Transcatheter Treatment Options for Functional Mitral Regurgitation: Which Device for Which Patients?

Mitral regurgitation is the most common valvular disease in the developed world, with approximately 24.2 million people being affected worldwide and a higher prevalence in older age groups. Surgical correction of degenerative mitral regurgitation is the standard of care and can restore cardiac function and provide a lasting result, especially when the mitral valve can be repaired. Secondary mitral regurgitation, or functional mitral regurgitation (FMR), describes atrial or ventricular factors leading to poor coaptation of an otherwise non-diseased valve. For FMR, traditional surgery has not produced the same level of benefit. Transcatheter mitral repair and replacement techniques that mimic surgical correction are under investigation. Transcatheter edge-to-edge repair is the only approved catheter-based therapy for FMR in the US. Here, the transcatheter treatment options for FMR are reviewed.

Potassium ion channel Kir2.1 negatively regulates protective responses to Mycobacterium bovis BCG.

Tuberculosis caused by the pathogen Mycobacterium tuberculosis leads to increased mortality and morbidity worldwide. The prevalence of highly drug resistant strains has reinforced the need for greater understanding of host-pathogen interactions at the cellular and molecular levels. Our previous work demonstrated critical roles of calcium ion channels in regulating protective responses to mycobacteria. In this report we deciphered the roles of inwardly rectifying K+ ion channel Kir2.1 in epithelial cells. Data showed that infection of epithelial cells (and macrophages) increases the surface expression of Kir2.1. This increased expression of Kir2.1 results in higher intracellular mycobacterial survival, since either inhibiting or knocking down Kir2.1 results in mounting of a higher oxidative burst leading to a significant attenuation of mycobacterial survival. Further, inhibiting Kir2.1 also led to increased expression of T cell costimulatory molecules accompanied with increased activation of MAP Kinases and transcription factors NF-κB and pCREB. Furthermore, inhibiting Kir2.1 induced increased autophagy and apoptosis that could also contribute to decreased bacterial survival. Interestingly, an increased association of heat shock protein-70 with Kir2.1 was observed. The above results showed that mycobacteria modulate the expression and function of Kir2.1 in epithelial cells to its advantage.

An Animal Model of Functional Tricuspid Regurgitation by Leaflet Tethering Using Image-Guided Chordal Encircling Snares.

Several interventional therapies are in development to treat functional tricuspid regurgitation. Most have failed to achieve adequate efficacy, as animal models of this lesion are lacking. We developed a new image-guided technique in swine, by tethering the tricuspid valve chordae using echo-guided chordal encircling snares. Five swine underwent baseline echocardiographic assessment of tricuspid valve function, followed by echo-guided placement of snares that encircle the chordae inserting into the anterior and posterior tricuspid valve leaflets. Tethering these snares and stabilizing them on the right ventricle caused the regurgitant fraction to increase from 8.48±5.38% to 48.76±12.5%, and the valve tenting area to increase from 60.26±52.19 to 160.9±86.92 mm2. Image-guided chordal encircling snares could reproducibly induce clinically significant levels of functional tricuspid regurgitation and create a valve geometry like that seen in patients, providing a new animal model for use to study novel interventional devices.

Expanding global vaccine manufacturing capacity: Strategic prioritization in small countries.

The COVID-19 pandemic highlighted significant gaps in equitable access to essential medical countermeasures such as vaccines. Manufacturing capacity for pandemic vaccines, therapeutics, and diagnostics is concentrated in too few countries. One of the major hurdles to equitable vaccine distribution was "vaccine nationalism", countries hoarded vaccines to vaccinate their own populations first which significantly reduced global vaccine supply, leaving significant parts of the world vulnerable to the virus. As part of equitably building global capacity, one proposal to potentially counter vaccine nationalism is to identify small population countries with vaccine manufacturing capacity, as these countries could fulfill their domestic obligations quickly, and then contribute to global vaccine supplies. This cross-sectional study is the first to assesses global vaccine manufacturing capacity and identifies countries with small populations, in each WHO region, with the capacity and capability to manufacture vaccines using various manufacturing platforms. Twelve countries were identified to have both small populations and vaccine manufacturing capacity. 75% of these countries were in the European region; none were identified in the African Region and South-East Asia Region. Six countries have facilities producing subunit vaccines, a platform where existing facilities can be repurposed for COVID-19 vaccine production, while three countries have facilities to produce COVID-19 mRNA vaccines. Although this study identified candidate countries to serve as key vaccine manufacturing hubs for future health emergencies, regional representation is severely limited. Current negotiations to draft a Pandemic Treaty present a unique opportunity to address vaccine nationalism by building regional capacities in small population countries for vaccine research, development, and manufacturing.

Evaluation of Lower Extremity Calcium Score as a Measure of Peripheral Arterial Disease Burden and Amputation Risk.

BACKGROUND: The ankle-brachial pressure index (ABI) and toe-brachial pressure index (TBI) are commonly used diagnostic tools for peripheral artery disease (PAD) that are unreliable in the presence of calcified vessels. In this study, we aimed to demonstrate the utility of the lower extremity calcium score (LECS) in addition to ABI and TBI in measuring disease burden and predicting the risk of amputation in patients with PAD. METHODS: Patients who were evaluated in the vascular surgery clinic at Emory University for PAD and who underwent noncontrast computed tomography of the aorta and lower extremities were included in the study. Aortoiliac, femoral-popliteal, and tibial calcium scores were measured using the Agatston method. ABI and TBI that were obtained within 6 months of the computed tomography scan were noted and divided into categories of PAD severity. Associations between ABI, TBI, and LECS of each anatomic segment were evaluated. Univariate and multivariate ordinal regression analyses were performed to predict the outcome of amputation. Receiver operating characteristic analysis was performed to compare LECS with other variables in its ability to predict amputation. RESULTS: Fifty patients included in the study cohort were divided into LECS quartiles, with 12-13 patients in each quartile. The highest quartile tended to be older (P = 0.016), had a higher percentage of diabetics (P = 0.034), and had a higher frequency of major amputations (P = 0.004) compared to the other quartiles. Patients in the highest quartile of tibial calcium score were more likely to have stage 3 chronic kidney disease (CKD) or greater (P = 0.011) and also had a higher frequency of amputation (P < 0.005) and mortality (P = 0.041). We found no significant association between each anatomic LECS and ABI/TBI categories. On univariate analysis, CKD (Odds Ratio [OR] 12.92 (95% CI 2.01 to 82.83), P = 0.007), diabetes mellitus (OR 5.47 (95% CI 1.27 to 23.64), P = 0.023), tibial calcium score (OR 6.62 (95% CI 1.79 to 24.54), P = 0.005), and total bilateral calcium score (OR 6.32 (95% CI 1.18 to 33.78), P = 0.031) were associated with increased risk of amputation. On multivariate stepwise ordinal regression, TBI and tibial calcium score were identified as important predictors of amputation, with hyperlipidemia and CKD increasing the overall prediction of the model. On Receiver operating characteristic analysis, the addition of the tibial calcium score (area under the curve 0.94, standard error 0.048) significantly improved the prediction of amputation compared to hyperlipidemia, CKD, and TBI alone (area under the curve 0.82, standard error 0.071, P = 0.022). CONCLUSIONS: The addition of tibial calcium score to other known PAD risk factors may improve the prediction of amputation in patients with PAD.

A novel technique of vagino-hysteroscopy using alginate gel interface: A proof of concept study.

OBJECTIVE: To compare the feasibility of vagino-hysteroscopy using alginate gel Interface (VAGI) with conventional vaginoscopic hysteroscopy (CVH). METHODS: Thirty women undergoing diagnostic vagino-hysteroscopy were randomly allocated into Group I (VAGI): Alginate occluder was used at introitus to facilitate hydrodistension during hysteroscopy; or Group II: Underwent no-touch hysteroscopy. Primary outcome was feasibility, defined as successful visualization of uterine cavity. Secondary outcomes included operative time, hydrostatic pressures for optimum visualization, pain experienced by patient on visual analog scale, maneuverability and surgeon satisfaction. Data analysis was performed using χ2 and Fisher exact tests for qualitative variables and Student t test for quantitative variables. RESULTS: VAGI was significantly better than CVH (80% vs. 33.3%; relative risk 8, P = 0.025). With VAGI, optimum visualization was achieved at significantly lower pressures at all levels (vagina, P = 0.034; cervix, P = 0.01; uterus, P < 0.001), in less time (P = 0.007), and using less irrigation fluid (P < 0.001). Surgeon satisfaction was significantly higher for VAGI (P = 0.009). Subgroup analysis showed higher likelihood of success of VAGI in women who were premenopausal (P = 0.015), younger than 45 years (P = 0.024), and had a history of vaginal birth (P = 0.03). CONCLUSIONS: VAGI is quicker to perform and provides optimum visualization at much lower pressures than CVH. Use of alginate is patient friendly and yields higher surgeon satisfaction rate.

Redo aortic surgery: Does one versus multiple affect outcomes?

Objective: Redo aortic surgery has a higher risk of morbidity and mortality because it is technically complex due to mediastinal adhesions, infection, and previously implanted prostheses. In this study, we sought to benchmark our single-center experience comparing outcomes in patients undergoing aortic surgery after 1 versus multiple previous cardiac operations. Methods: Between 2004 and 2019, 429 patients underwent redo aortic surgery. They were classified as aortic surgery after 1 previous surgery (first redo surgery, n = 360) and aortic surgery after 2 or more (multiple) previous surgeries (multiple redo surgery, n = 69). Postoperative outcomes and long-term survival were compared, and risk factors for mortality were identified. Results: Thirty-day mortality was lower in first redo surgery compared with multiple redo surgery (12.3% vs 21.7%, P = .03). Age, cardiopulmonary bypass time, intra-aortic balloon pump use, postoperative cerebrovascular accident, absence of postoperative atrial fibrillation, intra-aortic balloon pump, and multiple redo surgery were independent predictors of 30-day mortality. Long-term survival was similar at 15 years. Patients who received first redo surgery were older (57.9 ± 14.0 years vs 50.3 ± 15.8 years, P = .0001) and had a higher incidence of hypertension (84.7% vs 73.9%, P = .02), whereas patients who received multiple redo surgery had a higher incidence of cerebrovascular disease (31.9% vs 20.3%, P = .03). Aortic valve replacement was the most common previous operation with higher incidence in multiple redo surgery. Incidence of previous aortic surgery was similar. Cardiopulmonary bypass (246 ± 67.3 minutes vs 219.9 ± 57.5 minutes, P = .009) and crossclamp times (208.2 ± 51.8 vs 181.9 ± 50.8 minutes, P = .004) were longer in multiple redo surgery. Incidence of reentry injury and balloon pump insertion were similar. Extracorporeal membrane oxygenation use was higher in multiple redo surgery. Postoperative complications occurred at similar rates, except for higher incidence of dialysis in multiple redo surgery (14.5% vs 7.2%, P = .04). Conclusions: Multiple redo aortic procedures have a higher morbidity and mortality compared with first redo aortic procedures, with linearly increasing short-term mortality risk but similar long-term survival with the number of redo procedures.

Undersizing mitral annuloplasty alters left ventricular mechanics in a swine model of ischemic mitral regurgitation.

OBJECTIVE: Undersizing mitral annuloplasty (UMA) is a frequently used surgical repair technique to correct ischemic mitral regurgitation in patients with heart failure. In this study, we sought to test the hypothesis that downsizing the mitral annulus can adversely affect the shape and mechanics of the left ventricle inhibiting its functional recovery. METHODS: Eighteen farm swine that underwent an inferolateral myocardial infarction and developed ischemic mitral regurgitation of >2+ severity after 2 months were assigned as follows: 9 swine received an undersized mitral annuloplasty, 6 received papillary muscle approximation (PMA), and 3 animals did not receive any other intervention. Animals lived another 3 months and cardiac magnetic resonance imaging was performed before termination to assess ventricle mechanics and function. RESULTS: Ejection fraction was comparable between the 2 repair groups before surgery, but was significantly lower in UMA at 38.89% ± 7.91% versus 50.83% ± 9.04% in the PMA group (P = .0397). Animals receiving UMA had lower regional peak fractional shortening and reduced systolic and diastolic radial velocities compared with PMA and in some regions were lower than sham. Animals that underwent UMA had higher circumferential strain than sham, but lower than PMA. UMA animals have lower longitudinal strain compared to sham group and lower LV torsion than PMA. CONCLUSIONS: Undersizing the mitral annulus with an annuloplasty ring can restore valvular competence, but unphysiologically impair ventricle mechanics. Mitral valve repair strategies should focus not only on restoring valve competence, but preserving ventricle mechanics.

Papillary Muscle Approximation Reduces Systolic Tethering Forces and Improves Mitral Valve Closure in the Repair of Functional Mitral Regurgitation.

Background: Undersizing mitral annuloplasty (UMA) to repair functional mitral regurgitation lacks durability, as it forces leaflet coaptation without relieving the sub-leaflet tethering forces. In this biomechanical study, we demonstrate that papillary muscle approximation (PMA) prior to UMA can drastically relieve tethering forces and improve valve function, without the need for significant annular downsizing. Methods: An ex vivo model of functional mitral regurgitation (FMR) was used, in which pig mitral valves were geometrically perturbed to induce FMR, and the repairs were performed. Nine pig mitral valves were studied as follows: normal(baseline), functional mitral regurgitation (FMR), true-sized annuloplasty to 30mm (TSR), and undersized annuloplasty to 26mm (DSR); and concomitant papillary muscle approximation (PMA) at both ring sizes. Mitral regurgitation, valve kinematics, and chordal forces were measured and compared between groups. Results: FMR geometry induced a 16.31±7.33% regurgitant fraction, compared to none at baseline. 30mm/TSR reduced regurgitation to 6.05±5.63% and a 26mm/DSR to 5.06±6.76%. Addition of papillary muscle approximation prior to either rings, reduced regurgitation to 3.87±6.79% with the true sized ring (TSR+PMA), and 3.71±6.25% with the downsized ring (DSR+PMA). Peak anterior and posterior marginal chordal forces were elevated to 0.09±0.1N and 0.12±0.1N respectively with FMR, which were not reduced by annuloplasty of either sizes. Addition of PMA, reduced the forces significantly to 0.23±0.02N and 0.51±0.04N. Conclusion: This biomechanical study, demonstrates that papillary muscle approximation relieves tethering forces and when added to annuloplasty, and mobilizes the leaflets to achieve a good valve closure. Such a result could be achieved without the need for extensive annular downsizing.

Regurgitant Bicuspid Aortopathy: Is Valve-Sparing Root Replacement Equivalent to Bentall Procedure?

BACKGROUND: Repair of aortic root aneurysms with nonstenotic bicuspid valves (NS-BAVs) is achieved either with valve-sparing root replacement (VSRR) or conventional Bentall procedure (ROOT). Procedural and long-term outcomes comparing these 2 techniques are sparse and need investigation. METHODS: From March 2004 to January 2019, 158 patients with an aortic root aneurysm and NS-BAV underwent VSRR (n = 78, 49.3%) or ROOT (n = 80, 50.6%). VSRR involved optional aortic valve repair (n = 47, 60%), and ROOT was performed with bioprosthetic (81.3%) or mechanical valve replacement (18.7%). Procedural and postoperative outcomes were obtained, and univariate and Kaplan-Meier analyses were performed. RESULTS: VSRR patients were younger (42.7 ± 12.0 years of age) than ROOT (54.8 ± 13.6 years of age) (P < .001). Cardiopulmonary bypass (CPB) and cross-clamp duration were longer in VSRR (CPB: 228.0 ± 39.1 minutes; cross-clamp: 200.1 ± 36.2 minutes) compared with ROOT (CPB: 199.5 ± 55 minutes; cross-clamp: 170.3 ± 39.5 minutes) (P < .001). Postoperative stroke, renal failure, pneumonia, and reoperation for bleeding were similar, but postoperative atrial and ventricular arrhythmias was lower in VSRR (15% vs 42%; P < .001). Length of stay and 30-day mortality were similar. At discharge, none had greater than trivial aortic insufficiency. Long-term 10-year survival and incidence of moderate-severe aortic insufficiency, aortic stenosis, and reoperation were equivalent between groups. CONCLUSIONS: Surgery for aortopathy associated with NS-BAV is safe and effective with either VSRR or ROOT. Despite its complexity, VSRR should be considered in the surgical treatment of this population.

Pathological Remodeling of Mitral Valve Leaflets from Unphysiologic Leaflet Mechanics after Undersized Mitral Annuloplasty to Repair Ischemic Mitral Regurgitation.

Background Undersized ring annuloplasty is a commonly used surgical repair for ischemic mitral regurgitation, in which annular downsizing corrects regurgitation, but alters valve geometry and elevates tissue stresses. In this study, we investigated if unphysiological leaflet kinematics after annuloplasty might cause pathogenic biological remodeling of the mitral valve leaflets, and if preserving physiologic leaflet kinematics with a better technique can moderate such adverse remodeling. Methods and Results Twenty-nine swine were induced with ischemic mitral regurgitation, and survivors were assigned to groups: 7 underwent annuloplasty, 12 underwent annuloplasty with papillary-muscle approximation, 6 underwent papillary-muscle approximation, and 3 were sham controls. Pre-and post-surgery leaflet kinematics were measured, and valve tissue was explanted after 3 months to assess biological changes. Anterior leaflet excursion was unchanged across groups, but persistent tethering was observed with annuloplasty. Posterior leaflet was vertically immobile after annuloplasty, better mobile with the combined approach, and substantially ( P=0.0028) mobile after papillary-muscle approximation. Procollagen-1 was higher in leaflets from annuloplasty compared with the other groups. Heat shock protein-47 and lysyl oxidase were higher in groups receiving annuloplasty compared with sham. α- SMA was elevated in leaflets from animals receiving an annuloplasty, indicating activation of quiescent valve interstitial cells, paralleled by elevated transforming growth factor-ß expression. Conclusions This is the first study to demonstrate that surgical valve repairs that impose unphysiological leaflet mechanics have a deleterious, pathological impact on valve biology. Surgeons may need to consider restoring physiologic leaflet stresses as well as valve competence, while also exploring pharmacological methods to inhibit the abnormal signaling cascades.