Metabolic gene therapy in a canine with pulmonary hypertension secondary to degenerative mitral valve disease.

Myxomatous mitral valve disease (MMVD) stands out as the most prevalent acquired canine heart disease. Its occurrence can reach up to 40% in small breed dogs and escalates in geriatric canine populations. MMVD leads to thickening and incomplete coaptation of valve leaflets during systole, resulting in secondary mitral valve regurgitation. Serious complications may arise concurrently with the worsening of mitral valve regurgitation, including left-and right-sided congestive heart failure, and pulmonary hypertension (PH). Ultimately, the PH progression might contribute to the patient's demise or to the owner's decision of euthanasia. Most currently available FDA-approved therapies for PH are costly and aim to address the imbalance between vasoconstriction and vasodilation to restore endothelial cell function. However, none of these medications impact the molecular dysfunction of cells or impede the advancement of pulmonary vascular and right ventricular remodeling. Recent evidence has showcased successful gene therapy approaches in laboratory animal models of PH. In this manuscript, we summarize the latest advancements in gene therapy for the treatment of PH in animals. The manuscript incorporates original data showcasing sample presentations, along with non-invasive hemodynamic assessments. Our findings demonstrate that the use of metabolic gene therapy, combining synthetic adeno-associated virus with acid ceramidase, has the potential to significantly reduce the need for drug treatment and improve spontaneously occurring PH in dogs.

Feasibility and Exploration of a Standardized Protocol for Cardiac CT Assessment of Rheumatic Mitral Disease.

Rheumatic mitral valve disease often requires surgical interventions, such as percutaneous mitral commissurotomy, surgical mitral valve repair, or replacement, especially in severe cases. This necessitates a precise preoperative assessment of the extent of mitral valve disease. Currently, transthoracic echocardiography, the gold standard for preoperative assessment, has limitations, such as restricted acoustic windows and dependence on the operator, which can affect the evaluation of subvalvular structures and calcification of the mitral valve. Previous studies have shown that cardiac computed tomography (CT), with its high resolution, strong multiplanar reconstruction capabilities, and sensitivity to calcifications, can effectively overcome these limitations. Therefore, this study aims to summarize and evaluate the effectiveness of cardiac CT in examining mitral valve leaflets, annulus, and subvalvular structures. It also reviews the feasibility and guiding significance of using cardiac CT to assess characteristic rheumatic mitral valve lesions.

5-Year Outcomes of Anterior Mitral Leaflet Laceration to Prevent Outflow Obstruction.

BACKGROUND: Left ventricular outflow tract (LVOT) obstruction is a common, often fatal complication of transcatheter mitral valve replacement (TMVR). Laceration of the anterior mitral leaflet to prevent outflow obstruction (LAMPOON) was safe and effective at preventing LVOT obstruction at 30 days in the National Heart, Lung, and Blood Institute LAMPOON trial. OBJECTIVES: The authors report the 5-year outcomes of intentional anterior mitral leaflet laceration before SAPIEN 3 TMVR, in patients at risk of LVOT obstruction. METHODS: The National Heart, Lung, and Blood Institute LAMPOON trial was a prospective, multicenter, single-arm safety and feasibility study of LAMPOON and transseptal SAPIEN 3 TMVR in annuloplasty rings (valve-in-ring) or native mitral annular calcification (MAC) (valve-in-MAC). All subjects had high predicted risk for LVOT obstruction. Subjects were not excluded for excessive frailty or comorbidity. The primary endpoints were technical success and safety at 30 days. Secondary clinical and echocardiographic endpoints were assessed at 1 year and clinical follow-up at 5 years. RESULTS: Thirty subjects were enrolled between June 2017 and June 2018, equally between the valve-in-MAC and valve-in-ring arms. At 30 days, LAMPOON was successful in all 30 subjects, with no strokes, 1 (3%) death, and 1 (3%) moderate LVOT obstruction. Eighteen (65%) survived to 1 year, and 7 (25%) survived to 5 years. Six (20%) were hospitalized for heart failure in the first year. From baseline to 1 year, there was a 24-point improvement in Kansas City Cardiomyopathy Questionnaire score and a 60-m improvement in 6-minute walk distance. There was no significant change in N-terminal pro-brain natriuretic peptide. At 1 year, LVOT gradients remained low. CONCLUSIONS: LAMPOON enabled TMVR despite the risk for LVOT obstruction. There were no long-term complications associated with LAMPOON. The selection of inoperable patients limited assessment of long-term survival following TMVR. (NHLBI DIR LAMPOON Study: Intentional Laceration of the Anterior Mitral Leaflet to Prevent Left Ventricular Outflow Tract Obstruction During Transcatheter Mitral Valve Implantation; NCT03015194).

Predictive value of left atrial volumes assessed using real-time three-dimensional echocardiography for pulmonary hypertension in dogs with myxomatous mitral valve disease.

Introduction: Left atrial volume (LAV) obtained using real-time three-dimensional echocardiography (RT3DE) is an independent predictor of post-capillary pulmonary hypertension (PH) in humans; however, no studies have investigated LAV obtained using RT3DE as a predictor of post-capillary PH in dogs with myxomatous mitral valve disease (MMVD). Therefore, we aimed to evaluate the clinical applicability of LAV obtained using RT3DE compared to that obtained using two-dimensional echocardiography (2DE) in dogs with MMVD, with or without PH. Methods: Medical records and echocardiographic images of 237 privately owned dogs with naturally occurring MMVD with or without PH were retrospectively reviewed. A total of 49 privately owned dogs with naturally occurring MMVD, with or without PH, were finally included (35 MMVD without PH, 14 MMVD with PH). The LAV and left ventricular volumes were obtained using 2DE and RT3DE. Echocardiographic parameters were analyzed to identify independent predictors of post-capillary PH. Results: We found that the left atrial and left ventricular volumes obtained using 2DE and RT3DE indexed to body weight and several 2DE-derived variables were univariately associated with post-capillary PH. Furthermore, multivariable logistic regression analysis revealed that the RT3DE minimum LAV indexed to body weight (LAVi min) was the only significant independent predictor of post-capillary PH (odds ratio, 12.86; 95% confidence interval [CI], 2.40-68.99; p = 0.003), with the highest area under the curve value of 0.86 (95% CI, 0.75-0.96; p < 0.001). Discussion: In conclusion, LAV indexed to body weight obtained using 2DE and RT3DE, can be a useful predictor of post-capillary PH in dogs with MMVD. In particular, the RT3DE LAVi min was observed to be the strongest predictor of post-capillary PH.

Circumflex distortion following mitral valve repair.

Mitral valve repair or replacement poses a potential risk of injury to the left circumflex coronary artery (LCx). Such injuries can arise from either direct LCx injury caused by encircling or transfixing stitches, or indirect occlusion resulting from the distortion of adjacent tissues. We provide and illustrate a representative image depicting LCx distortion. Additionally, we offer guidance to aid angiographers in comprehending the angiographic appearance and the underlying mechanism of occlusion.

Perioperative changes in plasma cardiac troponin I concentration during mitral valvuloplasty for severe mitral regurgitation in dogs.

Background: Mitral valvuloplasty (MVP) is a surgical procedure for treating severe mitral regurgitation in dogs. Although MVP is considered highly invasive, the extent of myocardial injury, postoperative complications, and recovery has not been evaluated. Aim: This study examined the degree of MVP invasiveness, the extent of myocardial damage, postoperative complications, cardiomyocyte recovery, and timing of hospital discharge. Methods: Cardiac troponin I (cTnI) was used to investigate the myocardial damage caused by cardiac arrest associated with a surgical approach to the myocardium in 13 patients with MVP and five controls with patent ductus arteriosus (PDA) who underwent similar anesthesia and thoracotomy. Results: The level of cTnI peaked 1 day after surgery and was significantly higher in the MVP group (median, 19.90 ng/ml) than in the control group (median, 1.50 ng/ml p < 0.001). At day 7, the cTnI level was significantly higher in the MVP group (1.9 ng/ml) than in the control group (0.1 ng/ml) (p < 0.001), and recovery to the preoperative level took 10 days in the MVP group but returned to the preoperative level at day 7 in the control group. Although the mean arterial pressure of cardiopulmonary bypass (CPB) at the time of use was 42.92 mmHg, the peak cTnI levels in the two patients who exhibited a temporary decrease of 20 mmHg or less (46.03 ng/ml) were significantly higher than in the other 11 patients (19.70 ng/ml) (p < 0.05). Preoperative cTnI levels were correlated with the severity of postoperative complications (P = 0.03, F = 0.71). Conclusion: The results showed that MVP caused temporary greater myocardial tissue damage than thoracotomy, but postoperative recovery was smoother. A high preoperative cTnI level requires relatively more careful postoperative management, and measuring the level of cTnI over time after surgery can provide information about the extent of myocardial damage and recovery from surgery and help determine the time of discharge.

Impact of transcatheter edge to edge repair in functional mitral regurgitation and cardiac resynchronization-therapy nonresponders.

BACKGROUND: Despite optimal medical therapy and cardiac resynchronization therapy (CRT), significant functional mitral regurgitation (MR) persisted in 30% of the patients and labeled as CRT nonresponders. AIMS: We sought to study the impact of transcatheter edge-to-edge repair (TEER) in patients with symptomatic grade III and IV functional MR despite CRT. METHODS: A retrospective analysis was conducted of all patients who had prior CRT for at least 6 months and underwent TEER for significant residual functional MR (grade ≥3) and symptomatic heart failure (HF) at our institution. The primary outcomes were the change in New York Heart Association classification (NYHA), MR grade, echo parameters, and NT-ProBNP from baseline to 1-year post-procedure. RESULTS: A total of 28 patients were identified, mean age of 73 ± 6.7 years and 89% males. Procedure success was achieved in all patients. At 1-year follow-up, patients had lower MR grade (median 2, IQR 1 [1,2] vs. 4, IQR 1 [3,4]; p < 0.001), NYHA class (median 2, IQR 1 [2,3] vs. 3, IQR 1 [3,4]; p < 0.001), and NT-ProBNP (7658 ± 11322 vs. 3760 ± 4431; p = 0.035) compared to before the TEER procedure. The left ventricular end-diastolic volume (255 ± 59 vs. 244 ± 66 mm; p = 0.016) and the right ventricular systolic pressure (52 ± 14 mmHg vs. 37 ± 13 mmHg, <0.001) decreased. CONCLUSION: Patients who remain symptomatic after CRT with severe functional MR had improved functional status and MR grade at 1-year following TEER. There was a signal toward reverse remodeling.

Clinical and 2D/3D-Echo Cardiography Determinants of Mitral Valve Reoperation in Children With Congenital Mitral Valve Disease.

Background: Congenital mitral valve disease (CMVD) presents major challenges in its medical and surgical management. Objectives: The purpose of this study was to investigate the value of 3-dimensional echocardiography (3DE) and identify associations with MV reoperation in this setting. Methods: All children <18 years of age who underwent MV reconstruction for CMVD in 2002 to 2018 were included. Preoperative and postoperative 2-dimensional echocardiography (2DE) and 3DE data were collected. Competing risks and Cox regression analysis were used to identify independent associations with MV reoperation. Receiver operating characteristic and decision-tree analysis were implemented for comparison of 3DE vs 2DE. Results: A total of 206 children underwent MV reconstruction for CMVD (mitral stenosis, n = 105, mitral regurgitation [MR], n = 75; mixed disease, n = 26); 64 (31%) required MV reoperation. Variables independently associated with MV reoperation were age <1 year (HR: 2.65; 95% CI: 1.13-6.21), tethered leaflets (HR: 2.00; 95% CI: 1.05-3.82), ≥ moderate 2DE postoperative MR (HR: 4.26; 95% CI: 2.45-7.40), changes in 3D-effective orifice area (3D-EOA) and in 3D-vena contracta regurgitant area (3D-VCRA). Changes in 3D-EOA and 3D-VCRA were more strongly associated with MV reoperation than changes in mean gradients (area under the curve [AUC]: 0.847 vs AUC: 0.676, P = 0.006) and 2D-VCRA (AUC: 0.969 vs AUC: 0.720, P = 0.012), respectively. Decision-tree analysis found that a <30% increase in 3D-EOA had 80% accuracy (HR = 8.50; 95% CI: 2.9-25.1) and a <40% decrease in 3D-VCRA had 93% accuracy (HR: 22.50; 95% CI: 2.9-175) in discriminating MV reoperation for stenotic and regurgitant MV, respectively. Conclusions: Age <1 year, tethered leaflets, 2DE postoperative MR, changes in 3D-EOA and 3D-VCRA were all independently associated with MV reoperation. 3DE parameters showed a stronger association than 2DE. 3DE-based decision-tree algorithms may help prognostication and serve as a support tool for clinical decision-making.

Case Report: Allograft aortic valve replacement in irreparable infant mitral valve.

This case report describes a 3-month-old male infant diagnosed with severe mitral stenosis (MS) and mitral regurgitation (MR) by transthoracic echocardiography. The male infant initially underwent complex mitral valve repair surgery. However, postoperative deterioration occurred with hemodynamic instability and shock, necessitating multiple resuscitation efforts and ultimately requiring support from Extracorporeal Membrane Oxygenation (ECMO). Given the serious conditions, the cardiac team decided to perform mitral valve replacement with a fresh allograft aortic valve. Postoperatively, the patient was promptly weaned off ECMO support, and the valve demonstrated sustained functionality throughout the long-term follow-up.

Outcomes of Mitral Valve Regurgitation Management after Expert Multidisciplinary Valve Team Evaluation.

Background/Objectives: Mitral regurgitation (MR) affects millions worldwide, necessitating timely intervention. There are significant clinical challenges in the conservative management of MR, leaving a knowledge gap regarding the impact of multidisciplinary decision-making on treatment outcomes. This study aimed to provide insights into the impact of multidisciplinary decision-making on the survival outcomes of MR patients, focusing on conservative approaches. Methods: This study retrospectively analyzes 1365 patients evaluated by an expert multidisciplinary heart team (MDT) in a single center from 2015 to 2022. Treatments included surgery, catheter-based interventions, and conservative management. Propensity matching was utilized to compare surgery and conservative approaches. Results: Surgical intervention was associated with superior long-term survival outcomes compared to conservative and catheter-based treatments, particularly for degenerative MR (DMR). Survival rates of patients deemed by the MDT to have non-severe DMR were comparable to surgical patients (HR 1.07, 95% CI: 0.37-3.12, p = 0.90). However, non-severe functional MR (FMR) patients trended towards elevated mortality risk (HR 1.77, 95% CI: 0.94-3.31, p = 0.07). Pharmacological treatment for DMR was associated with significantly higher mortality compared to surgery (HR 8.0, 95% CI: 1.78-36.03, p = 0.001). Functional MR patients treated pharmacologically exhibited a non-significantly higher mortality risk compared to surgical intervention (HR 1.93, 95% CI: 0.77-4.77, p = 0.20). Conclusions: Survival analysis revealed significant benefits for surgical intervention, contrasting with elevated mortality risks associated with conservative management. "Watchful waiting" may be appropriate for non-severe DMR, while FMR may require closer monitoring. Further research is needed to assess the impact of regular follow-up or delayed surgery on survival rates, as pharmacological therapy has limited long-term efficacy for DMR.

Global Epidemiologic Trends and Projections to 2030 in Non-Rheumatic Degenerative Mitral Valve Disease from 1990 to 2019: An Analysis of the Global Burden of Disease Study 2019.

Background: No studies have updated the epidemiologic changes in non-rheumatic degenerative mitral valve disease (DMVD) since 2019, thus this study utilized data from the Global Study of Diseases, Injuries, and Risk Factors 2019 (GBD2019) to assess the burden of DMVD in 204 countries and territories over the period 1990-2019, as well as changes in the prevalence, incidence, deaths and changes in disability-adjusted life years (DALYs). Methods: Using the results from the GBD2019, analyzing the incidence, prevalence, deaths, and DALYs rates, as well as their age-standardized rates (ASR). Based on the human development index (HDI), the socio-demographic index (SDI), age, and sex. Results: In 2019, there were 24.229 million (95% uncertainty interval (UI) 23.081-25.419 million) existing cases of DMVD worldwide, with 1.064 million (95% UI 1.010-1.122 million) new cases and 0.034 million (95% UI 0.028-0.043 million) deaths, and 0.883 million (95% UI 0.754-1.092 million) disability-adjusted life years. The incidence, prevalence, deaths, and DALYs of DMVD and their ASR showed significant differences across sex, age groups, regions, and countries from 1990 to 2019. It is projected that by 2030, the incidence of DMVD in females will be 0.72 million with an ASR of 15.59 per 100,000 population, 0.51 million in males with an ASR of 11.75 per 100,000 population, and a total incidence of 1.23 million with an ASR of 14.03 per 100,000 population. Conclusions: DMVD remains a significant public health problem that cannot be ignored, despite a decreasing trend in the ASR of global incidence, prevalence, deaths and DALYs from 1990 to 2019. However, we note an adverse development trend in countries with low socio-demographic indexes and seriously aging societies, and sex inequality is particularly prominent. This indicates the need to reposition current prevention and treatment strategies, with some national health administrations developing corresponding strategies for preventing an increase in DMVD based on local health, education, economic conditions, sex differences, and age differences.

The Hemodynamic Effects of Interatrial Septostomy in Iatrogenic Mitral Stenosis Following MitraClip.

Iatrogenic mitral stenosis is a rare complication of the MitraClip procedure for which limited therapeutic options exist. We present a unique case using real-time echocardiographic and hemodynamic data demonstrating a potential role for interatrial septostomy creation as a percutaneous management option in this challenging population.

Mitochondrial bioenergetic dysfunction linked to myxomatous mitral valve degeneration explored by PBMCs metabolism analysis.

Impaired mitochondria cause an impressive decrease in ATP production becoming a common condition of cardiovascular diseases. Myxomatous mitral valve disease (MMVD) is characterized by mitochondrial dysfunction. By a non-invasive procedure of metabolism analysis on peripheral blood mononuclear cells, we exploit ex-vivo studies that directly constitute a translational approach to evaluate the cell bioenergetics. Cell ATP production decreased in the presence of MMVD, whereas glycolysis was unaffected. In MMVD, the mitochondrial activity underwent a significant reduction of basal respiration, maximal respiration, and ATP production. Our results depicted a pathological condition of MMVD characterized by cell metabolism deprived of mitochondrial energy support.

How accurate are NT-proBNP, ANP, and cTnI levels in diagnosing dogs with myxomatous mitral valve disease?

Background: Myxomatous mitral valve disease (MMVD) is prevalent in dogs. Specialized diagnostics (radiography and echocardiography) may be unavailable in some veterinary settings. Cardiac biomarkers offer potential alternatives. Aim: This study evaluated the diagnostic value of N-terminal fragments of pro-brain natriuretic peptides (NT-proBNPs), atrial natriuretic peptides (ANPs), and cardiac troponin I (cTnI) levels in dogs with MMVD. Methods: 69 dogs with MMVD (asymptomatic and symptomatic) and 19 healthy controls were assessed. Biomarker levels were measured using commercial kit rapid tests. Results: Our results showed that the median NT-proBNP level in the symptomatic group was higher than those in the asymptomatic (p < 0.001) and control (p < 0.001) groups. Moreover, the median NT-proBNP level in the asymptomatic group was higher than that in the control group (p < 0.001). The cTnI level in the control group was lower than those in the asymptomatic (p = 0.039) and symptomatic (p = 0.001) groups. No statistically significant difference in the cTnI level was noted between the asymptomatic and symptomatic groups. The best cutoff value of the NT-proBNP level to differentiate the normal controls from dogs with MMVD with or without congestive heart failure was > 505.65 pmol/l [sensitivity, 76.8%; specificity, 89.5%; and area under the curve (AUC), 0.862]. The suggested cutoff value of the NT-proBNP level to differentiate symptomatic MMVD from asymptomatic MMVD was >787.65 pmol/l (sensitivity, 78.38%; specificity, 72.55%; and AUC, 0.792). Conclusion: NT-proBNP and cTnI may serve as point-of-care tests for dyspneic dogs, aiding MMVD assessment where specialized diagnostics are limited.

Quantified planar collagen distribution in healthy and degenerative mitral valve: biomechanical and clinical implications.

Degenerative mitral valve disease is a common valvular disease with two arguably distinct phenotypes: fibroelastic deficiency and Barlow's disease. These phenotypes significantly alter the microstructures of the leaflets, particularly the collagen fibers, which are the main mechanical load carriers. The predominant method of investigation is histological sections. However, the sections are cut transmurally and provide a lateral view of the microstructure of the leaflet, while the mechanics and function are determined by the planar arrangement of the collagen fibers. This study, for the first time, quantitatively examined planar collagen distribution quantitatively in health and disease using second harmonic generation microscopy throughout the thickness of the mitral valve leaflets. Twenty diseased samples from eighteen patients and six control samples were included in this study. Healthy tissue had highly aligned collagen fibers. In fibroelastic deficiency they are less aligned and in Barlow's disease they are completely dispersed. In both diseases, collagen fibers have two preferred orientations, which, in contrast to the almost constant one orientation in healthy tissues, also vary across the thickness. The results indicate altered in vivo mechanical stresses and strains on the mitral valve leaflets as a result of disease-related collagen remodeling, which in turn triggers further remodeling.

Clinical outcome of patients with rheumatic tricuspid valve disease: matched cohort study.

Rheumatic heart disease (RHD) is still a major health problem, especially in low- to mid-income countries, leading premature deaths owing to valvular disease. Although left-sided valvular involvement is most commonly seen in RHD, the tricuspid valve can also be affected. However, there is a lack of information about the prognostic value of primary tricuspid valve (TV) disease in RHD. This study aimed to determine the impact of TV disease on clinical outcome in RHD. This prospective study enrolled patients with rheumatic mitral valve disease (MVD) referred to a tertiary center for management of heart valve disease. Primary rheumatic TV disease was defined by echocardiographic features including thickening of leaflets associated with some degree of restricted mobility. Patients with rheumatic TV disease were matched to patients with MVD using 1:1 genetic matching algorithm that maximized balance of baseline covariates prior to exploring outcome differences. The main outcome was either need for MV replacement or death. Among 694 patients eligible for the study, age of 47 ± 13 years, 84% female, 39 patients (5.6%) had rheumatic TV disease. After excluding patients with incomplete data, 33 patients with TV disease were matched to 33 controls based on age, right-sided heart failure, atrial fibrillation, and MV area. During a mean follow-up of 42 months (median 28, IQR 8 to 71 months), 32 patients (48.5%) experienced adverse events, including 6 cardiovascular deaths and 26 patients who underwent surgery for mitral valve replacement. The adjusted analysis demonstrated a significant association between TV disease and the outcome, with a hazard ratio (HR) of 3.386 (95% CI 1.559-7.353; P = 0.002) in the genetic matched cohort with balance on baseline covariates of interest. The model exhibited good discriminative ability, as indicated by a C-statistic of 0.837. In patients with rheumatic mitral valve disease, rheumatic TV disease significantly increased risk of adverse events compared with matched controls. The involvement of TV may express overall disease severity that adversely affects clinical outcome.