinical models of aortic stenosis can induce left ventricular pressure overload and coarsely control the severity of aortic constriction. However, they do not recapitulate the haemodynamics and flow patterns associated with the disease. Here we report the development of a customizable soft robotic aortic sleeve that can mimic the haemodynamics and biomechanics of aortic stenosis. By allowing for the adjustment of actuation patterns and blood-flow dynamics, the robotic sleeve recapitulates clinically relevant haemodynamics in a porcine model of aortic stenosis, as we show via in vivo echocardiography and catheterization studies, and a combination of in vitro and computational analyses. Using in vivo and in vitro magnetic resonance imaging, we also quantified the four-dimensional blood-flow velocity profiles associated with the disease and with bicommissural and unicommissural defects re-created by the robotic sleeve. The design of the sleeve, which can be adjusted on the basis of computed tomography data, allows for the design of patient-specific devices that may guide clinical decisions and improve the management and treatment of patients with aortic stenosis.

Malignant Mitral Valve Prolapse: Risk and Prevention of Sudden Cardiac Death.

Purpose of review: The purpose of this review is to explore the prevalence and risk factors for a malignant phenotype in mitral valve prolapse (MVP) characterized by life-threatening ventricular arrhythmias and sudden cardiac arrest and death (SCD), including mechanistic and pathophysiologic findings and mechanism-based potential therapies. Recent findings: A malignant phenotype in MVP characterized by life-threatening arrhythmias has long been recognized, although MVP is often benign. Efforts to identify this malignant phenotype have revealed potential risk factors for SCD that include elongated, myxomatous leaflets, ECG changes and complex ventricular ectopy. More recently, malignant MVP has been associated with myocardial fibrosis in the papillary muscles and inferobasal left ventricular wall. This localization suggests a central role of prolapse-induced mechanical forces on the myocardium in creating an arrhythmogenic substrate and triggering life-threatening arrhythmias. This mechanism for fibrosis is also consistent with imaging evidence of prolapse-induced mechanical changes in the papillary muscles and inferobasal left ventricular wall. Currently, no therapy to prevent SCD in malignant MVP has been established and limited clinical data are available. Mechanistic information and prospective study have the potential to identify patients at risk of SCD and preventive strategies. Summary: Malignant MVP relates to unique properties and mechanical abnormalities in the mitral valve apparatus and adjacent myocardium. Increased understanding of disease mechanisms and determinants of arrhythmias is needed to establish effective therapies.

Wnt Site Signaling Inhibitor Secreted Frizzled-Related Protein 3 Protects Mitral Valve Endothelium From Myocardial Infarction-Induced Endothelial-to-Mesenchymal Transition.

Background The onset and mechanisms of endothelial-to-mesenchymal transition (EndMT) in mitral valve (MV) leaflets following myocardial infarction (MI) are unknown, yet these events are closely linked to stiffening of leaflets and development of ischemic mitral regurgitation. We investigated whether circulating molecules present in plasma within days after MI incite EndMT in MV leaflets. Methods and Results We examined the onset of EndMT in MV leaflets from 9 sheep with inferior MI, 8 with sham surgery, and 6 naïve controls. Ovine MVs 8 to 10 days after inferior MI displayed EndMT, shown by increased vascular endothelial cadherin/α-smooth muscle actin-positive cells. The effect of plasma on EndMT in MV endothelial cells (VECs) was assessed by quantitative polymerase chain reaction, migration assays, and immunofluorescence. In vitro, post-MI plasma induced EndMT marker expression and enhanced migration of mitral VECs; sham plasma did not. Analysis of sham versus post-MI plasma revealed a significant drop in the Wnt signaling antagonist sFRP3 (secreted frizzled-related protein 3) in post-MI plasma. Addition of recombinant sFRP3 to post-MI plasma reversed its EndMT-inducing effect on mitral VECs. RNA-sequencing analysis of mitral VECs exposed to post-MI plasma showed upregulated FOXM1 (forkhead box M1). Blocking FOXM1 reduced EndMT transcripts in mitral VECs treated with post-MI plasma. Finally, FOXM1 induced by post-MI plasma was downregulated by sFRP3. Conclusions Reduced sFRP3 in post-MI plasma facilitates EndMT in mitral VECs by increasing the transcription factor FOXM1. Restoring sFRP3 levels or inhibiting FOXM1 soon after MI may provide a novel strategy to modulate EndMT in the MV to prevent ischemic mitral regurgitation and heart failure.

Impact of Pulmonary Hypertension on Outcomes in Patients With Mitral Annular Calcium and Associated Mitral Valve Dysfunction.

The prevalence of mitral annular calcium (MAC) is increasing in our aging population. However, data regarding prognostication in MAC-related mitral valve (MV) disease remain limited. This retrospective observational study aims to explore the prognostic impact of systolic pulmonary artery pressure (SPAP) in MAC-related MV dysfunction and define its determinants. We identified 4,384 patients (mean age 78 ± 11 years and 69% female) with MAC-related MV dysfunction (documented transmitral gradient ≥3 mm Hg) from a large institutional echocardiographic database between 2001 and 2019. In Cox regression analysis, higher SPAP strongly associated with all-cause mortality, independent of cardiovascular risk factors and indices of MV dysfunction (adjusted hazard ratio 1.22 per 10 mm Hg SPAP increase, 95% confidence interval 1.17 to 1.27). Patients with SPAP ≥50 mm Hg had significantly higher mortality compared with SPAP <50 mm Hg (log-rank p <0.001), a finding that was consistent across different transmitral gradient subgroups (≤5, 5 to 10, and ≥10 mm Hg). Independent determinants of SPAP included the mean transmitral gradient, mitral regurgitation severity, left ventricular ejection fraction, and ≥moderate aortic stenosis (adjusted p <0.05), and atrial fibrillation and left atrial dimension. The impact of concomitant mitral regurgitation on SPAP decreased at higher transmitral gradients and was no longer significant at gradients ≥10 mm Hg (p = 0.100). In conclusion, SPAP strongly associates with mortality in MAC, independent of cardiovascular risk factors and indices of MAC-related MV dysfunction. These findings suggest an incremental role for SPAP in the risk stratification and prognostication in this increasingly prevalent condition with expanding the scope of possible interventions.

Mitral Valve Prolapse Induces Regionalized Myocardial Fibrosis.

Background Mitral valve prolapse (MVP) is one of the most common forms of cardiac valve disease and affects 2% to 3% of the population. Previous imaging reports have indicated that myocardial fibrosis is common in MVP and described its association with sudden cardiac death. These data combined with evidence for postrepair ventricular dysfunction in surgical patients with MVP support a link between fibrosis and MVP. Methods and Results We performed histopathologic analysis of left ventricular (LV) biopsies from peripapillary regions, inferobasal LV wall and apex on surgical patients with MVP, as well as in a mouse model of human MVP (Dzip1S14R/+). Tension-dependent molecular pathways were subsequently assessed using both computational modeling and cyclical stretch of primary human cardiac fibroblasts in vitro. Histopathology of LV biopsies revealed regionalized fibrosis in the peripapillary myocardium that correlated with increased macrophages and myofibroblasts. The MVP mouse model exhibited similar regional increases in collagen deposition that progress over time. As observed in the patient biopsies, increased macrophages and myofibroblasts were observed in fibrotic areas within the murine heart. Computational modeling revealed tension-dependent profibrotic cellular and molecular responses consistent with fibrosis locations related to valve-induced stress. These simulations also identified mechanosensing primary cilia as involved in profibrotic pathways, which was validated in vitro and in human biopsies. Finally, in vitro stretching of primary human cardiac fibroblasts showed that stretch directly activates profibrotic pathways and increases extracellular matrix protein production. Conclusions The presence of prominent regional LV fibrosis in patients and mice with MVP supports a relationship between MVP and progressive damaging effects on LV structure before overt alterations in cardiac function. The regionalized molecular and cellular changes suggest a reactive response of the papillary and inferobasal myocardium to increased chordal tension from a prolapsing valve. These studies raise the question whether surgical intervention on patients with MVP should occur earlier than indicated by current guidelines to prevent advanced LV fibrosis and potentially reduce residual risk of LV dysfunction and sudden cardiac death.

Integration of Functional Imaging, Cytometry, and Unbiased Proteomics Reveals New Features of Endothelial-to-Mesenchymal Transition in Ischemic Mitral Valve Regurgitation in Human Patients.

Background: Following myocardial infarction, mitral regurgitation (MR) is a common complication. Previous animal studies demonstrated the association of endothelial-to-mesenchymal transition (EndMT) with mitral valve (MV) remodeling. Nevertheless, little is known about how MV tissue responds to ischemic heart changes in humans. Methods: MVs were obtained by the Cardiothoracic Surgical Trials Network from 17 patients with ischemic mitral regurgitation (IMR). Echo-doppler imaging assessed MV function at time of resection. Cryosections of MVs were analyzed using a multi-faceted histology and immunofluorescence examination of cell populations. MVs were further analyzed using unbiased label-free proteomics. Echo-Doppler imaging, histo-cytometry measures and proteomic analysis were then integrated. Results: MVs from patients with greater MR exhibited proteomic changes associated with proteolysis-, inflammatory- and oxidative stress-related processes compared to MVs with less MR. Cryosections of MVs from patients with IMR displayed activated valvular interstitial cells (aVICs) and double positive CD31+ αSMA+ cells, a hallmark of EndMT. Univariable and multivariable association with echocardiography measures revealed a positive correlation of MR severity with both cellular and geometric changes (e.g., aVICs, EndMT, leaflet thickness, leaflet tenting). Finally, proteomic changes associated with EndMT showed gene-ontology enrichment in vesicle-, inflammatory- and oxidative stress-related processes. This discovery approach indicated new candidate proteins associated with EndMT regulation in IMR. Conclusion: We describe an atypical cellular composition and distinctive proteome of human MVs from patients with IMR, which highlighted new candidate proteins implicated in EndMT-related processes, associated with maladaptive MV fibrotic remodeling.

Differences in Levels of Biomarkers of Potential Harm Among Users of a Heat-Not-Burn Tobacco Product, Cigarette Smokers, and Never-Smokers in Japan: A Post-Marketing Observational Study.

INTRODUCTION: Cigarette smoking is associated with the risk of certain diseases, but non-combustible products may lower these risks. The potential long-term health effects of the next-generation non-combustible products (heat-not-burn tobacco products (HNBP) or electronic vapor products) have not been thoroughly studied. The present study aimed to investigate the impact of biomarkers of potential harm (BoPH) of one of HNBP (a novel vapor product: NTV (novel tobacco vapor)), under the conditions of actual use. AIMS AND METHODS: This study was an observational, cross-sectional, three-group, multi-center study. Exclusive NTV users (NTV, n = 259), conventional cigarette smokers (CC, n = 100) and never-smokers (NS, n = 100) were enrolled. Biomarkers of tobacco smoke exposure (cotinine and total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)) and BoPH including parameters of physical pulmonary functions relevant to smoking-related diseases were examined, and subjects answered a questionnaire on cough-related symptoms (J-LCQ) and health-related quality of life (SF-36v2®). RESULTS: Levels of cotinine, total NNAL and BoPH (high-density lipoprotein (HDL)-cholesterol, triglyceride, sICAM-1, WBC count, 11-DHTXB2, 2,3-d-TXB2, 8-epi-PGF2α, forced expiratory volume in 1 second (FEV1), % predicted value of FEV1 (%FEV1) and maximum midexpiratory flow (FEF25-75)) were significantly different in the NTV group as compared to levels in CC group (p < .05). Significantly higher levels of cotinine, total NNAL, and 2,3-d-TXB2, and lower levels of FEV1 and %FEV1, were observed among NTV users compared to the NS group. CONCLUSION: In a post-marketing study under actual use conditions, BoPH associated with smoking-related disease examined in exclusive NTV users were found to be favorably different from those of CC smokers, a finding attributable to a reduction in exposure to harmful substances of tobacco smoke. IMPLICATIONS: Cigarette smoking is associated with an increased risk of pulmonary diseases like COPD, cardiovascular diseases, and certain cancers. There is a growing body of evidence that HNBP reduces the exposure associated with smoking and that there is a favorable change in BoPH. However, long-term effects regarding the relative health risks to HNBP users compared to CC smokers have not been examined. This study provides post-marketing data under actual use conditions of the effects on biomarkers of potential harm in NTV, one of HNBP, exclusive users compared to CC smokers and never-smokers. The evidence suggests that exclusive NTV users have favorable levels of BoPH compared to CC smokers, and that is result from a sustained reduction in exposure to harmful substances of tobacco smoke.

Prognostic importance of the transmitral pressure gradient in mitral annular calcification with associated mitral valve dysfunction.

AIMS: The aim of this study was to define the natural history of patients with mitral annular calcification (MAC)-related mitral valve dysfunction and to assess the prognostic importance of mean transmitral pressure gradient (MG) and impact of concomitant mitral regurgitation (MR). METHODS AND RESULTS: The institutional echocardiography database was examined from 2001 to 2019 for all patients with MAC and MG ≥3 mmHg. A total of 5754 patients were stratified by MG in low (3-5 mmHg, n = 3927), mid (5-10 mmHg, n = 1476), and high (≥10 mmHg, n = 351) gradient. The mean age was 78 ± 11 years, and 67% were female. MR was none/trace in 32%, mild in 42%, moderate in 23%, and severe in 3%. Primary outcome was all-cause mortality, and outcome models were adjusted for age, sex, and MAC-related risk factors (hypertension, diabetes, coronary artery disease, chronic kidney disease). Survival at 1, 5, and 10 years was 77%, 42%, and 18% in the low-gradient group; 73%, 38%, and 17% in the mid-gradient group; and 67%, 25%, and 11% in the high-gradient group, respectively (log-rank P < 0.001 between groups). MG was independently associated with mortality (adjusted HR 1.064 per 1 mmHg increase, 95% CI 1.049-1.080). MR severity was associated with mortality at low gradients (P < 0.001) but not at higher gradients (P = 0.166 and 0.372 in the mid- and high-gradient groups, respectively). CONCLUSION: In MAC-related mitral valve dysfunction, mean transmitral gradient is associated with increased mortality after adjustment for age, sex, and MAC-related risk factors. Concomitant MR is associated with excess mortality in low-gradient ranges (3-5 mmHg) but gradually loses prognostic importance at higher gradients, indicating prognostic utility of transmitral gradient in MAC regardless of MR severity.