Cardiac sarcoidosis with extensive and heterogeneous left ventricular FDG uptake in absence of guidelines indication for an implantable defibrillator: Ventricular tachycardia precipitated by immunosuppressive therapy, should we have done differently?

A 40-year-old man, newly diagnosed with cardiac sarcoidosis (CS) presented with symptomatic ventricular tachycardia three days after starting steroid-based immunosuppressive therapy (IT). There was no clear guideline indication for implantable cardioverter-defibrillator (ICD) before the initiation of IT. Shortly after ICD implantation and the initiation of anti-arrhythmic drugs, recurring ventricular arrhythmias required titration of the anti-arrhythmic drug therapy. One-year follow-up assessment showed no significant arrhythmias and complete PET scan FDG uptake suppression. This case, along with recent publications, suggests transient pro-arrhythmic effects of steroids in patients with CS, which are not appropriately addressed in the current guidelines. We believe ICD implantation should be considered in clinically manifest CS before initiating IT, particularly in cases with heterogeneous and/or extensive FDG uptake on PET scans.

Clinical and echocardiographic evolution of patients with arrhythmogenic cardiomyopathy before heart transplantation.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterized by fibrofatty myocardial replacement, and accurate diagnosis can be challenging. The clinical course of patients expressing a severe phenotype of the disease needing heart transplantation (HTx) is not well described in the literature. Therefore, this study aims to describe the clinical and echocardiographic evolution of patients with ACM necessitating HTx. METHODS: We retrospectively studied all patients who underwent HTx in our institution between 1998 and 2019 with a definite diagnosis of ACM according to the explanted heart examination. RESULTS: Ten patients with confirmed ACM underwent HTx. Only four of them had a diagnosis of ACM before HTx. These patients were 28 ± 15 years old at the time of their first symptoms. Patients received a diagnosis of heart failure (HF) after 5.9 ± 8.7 years of symptom evolution. The mean age at transplantation was 40 ± 17 years old. All the patients experienced ventricular tachycardia (VT) at least once before their HTx and 50% were resuscitated after sudden death. The mean left ventricular ejection at diagnosis and before transplantation was similar (32% ± 21% vs. 35.0% ± 19.3%, p = NS). Right ventricular dysfunction was present in all patients at the time of transplantation. CONCLUSION: Patients with ACM necessitating HTx show a high burden of ventricular arrhythmias and frequently present a biventricular involvement phenotype, making early diagnosis challenging. HF symptoms are the most frequent reason leading to the decision to transplant.

Survival, ventricular arrhythmia, and implantable cardioverter-defibrillator usefulness in toxic cardiomyopathy due to substance abuse.

BACKGROUND: Toxic dilated cardiomyopathy (T-DCM) due to substance abuse is now recognized as a potential cause of severe left ventricular dysfunction. The burden of ventricular arrhythmias (VA) and the role of a prophylactic implantable cardioverter-defibrillator (ICD) are not well documented in this population. We aim to assess the usefulness of ICD implantation in a T-DCM cohort. METHODS: Patients younger than 65 years with a left ventricular ejection fraction (LVEF) < 35% followed at a tertiary center heart failure (HF) clinic between January 2003 and August 2019 were screened for inclusion. The diagnosis of T-DCM was confirmed after excluding other etiologies, and substance abuse was established according to the DSM-5 criteria. The composite primary endpoints were arrhythmic syncope, sudden cardiac death (SCD), or death of unknown cause. The secondary endpoints were the occurrence of sustained VA and/or appropriate therapies in ICD carriers. RESULTS: Thirty-eight patients were identified, and an ICD was implanted in 19 (50%) of these patients, only one for secondary prevention. The primary outcome was similar between the two groups (ICD vs. non-ICD; p = 1.00). After a mean follow-up of 33 ± 36 months, only two VA episodes were reported in the ICD group. Three patients received inappropriate ICD therapies. One ICD implantation was complicated with cardiac tamponade. Twenty-three patients (61%) had an LVEF ≥35% at 12 months. CONCLUSION: VA are infrequent in the T-DCM population. The prophylactic ICD benefit was not observed in our cohort. The ideal timing for potential prophylactic ICD implantation in this population needs further studies.

Impact of sex on the management and outcome of aortic stenosis patients.

OBJECTIVE: The aim of this study was to assess the impact of sex on the management and outcome of patients according to aortic stenosis (AS) severity. INTRODUCTION: Sex differences in the management and outcome of AS are poorly understood. METHODS: Doppler echocardiography data of patients with at least mild-to-moderate AS [aortic valve area (AVA) ≤1.5 cm2 and peak jet velocity (VPeak) ≥2.5 m/s or mean gradient (MG) ≥25 mmHg] were prospectively collected between 2005 and 2015 and retrospectively analysed. Patients with reduced left ventricular ejection fraction (<50%), or mitral or aortic regurgitation >mild were excluded. RESULTS: Among 3632 patients, 42% were women. The mean indexed AVA (0.48 ± 0.17 cm2/m2), VPeak (3.74 ± 0.88 m/s), and MG (35.1 ± 18.2 mmHg) did not differ between sexes (all P ≥ 0.18). Women were older (72.9 ± 13.0 vs. 70.1 ± 11.8 years) and had more hypertension (75% vs. 70%; P = 0.0005) and less coronary artery disease (38% vs. 55%, P < 0.0001) compared to men. After inverse-propensity weighting (IPW), female sex was associated with higher mortality (IPW-HR: 1.91 [1.14-3.22]; P = 0.01) and less referral to valve intervention (competitive model IPW-HR: 0.88 [0.82-0.96]; P = 0.007) in the whole cohort. This excess mortality in women was blunted in concordant non-severe AS initially treated conservatively (IPW-HR = 1.03 [0.63-1.68]; P = 0.88) or in concordant severe AS initially treated by valve intervention (IPW-HR = 1.25 [0.71-2.21]; P = 0.43). Interestingly, the excess mortality in women was observed in discordant low-gradient AS patients (IPW-HR = 2.17 [1.19-3.95]; P = 0.01) where women were less referred to valve intervention (IPW-Sub-HR: 0.83 [0.73-0.95]; P = 0.009). CONCLUSION: In this large series of patients, despite similar baseline hemodynamic AS severity, women were less referred to AVR and had higher mortality. This seemed mostly to occur in the patient subset with discordant markers of AS severity (i.e. low-gradient AS) where women were less referred to AVR.

Echocardiographic Results of Transcatheter Versus Surgical Aortic Valve Replacement in Low-Risk Patients: The PARTNER 3 Trial.

BACKGROUND: This study aimed to compare echocardiographic findings in low-risk patients with severe aortic stenosis after surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR). METHODS: The PARTNER 3 trial (Placement of Aortic Transcatheter Valves) randomized 1000 patients with severe aortic stenosis and low surgical risk to undergo either transfemoral TAVR with the balloon-expandable SAPIEN 3 valve or SAVR. Transthoracic echocardiograms obtained at baseline and at 30 days and 1 year after the procedure were analyzed by a consortium of 2 echocardiography core laboratories. RESULTS: The percentage of moderate or severe aortic regurgitation (AR) was low and not statistically different between the TAVR and SAVR groups at 30 days (0.8% versus 0.2%; P=0.38). Mild AR was more frequent after TAVR than SAVR at 30 days (28.8% versus 4.2%; P<0.001). At 1 year, mean transvalvular gradient (13.7±5.6 versus 11.6±5.0 mm Hg; P=0.12) and aortic valve area (1.72±0.37 versus 1.76±0.42 cm2; P=0.12) were similar in TAVR and SAVR. The percentage of severe prosthesis-patient mismatch at 30 days was low and similar between TAVR and SAVR (4.6 versus 6.3%; P=0.30). Valvulo-arterial impedance (Zva), which reflects total left ventricular hemodynamic burden, was lower with TAVR than SAVR at 1 year (3.7±0.8 versus 3.9±0.9 mm Hg/mL/m2; P<0.001). Tricuspid annulus plane systolic excursion decreased and the percentage of moderate or severe tricuspid regurgitation increased from baseline to 1 year in SAVR but remained unchanged in TAVR. Irrespective of treatment arm, high Zva and low tricuspid annulus plane systolic excursion, but not moderate to severe AR or severe prosthesis-patient mismatch, were associated with increased risk of the composite end point of mortality, stroke, and rehospitalization at 1 year. CONCLUSIONS: In patients with severe aortic stenosis and low surgical risk, TAVR with the SAPIEN 3 valve was associated with similar percentage of moderate or severe AR compared with SAVR but higher percentage of mild AR. Transprosthetic gradients, valve areas, percentage of severe prosthesis-patient mismatch, and left ventricular mass regression were similar in TAVR and SAVR. SAVR was associated with significant deterioration of right ventricular systolic function and greater tricuspid regurgitation, which persisted at 1 year. High Zva and low tricuspid annulus plane systolic excursion were associated with worse outcome at 1 year whereas AR and severe prosthesis-patient mismatch were not. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02675114.

Accuracy of stroke volume measurement with phase-contrast cardiovascular magnetic resonance in patients with aortic stenosis.

BACKGROUND: Phase contrast (PC) cardiovascular magnetic resonance (CMR) in the ascending aorta (AAo) is widely used to calculate left ventricular (LV) stroke volume (SV). The accuracy of PC CMR may be altered by turbulent flow. Measurement of SV at another site is suggested in the presence of aortic stenosis, but very few data validates the accuracy or inaccuracy of PC in that setting. Our objective is to compare flow measurements obtained in the AAo and LV outflow tract (LVOT) in patients with aortic stenosis. METHODS: Retrospective analysis of patients with aortic stenosis who had CMR and echocardiography. Patients with mitral regurgitation were excluded. PC in the AAo and LVOT were acquired to derive SV. LV SV from end-systolic and end-diastolic tracings was used as the reference measure. A difference ≥ 10% between the volumetric method and PC derived SVs was considered discordant. Metrics of turbulence and jet eccentricity were assessed to explore the predictors of discordant measurements. RESULTS: We included 88 patients, 41% with bicuspid aortic valve. LVOT SV was concordant with the volumetric method in 79 (90%) patients vs 52 (59%) patients for AAo SV (p = 0.015). In multivariate analysis, aortic stenosis flow jet angle was a strong predictor of discordant measurement in the AAo (p = 0.003). Mathematical correction for the jet angle improved the concordance from 59 to 91%. Concordance was comparable in patients with bicuspid and trileaflet valves (57% and 62% concordance respectively; p = 0.11). Accuracy of SV measured in the LVOT was not influenced by jet eccentricity. For aortic regurgitation quantification, PC in the AAo had better correlation to volumetric assessments than LVOT PC. CONCLUSION: LVOT PC SV in patients with aortic stenosis and eccentric jet might be more accurate compared to the AAo SV. Mathematical correction for the jet angle in the AAo might be another alternative to improve accuracy.

Safety and effects of volume loading during transesophageal echocardiography in the pre-procedural work-up for left atrial appendage closure.

BACKGROUND: In patients undergoing left atrial appendage (LAA) closure, an accurate sizing of the LAA is key to optimize device sizing, procedural success and reduce complications. Previous studies have shown that intraprocedural volume loading increases LAA dimensions and improves device sizing. However, the safety and effects on LAA and device sizing of administering a fluid bolus during pre-procedural transesophageal echocardiography (TEE) are unknown. The aim of this study was to determine the safety and impact on LAA dimensions and device sizing of an intravenous (IV) fluid bolus administered during TEE in the setting of the pre-procedural work-up for LAA closure. METHODS: The study included a total of 72 patients who underwent TEE to assess suitability for LAAC and received a 500 ml IV bolus of normal saline. The LAA landing zone (LZ) and depth were measured by TEE before and after volume loading, and these measurements were used to predict the device size implanted during a subsequent percutaneous LAAC procedure. RESULTS: There were no complications associated with volume loading. The baseline mean LZ was 19.6 ± 3.6 mm at 90o, and 20.2 ± 4.1 mm at 135o. Following fluid bolus, the maximum diameter increased 1.5 ± 1.0 mm at 90o (p<0.001), and 1.3 ± 1.0 mm at 135o (p<0.001). The baseline mean depth of the LAA was 26.5 ± 5.5 mm at 90o, and 23.9 ± 5.8 mm at 135o. After fluid bolus, the mean depth increased by 1.5 ± 1.8 mm (p<0.001) and 1.6 ± 2.0 (p<0.001), at 90o and 135o, respectively. Sizing based on post-bolus measurements of the LZ significantly improved the agreement with the final device size selection during the procedure in 71.0% of cases (vs. 42.0% with pre-bolus measurements). CONCLUSIONS: Volume loading during ambulatory TEE as part of the pre-procedural work-up of LAAC is safe and significantly increases LAA dimensions. This strategy may become the new standard, particularly in centers performing LAAC with no TEE guidance, as it improves LAA sizing and more accurately predicts the final device size.

Prognosis of functional mitral regurgitation after aortic valve replacement for pure severe aortic stenosis.

OBJECTIVE: Whether patients with severe aortic stenosis (AS) and significant functional mitral regurgitation (MR) should undergo isolated aortic (aortic valve replacement [AVR]) or double aortic-mitral valve procedure (DVP) remains controversial. We sought to determine outcomes of such patients undergoing surgical (surgical aortic valve replacement [SAVR]) and transcatheter AVR (TAVR) or DVP, identify echocardiographic parameters predictive of significant residual MR after isolated AVR, and determine its impact on long-term survival. METHODS: Data prospectively collected from 736 consecutive patients with severe AS and significant MR undergoing AVR or DVP were retrospectively analyzed. Exclusion of organic MR, other valve diseases and concomitant CABG yielded a final population of 74 patients with significant functional MR (32 TAVR, 23 SAVR, 19 DVP). Demographics, postoperative complications and age-adjusted survival were compared. Echocardiographic predictors of significant residual MR and its impact on survival were analyzed for patients undergoing isolated AVR. RESULTS: In the isolated AVR group, MR improvement occurred in 60% of patients and was associated with a significant increase in survival compared to persistence of significant MR (p = .03). Patients with improved MR had significantly greater preoperative left ventricular dilatation (LVEDD: 49 vs. 43 mm, p = .001; LVESD: 35 vs. 29 mm, p = .03; LVEDV: 101 vs. 71 ml, p = .0003; LVESV: 57 vs. 33 ml, p = .002). There was no significant difference in perioperative mortality (5.3 vs. 4.4 vs. 9.4%, p = .85) or age-adjusted long-term survival between isolated AVR and DVP groups (76.3 vs. 84.2% survival at 2-year follow-up, p = .26), or between SAVR, TAVR and DVP groups (78.2 vs. 75.0 vs. 84.2% survival at 2-year follow-up, p = .13). CONCLUSIONS: After isolated AVR, MR improvement occurs in 60% of patients. It is predicted by greater ventricular dimensions and associated with significantly better long-term survival. Whether a staged approach with transcatheter correction of MR should be considered in patients with significant residual MR following AVR remains undetermined.

Airway smooth muscle adapting in dynamic conditions is refractory to the bronchodilator effect of a deep inspiration.

Airway smooth muscle (ASM) is continuously strained during breathing at tidal volume. Whether this tidal strain influences the magnitude of the bronchodilator response to a deep inspiration (DI) is not clearly defined. The present in vitro study examines the effect of tidal strain on the bronchodilator effect of DIs. ASM strips from sheep tracheas were mounted in organ baths and then subjected to stretches (30% strain), simulating DIs at varying time intervals. In between simulated DIs, the strips were either held at a fixed length (isometric) or oscillated continuously by 6% (length oscillations) to simulate tidal strain. The contractile state of the strips was also controlled by adding either methacholine or isoproterenol to activate or relax ASM, respectively. Although the time-dependent gain in force caused by methacholine was attenuated by length oscillations, part of the acquired force in the oscillating condition was preserved postsimulated DIs, which was not the case in the isometric condition. Consequently, the bronchodilator effect of simulated DIs (i.e., the decline in force postsimulated versus presimulated DIs) was attenuated in oscillating versus isometric conditions. These findings suggest that an ASM operating in a dynamic environment acquired adaptations that make it refractory to the decline in contractility inflicted by a larger strain simulating a DI.

Transesophageal echocardiography complications associated with interventional cardiology procedures.

BACKGROUND: Although there have been several reports documenting complications related with transesophageal echocardiography (TEE) manipulation following cardiac surgery, there is a paucity of data regarding the safety of TEE used to guide catheter-based interventions. The aim of this study was to determine the prevalence, types and risk factors of complications associated with procedures requiring active TEE guidance. METHODS: This study included 1249 consecutive patients undergoing either transcatheter aortic valve implantation (TAVI), Mitraclip, left atrial appendage occlusion (LAAO) or paravalvular leak closure (PVLC). Patients were divided into 2 cohorts based on the degree of probe manipulation required to guide the procedure and the risk of developing a TEE-related complication: low-risk (TAVI, n = 1037) and high-risk (Mitraclip, LAAO and PVLC, n = 212). Patients were further analyzed according to the occurrence of major and minor TEE-related complications. RESULTS: The overall incidence of TEE-related complications was 0.9% in the TAVI group and 6.1% in the rest of the cohort (P < .001). Patients in the high-risk cohort had also a higher incidence of major-complications (2.8% vs 0.6%, P = .008), and factors associated with an increased risk were being underweight, having a prior history of gastrointestinal bleeding and the use of chronic steroids/immunosuppressive medications. Procedural time under TEE-manipulation was longer in patients exhibiting complications and was an independent predictor of major complications (OR = 1.13, 95% CI 1.01-1.25, for each 10 minutes increments in imaging time). Patients with major complications undergoing Mitraclip had the longest median time under TEE-manipulation (297 minutes) and a risk of developing a major-complication that was 10.64 times higher than the rest of the cohort (95% CI 3.30-34.29, P < .001). CONCLUSION: The prevalence of TEE-related complications associated with interventional procedures is higher than previously reported. Undergoing a prolonged procedure, particularly in the setting of Mitraclip, was the main factor linked to TEE-related complications.

Secondary prevention after CABG: do new agents change the paradigm?

PURPOSE OF REVIEW: Coronary artery bypass graft (CABG) surgery remains the gold-standard treatment for multivessel and left main coronary artery disease. Despite significant improvement in cardiovascular outcomes, patients undergoing CABG remain at risk for recurrent adverse ischemic events and other cardiovascular outcomes (coronary revascularisation, stroke, cardiac death, etc.). The purpose of this review is to summarize the most recent evidence in pharmacological preventive therapies addressing the residual cardiovascular risk in patients who have undergone CABG. RECENT FINDINGS: Novel cardiovascular pharmacological preventive strategies targeting inflammatory, metabolic and prothrombotic (antiplatelet and anticoagulation) pathways have been recently assessed, with promising results for secondary prevention after CABG. SUMMARY: Secondary prevention is an essential part of postoperative care after CABG. Novel lipid-lowering and glucose-controlling agents suggest a strong and consistent benefit on native coronary artery disease and overall cardiovascular outcomes. The role and the choice of enhanced antiplatelet/anticoagulation/lipid/glucose-modulating therapies following CABG should be better defined and deserves further investigation. Additional studies are required to identify new therapeutic target addressing the specific multifactorial nature of the graft CV disease and identifying the best preventive strategies for long-term graft patency.

Clinical and echocardiographic presentation of postmyocardial infarction papillary muscle rupture.

BACKGROUND: Severe mitral regurgitation (MR) can occur following myocardial infarction (MI) with either partial or complete papillary muscle rupture (pPMR or cPMR). Although the incidence of this complication has significantly decreased, it is still associated with significant mortality. We sought to evaluate the different echocardiographic and clinical presentations of pPMR and cPMR. METHODS AND RESULTS: A review of all the urgent procedures for ischemic MR between January 2000 and June 2016 was performed to identify patients who underwent surgery for PMR. Surgical protocols and echocardiographic studies were used to identify patients with cPMR and pPMR. A total of 37 patients had cardiac surgery for PMR (18 cPMR, 19 pPMR). All patients with cPMR were in cardiogenic shock at the time of diagnosis, as opposed to only 53% of patients with pPMR (P = 0.0008). Between the time of diagnosis and surgery, 7 patients with pPMR developed cardiogenic shock. Transthoracic echocardiography (TTE) led to the diagnosis in 72% of cPMR and 32% of pPMR (P = 0.02). TEE had a yield of 100% for both cPMR and pPMR. Six pathologic varieties of post-MI PMR were recognized on echocardiography and during surgery. Early postoperative, 1 (72% vs 84%), 3 (67% vs 84%), and 5 years (67% vs 74%) survival rates were similar for cPMR and pPMR (P = 0.26). CONCLUSIONS: Partial PMR is associated with a different clinical and echocardiographic presentation than cPMR. Still, most pPMR patients progress toward cardiogenic shock. Prompt diagnosis and referral for surgery are critical and could potentially decrease mortality.

Significant mitral regurgitation in patients undergoing TAVR: Mechanisms and imaging variables associated with improvement.

BACKGROUND: Significant mitral regurgitation (MR) is associated with poorer outcomes in patients undergoing transcatheter aortic valve replacement (TAVR). Factors associated with MR improvement have not been studied thoroughly. METHODS: Retrospective analysis of consecutive patients treated with TAVR with more than mild MR at baseline. MR evolution was assessed at 1-3 and 6-12 months after intervention. MR severity and mechanisms were assessed by echocardiography. Mitral annulus calcification (MAC) was quantified using preoperative cardiac CT. RESULTS: From 674 consecutive TAVR recipients, 78 with more than mild MR had a 6-12 months follow-up. Following TAVR, MR improved in 34 patients (43%), remained stable in 38 (49%) and worsened in 6 (8%). Patients with MR improvement had greater tenting area (141 ± 56 vs. 99 ± 40 mm2 , P < 0.01), tenting height (7.2 ± 1.9 vs. 5.6 ± 1.9 mm, P < 0.01) and lower ejection fraction (43 ± 16 vs. 52 ± 14%, P = 0.01). MAC was frequent (87.7% of patients) and a trend in greater MAC was observed in patients without MR improvement (3560 ± 5587 vs. 2053 ± 2800, P = 0.16). In multivariable analysis, tenting area (OR per 10 mm2 increase: 1.012, 95% CI, 1.001-1.024 P = 0.039) and annulus calcifications associated with leaflet restriction (OR = 0.108, 95% CI, 0.012-0.956, P = 0.045) were independently associated with MR outcome after TAVR. CONCLUSION: Larger mitral valve tenting area was associated with more improvement of MR after TAVR whereas extensive MAC associated with leaflet restriction was associated with less improvement. This may help in the clinical decision-making process of TAVR candidates with concomitant MR.

Infective endocarditis following transcatheter edge-to-edge mitral valve repair: A systematic review.

OBJECTIVES: To assess the clinical characteristics, management, and outcomes of patients diagnosed with infective endocarditis (IE) after edge-to-edge mitral valve repair with the MitraClip device. BACKGROUND: Transcatheter edge-to-edge mitral valve repair has emerged as an alternative to surgery in high-risk patients. However, few data exist on IE following transcatheter mitral procedures. METHODS: Four electronic databases (PubMed, Google Scholar, Embase, and Cochrane Library) were searched for original published studies on IE after edge-to-edge transcatheter mitral valve repair from 2003 to 2017. RESULTS: A total of 10 publications describing 12 patients with definitive IE (median age 76 years, 55% men) were found. The mean logistic EuroSCORE/EuroSCORE II were 41% and 45%, respectively. The IE episode occurred early (within 12 months post-procedure) in nine patients (75%; within the first month in five patients). Staphylococcus aureus was the most frequent (60%) causal microorganism, and severe mitral regurgitation was present in all cases but one. Surgical mitral valve replacement (SMVR) was performed in most (67%) patients, and the mortality associated with the IE episode was high (42%). CONCLUSIONS: IE following transcatheter edge-to-edge mitral valve repair is a rare but life-threatening complication, usually necessitating SMVR despite the high-risk profile of the patients. These results highlight the importance of adequate preventive measures and a prompt diagnosis and treatment of this serious complication.

CD45 Expression in Mitral Valve Endothelial Cells After Myocardial Infarction.

RATIONALE: Ischemic mitral regurgitation, a complication after myocardial infarction (MI), induces adaptive mitral valve (MV) responses that may be initially beneficial but eventually lead to leaflet fibrosis and MV dysfunction. We sought to examine the MV endothelial response and its potential contribution to ischemic mitral regurgitation. OBJECTIVE: Endothelial, interstitial, and hematopoietic cells in MVs from post-MI sheep were quantified. MV endothelial CD45, found post MI, was analyzed in vitro. METHODS AND RESULTS: Ovine MVs, harvested 6 months after inferior MI, showed CD45, a protein tyrosine phosphatase, colocalized with von Willebrand factor, an endothelial marker. Flow cytometry of MV cells revealed significant increases in CD45+ endothelial cells (VE-cadherin+/CD45+/α-smooth muscle actin [SMA]+ and VE-cadherin+/CD45+/αSMA- cells) and possible fibrocytes (VE-cadherin-/CD45+/αSMA+) in inferior MI compared with sham-operated and normal sheep. CD45+ cells correlated with MV fibrosis and mitral regurgitation severity. VE-cadherin+/CD45+/αSMA+ cells suggested that CD45 may be linked to endothelial-to-mesenchymal transition (EndMT). MV endothelial cells treated with transforming growth factor-ß1 to induce EndMT expressed CD45 and fibrosis markers collagen 1 and 3 and transforming growth factor-ß1 to 3, not observed in transforming growth factor-ß1-treated arterial endothelial cells. A CD45 protein tyrosine phosphatase inhibitor blocked induction of EndMT and fibrosis markers and inhibited EndMT-associated migration of MV endothelial cells. CONCLUSIONS: MV endothelial cells express CD45, both in vivo post MI and in vitro in response to transforming growth factor-ß1. A CD45 phosphatase inhibitor blocked hallmarks of EndMT in MV endothelial cells. These results point to a novel, functional requirement for CD45 phosphatase activity in EndMT. The contribution of CD45+ endothelial cells to MV adaptation and fibrosis post MI warrants investigation.

Left atrial appendage closure: Initial experience with the ultraseal device.

OBJECTIVES: We report the initial experience of percutaneous left atrial appendage (LAA) closure with the Ultraseal device. BACKGROUND: LAA closure is an alternative to oral anticoagulation for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) and high risk of bleeding. The Ultraseal device is a new LAA closure prosthesis that consists of a distal soft bulb and a proximal sail attached by an articulating joint that allows a high degree of device conformability to the different variations of the LAA anatomy. METHODS: We included 12 consecutive patients with NVAF who underwent LAA closure with the Ultraseal device between January and December 2015 in our center. Patients had clinical and transesophageal echocardiography (TEE) examinations at baseline and at 45 days following LAA closure. RESULTS: The device was successfully implanted in all patients, with no periprocedural complications. There were no episodes of bleeding, stroke, pericardial effusion, or device embolization at 45-day follow-up. No cases with residual leaks >5 mm were observed at TEE. One patient presented a device related thrombus without clinical consequences. CONCLUSIONS: This initial experience with the Ultraseal LAA closure device demonstrates preliminary safety and feasibility. Further larger studies with longer follow-up are warranted. © 2016 Wiley Periodicals, Inc.

Early Activation of Growth Pathways in Mitral Leaflets Exposed to Aortic Regurgitation: New Insights from an Animal Model.

BACKGROUND AND AIM OF THE STUDY: Mitral leaflet enlargement in patients with chronic aortic regurgitation (AR) has been identified as an adaptive mechanism potentially able to prevent functional mitral regurgitation (FMR) in response to left ventricular (LV) dilatation. The timing of valve enlargement is not known, and the related mechanisms are largely unexplored. METHODS: AR was induced in 58 rats, and another 54 were used as sham controls. Animals were euthanized at different time points after AR creation (48 h, one week, and three months), and AR severity, FMR and LV dilatation were assessed using echocardiography. Mitral valves were harvested to document the reactivation of embryonic growth pathways. RESULTS: AR animals had increased LV dimensions and mitral annulus size. No animal developed FMR. No change in leaflet length or thickness was seen at 48 h; however, anterior mitral leaflets were longer and thicker in AR animals at one week and three months. Molecular changes were present early (at 48 h and at one week), with positive staining for transforming growth factor-b1 (TGF-b1), Alpha-smooth muscle actin (α-SMA) and matrix metalloproteinase-2 (MMP-2), which suggested active matrix remodeling. Increased gene expression for collagen 1, TGF-ß1, α-SMA and MMP-2 was found in the mitral valve at 48 h and at one week, but after three months their expression had returned to normal. CONCLUSIONS: This model of AR induces active expansion and thickening of the mitral leaflets. Growth signals are expressed acutely, but not at three months, which suggests that most of this enlargement occurs at an early stage. The stimulation of valvular growth could represent a new strategy for the prevention of FMR.

Late repair of ischemic mitral regurgitation does not prevent left ventricular remodeling: importance of timing for beneficial repair.

BACKGROUND: Ischemic mitral regurgitation (MR) is a frequent complication of myocardial infarction associated with left ventricular (LV) dilatation and dysfunction, which doubles mortality. At the molecular level, moderate ischemic MR is characterized by a biphasic response, with initial compensatory rise in prohypertrophic and antiapoptotic signals, followed by their exhaustion. We have shown that early MR repair 30 days after myocardial infarction is associated with LV reverse remodeling. It is not known whether MR repair performed after the exhaustion of compensatory mechanisms is also beneficial. We hypothesized that late repair will not result in LV reverse remodeling. METHODS AND RESULTS: Twelve sheep underwent distal left anterior descending coronary artery ligation to create apical myocardial infarction and implantation of an LV-to-left atrium shunt to create standardized moderate volume overload. At 90 days, animals were randomized to shunt closure (late repair) versus sham (no repair). LV remodeling was assessed by 3-dimensional echocardiography, dP/dt, preload-recruitable stroke work, and myocardial biopsies. At 90 days, animals had moderate volume overload, LV dilatation, and reduced ejection fraction (all P<0.01 versus baseline, P=NS between groups). Shunt closure at 90 days corrected the volume overload (regurgitant fraction 6 ± 5% versus 27 ± 16% for late repair versus sham, P<0.01) but was not associated with changes in LV volumes (end-diastolic volume 106 ± 15 versus 110 ± 22 mL; end-systolic volume 35 ± 6 versus 36 ± 6 mL) or increases in preload-recruitable stroke work (41 ± 7 versus 39 ± 13 mL mm Hg) or dP/dt (803 ± 210 versus 732 ± 194 mm Hg/s) at 135 days (all P=NS). Activated Akt, central in the hypertrophic process, and signal transducer and activator of transcription 3 (STAT3), a critical node in the hypertrophic stimulus by cytokines, were equally depressed in both groups. CONCLUSIONS: Late correction of moderate volume overload after myocardial infarction did not improve LV volume or contractility. Upregulation of prohypertrophic intracellular pathways was not observed. This contrasts with previously reported study in which early repair (30 days) reversed LV remodeling. This suggests a window of opportunity to repair ischemic MR after which no beneficial effect on LV is observed, despite successful repair.

Multimarker Approach to Improve Risk Stratification of Patients Undergoing Transcatheter Aortic Valve Implantation.

Background: A blood multimarker approach may be useful to enhance risk stratification in patients undergoing TAVI. Objectives: The objective of this study was to determine the prognostic value of multiple blood biomarkers in transcatheter aortic valve implantation (TAVI) patients. Methods: In this prospective study, several blood biomarkers of cardiovascular function, inflammation, and renal function were measured in 362 patients who underwent TAVI. The cohort was divided into 3 groups according to the number of elevated blood biomarkers (ie, ≥ median value for the whole cohort) for each patient before the procedure. Survival analyses were conducted to evaluate the association between blood biomarkers and risk of adverse event following TAVI. Results: During a median follow-up of 2.5 (IQR: 1.9-3.2) years, 34 (9.4%) patients were rehospitalized for heart failure, 99 (27%) patients died, and 113 (31.2%) met the composite endpoint of all-cause mortality or heart failure rehospitalization. Compared to patients with 0 to 3 elevated biomarkers (referent group), those with 4 to 7 and 8 to 9 elevated biomarkers had a higher risk of all-cause mortality (HR: 1.54 [95% CI: 0.84-2.80], P = 0.16, and HR: 2.81 [95% CI: 1.53-5.15], P < 0.001, respectively) and of the composite endpoint (HR: 1.65 [95% CI: 0.95-2.84], P = 0.07, and HR: 2.67 [95% CI: 1.52-4.70] P < 0.001, respectively). Moreover, adding the number of elevated blood biomarkers into the clinical multivariable model provided significant incremental predictive value for all-cause mortality (Net Reclassification Index = 0.71, P < 0.001). Conclusions: An increasing number of elevated blood biomarkers is associated with higher risks of adverse clinical outcomes following TAVI. The blood multimarker approach may be helpful to enhance risk stratification in TAVI patients.

Left and Right Ventricular Longitudinal Systolic Function Following Aortic Valve Replacement in the PARTNER 2 Trial And Registry.

AIMS: Evaluation of left and right ventricular longitudinal systolic function may enhance risk stratification following aortic valve replacement (AVR). The study objective was to evaluate the changes in left and right ventricular longitudinal systolic function and RV-pulmonary artery (RV-PA) coupling from baseline to 30-days and 1-year after aortic valve replacement (AVR). METHODS AND RESULTS: LV longitudinal strain (LS), tricuspid annulus plane systolic excursion (TAPSE), and RV-PA coupling were evaluated in patients from the PARTNER-2A surgical AVR (SAVR) arm (n=985) and from the PARTNER-2 SAPIEN-3 registry (n=719). TAPSE and RV-PA coupling decreased significantly following SAVR, but remained stable following TAVR. Lower LV LS, TAPSE, or RV-PA coupling at baseline were associated with increased risk of the composite of death, hospitalization, and stroke at 5-years (Adjusted-HRs for LV LS<15%: 1.24 95%CI 1.05-1.45, p=0.001; TAPSE<14mm: 1.44 95%CI 1.21-1.73, p<0.001; RV/PA coupling<0.55mm/mmHg: 1.32 95% CI 1.07-1.63, p=0.011). Reduced TAPSE at baseline was the most powerful predictor of the composite endpoint at 5-years. Patients with LV ejection fraction <50% at baseline had increased risk of the primary endpoint with SAVR (HR: 1.34, 95%CI 1.08-1.68, p=0.009) but not with TAVR (HR: 1.12, 95%CI 0.88-1.42). Lower RV-PA coupling at 30-days showed the strongest association with cardiac mortality. CONCLUSION: SAVR but not TAVR was associated with a marked deterioration in RV longitudinal systolic function and RV-PA coupling. Lower TAPSE and RV-PA coupling at 30-days were associated with inferior clinical outcomes at 5-years. In patients with LVEF<50%, TAVR was associated with superior 5-year outcomes.