Hadi Toeg

Predictive factors, management, and clinical outcomes of coronary obstruction following transcatheter aortic valve implantation: Insights from a large multicenter registry

OBJECTIVES This study sought to evaluate the main baseline and procedural characteristics, management, and clinical outcomes of patients from a large cohort of patients undergoing transcatheter aortic valve implantation (TAVI) who suffered coronary obstruction (CO). BACKGROUND Very little data exist on CO following TAVI. METHODS This multicenter registry included 44 patients who suffered symptomatic CO following TAVI of 6,688 patients (0.66%). Pre-TAVI computed tomography data was available in 28 CO patients and in a control group of 345 patients (comparisons were performed including all patients and a cohort matched 1:1 by age, sex, previous coronary artery bypass graft, transcatheter valve type, and size). RESULTS Baseline and procedural variables associated with CO were older age (p < 0.001), female sex (p < 0.001), no previous coronary artery bypass graft (p = 0.043), the use of a balloon-expandable valve (p = 0.023), and previous surgical aortic bioprosthesis (p = 0.045). The left coronary artery was the most commonly involved (88.6%). The mean left coronary artery ostia height and sinus of Valsalva diameters were lower in patients with obstruction than in control subjects (10.6 ± 2.1 mm vs. 13.4 ± 2.1 mm, p < 0.001; 28.1 ± 3.8 mm vs. 31.9 ± 4.1 mm, p < 0.001). Differences between groups remained significant after the case-matched analysis (p < 0.001 for coronary height; p = 0.01 for sinus of Valsalva diameter). Most patients presented with persistent severe hypotension (68.2%) and electrocardiographic changes (56.8%). Percutaneous coronary intervention was attempted in 75% of the cases and was successful in 81.8%. Thirty-day mortality was 40.9%. After a median follow-up of 12 (2 to 18) months, the cumulative mortality rate was 45.5%, and there were no cases of stent thrombosis or reintervention. CONCLUSIONS Symptomatic CO following TAVI was a rare but life-threatening complication that occurred more frequently in women, in patients receiving a balloon-expandable valve, and in those with a previous surgical bioprosthesis. Lower-lying coronary ostium and shallow sinus of Valsalva were associated anatomic factors, and despite successful treatment, acute and late mortality remained very high, highlighting the importance of anticipating and preventing the occurrence of this complication.

Cardiovascular progenitor-derived extracellular vesicles recapitulate the beneficial effects of their parent cells in the treatment of chronic heart failure

BACKGROUND Cell-based therapies are being explored as a therapeutic option for patients with chronic heart failure following myocardial infarction. Extracellular vesicles (EV), including exosomes and microparticles, secreted by transplanted cells may orchestrate their paracrine therapeutic effects. We assessed whether post-infarction administration of EV released by human embryonic stem cell-derived cardiovascular progenitors (hESC-Pg) can provide equivalent benefits to administered hESC-Pg and whether hESC-Pg and EV treatments activate similar endogenous pathways. METHODS Mice underwent surgical occlusion of their left coronary arteries. After 2-3 weeks, 95 mice included in the study were treated with hESC-Pg, EV, or Minimal Essential Medium Alpha Medium (alpha-MEM; vehicle control) delivered by percutaneous injections under echocardiographic guidance into the peri-infarct myocardium. functional and histologic end-points were blindly assessed 6 weeks later, and hearts were processed for gene profiling. Genes differentially expressed between control hearts and hESC-Pg-treated and EV-treated hearts were clustered into functionally relevant pathways. RESULTS At 6 weeks after hESC-Pg administration, treated mice had significantly reduced left ventricular end-systolic (-4.20 ± 0.96 µl or -7.5%, p = 0.0007) and end-diastolic (-4.48 ± 1.47 µl or -4.4%, p = 0.009) volumes compared with baseline values despite the absence of any transplanted hESC-Pg or human embryonic stem cell-derived cardiomyocytes in the treated mouse hearts. Equal benefits were seen with the injection of hESC-Pg-derived EV, whereas animals injected with alpha-MEM (vehicle control) did not improve significantly. Histologic examination suggested a slight reduction in infarct size in hESC-Pg-treated animals and EV-treated animals compared with alpha-MEM-treated control animals. In the hESC-Pg-treated and EV-treated groups, heart gene profiling identified 927 genes that were similarly upregulated compared with the control group. Among the 49 enriched pathways associated with these up-regulated genes that could be related to cardiac function or regeneration, 78% were predicted to improve cardiac function through increased cell survival and/or proliferation or DNA repair as well as pathways related to decreased fibrosis and heart failure. CONCLUSIONS In this post-infarct heart failure model, either hESC-Pg or their secreted EV enhance recovery of cardiac function and similarly affect cardiac gene expression patterns that could be related to this recovery. Although the mechanisms by which EV improve cardiac function remain to be determined, these results support the idea that a paracrine mechanism is sufficient to effect functional recovery in cell-based therapies for post-infarction-related chronic heart failure.

The extracellular matrix controls gap junction protein expression and function in postnatal hippocampal neural progenitor cells

BackgroundGap junction protein and extracellular matrix signalling systems act in concert to influence developmental specification of neural stem and progenitor cells. It is not known how these two signalling systems interact. Here, we examined the role of ECM components in regulating connexin expression and function in postnatal hippocampal progenitor cells.ResultsWe found that Cx26, Cx29, Cx30, Cx37, Cx40, Cx43, Cx45, and Cx47 mRNA and protein but only Cx32 and Cx36 mRNA are detected in distinct neural progenitor cell populations cultured in the absence of exogenous ECM. Multipotential Type 1 cells express Cx26, Cx30, and Cx43 protein. Their Type 2a progeny but not Type 2b and 3 neuronally committed progenitor cells additionally express Cx37, Cx40, and Cx45. Cx29 and Cx47 protein is detected in early oligodendrocyte progenitors and mature oligodendrocytes respectively. Engagement with a laminin substrate markedly increases Cx26 protein expression, decreases Cx40, Cx43, Cx45, and Cx47 protein expression, and alters subcellular localization of Cx30. These changes are associated with decreased neurogenesis. Further, laminin elicits the appearance of Cx32 protein in early oligodendrocyte progenitors and Cx36 protein in immature neurons. These changes impact upon functional connexin-mediated hemichannel activity but not gap junctional intercellular communication.ConclusionTogether, these findings demonstrate a new role for extracellular matrix-cell interaction, specifically laminin, in the regulation of intrinsic connexin expression and function in postnatal neural progenitor cells.

Electrocardiographic monitoring for detecting atrial fibrillation after ischemic stroke or transient ischemic attack: systematic review and meta-analysis.

Background—Atrial fibrillation (AF) is a major cause of stroke. Although standard investigations after an event include electrocardiographic monitoring, the optimal duration to detect AF is unclear. We performed a systematic review and meta-analysis to determine whether the duration of electrocardiographic monitoring after an ischemic event is related to the detection of AF. Methods and Results—Prospective studies that reported the proportion of new AF diagnosed using electrocardiographic monitoring for >12 hours in patients with recent stroke or transient ischemic attack were analyzed. Studies were excluded if the stroke was hemorrhagic or AF was previously diagnosed. A total of 31 articles met inclusion criteria. Longer duration of monitoring was associated with an increased detection of AF when examining monitoring time as a continuous variable (P<0.001 for metaregression analysis). When dichotomizing studies based on monitoring duration, studies with monitoring lasting ⩽72 hours detected AF in 5.1%, whereas monitoring lasting ≥7 days detected AF in 15%. The proportion of new diagnosis increased to 29.15% with extended monitoring for 3 months. Significant heterogeneity within studies was detected for both groups (⩽72 hours, I2=91.3%; ≥7 days, I2=75.8). When assessing the odds of AF detection in the 3 randomized controlled trial, there was a 7.26 increased odds of AF with long-term monitoring (95% confidence intervals [3.99–12.83]; P value <0.001). Conclusions—Longer duration of electrocardiographic monitoring after cryptogenic stroke is associated with a greater detection of AF. Future investigation is needed to determine the optimal duration of long-term monitoring.

Injectable Small Intestine Submucosal Extracellular Matrix in an Acute Myocardial Infarction Model

BACKGROUND The mechanisms involved in myocardial regeneration and cardiac remodeling were examined by injecting porcine-derived small intestine submucosal extracellular matrix (SIS-ECM), with and without circulating angiogenic cells (CACs), in a mouse model of acute myocardial infarction (MI). METHODS Nine- to 10-week-old female C57BL/6J mice had the left anterior descending (LAD) coronary artery ligated. Seven days after ligation, 38 randomly allocated animals received echocardiographically guided intramyocardial injections of phosphate buffered saline (PBS), CACs, SIS-ECM, or SIS-ECM + CACs. Repeated echocardiography and immunohistochemical analysis were performed at 28 days after ligation. RESULTS Baseline postligation left ventricular ejection fraction (LVEF) was equivalent in all groups. Twenty-one days after treatment, ejection fraction improved in the SIS-ECM + CAC treatment group (by 38% ± 2.12%) and the SIS-ECM treatment group (by 36% ± 3.71%), compared with the CAC-alone and PBS treatment groups (p < 0.1). Massons trichrome staining showed reduced infarct size in SIS-ECM + CACs (34.2% ± 3.1%) and SIS-ECM alone (34.5% ± 4.7%) compared with CACs alone (47.3% ± 6.0%) and PBS (61.9% ± 5.5%; p < 0.002). Arteriolar density in periinfarct regions was enhanced in both SIS-ECM-treated groups (by ≥ 78% ± 7%; p = 0.03). More GATA4- and β-catenin-positive cardiac cells were found in the myocardium of SIS-ECM-treated animals. CONCLUSIONS Intramyocardial delivery of SIS-ECM 7 days after MI in a mouse model reduced infarct size and improved myocardial vessel density and function; when combined with CACs it helped restore myocardial cellularity, suggesting a potential therapeutic role for SIS-ECM in cardiac regeneration.

The impact of prosthesis–patient mismatch after aortic valve replacement varies according to age at operation

Objectives Age may modify the impact of prosthesis–patient mismatch (PPM) on outcomes after aortic valve replacement (AVR), as physical functioning decreases with age, and comorbidities become more prevalent. We hypothesised that the consequences of PPM in patients 70 years old or older may be less important than in younger patients. Methods In total, 707 aortic stenosis patients were followed for a maximum of 17.5 years after AVR. PPM was defined as an in vivo indexed effective orifice area ≤0.85 cm2/m2, and severe PPM as ≤0.65 cm2/m2. Results In patients less than 70 years of age with normal LV function, the presence of PPM did not significantly alter survival. However, in patients under 70 with LV dysfunction, PPM was associated with decreased survival (HR 2.2; p=0.046). In patients aged 70 years of age or older, PPM had no effect on survival, regardless of LV function. Similarly, PPM was predictive of postoperative congestive heart failure (CHF) in patients under 70 with LV dysfunction (HR 3.6; p=0.046) but not in older patients. Similar results were observed for the composite endpoint of death or CHF. Postoperative LV mass regression was impaired by increased age (p=0.019), and by PPM in patients aged 70 years of age or older with LV dysfunction (by 28.8 g/m2; p=0.026). Conclusions The impact of PPM on outcomes after AVR depends on age at operation. PPM in patients under age 70 years with LV dysfunction is associated with decreased survival and lower freedom from CHF. In patients 70 years of age or older, PPM does not impact mortality or symptoms, but impairs LV mass regression beyond that explained by age alone.

Finding the ideal biomaterial for aortic valve repair with ex vivo porcine left heart simulator and finite element modeling

OBJECTIVES Aortic valve (AV) repair (AVr) has become an attractive alternative to AV replacement for the correction of aortic insufficiency; however, little clinical evidence exists in determining which biomaterial at AVr would be optimal. Cusp replacement in AVr has been associated with increased long-term AVr failure. We measured the hemodynamic and biomaterial properties using an ex vivo porcine AVr model with clinically relevant biomaterials and generated a finite element model to ascertain which materials would be best suited for valve repair. METHODS Porcine aortic roots with intact AVs were placed in a left heart simulator mounted with a high-speed camera for baseline valve assessment. The noncoronary cusp was excised and replaced with autologous porcine pericardium, glutaraldehyde-fixed bovine pericardial patch (Synovis), extracelluar matrix scaffold (CorMatrix), or collagen-impregnated Dacron (Hemashield). The hemodynamic parameters were measured for a range of cardiac outputs (2.5-6.5 L/min) after repair. The biomaterial properties and St Jude Medical pericardial patch were determined using pressurization experiments. Finite element models of the AV and root complex were constructed to determine the hemodynamic characteristics and leaflet stresses. RESULTS The geometric orifice areas after repair were significantly reduced in the Hemashield (P<.05) and CorMatrix (P=.0001) groups. Left ventricular work increased with increasing cardiac output (P=.001) in unrepaired valves, as expected, and was similar among all biomaterial groups. Finite element modeling of the biomaterials displayed differences in the percentage of changes in total Von Mises stress for both replaced (noncoronary cusp) and nonreplaced left and right cusps with the St Jude Medical pericardial patch (+4%, +24%) and autologous porcine pericardium (+5, +26%), with a lower percentage of changes than for the bovine pericardial patch (+12%, +27%), Hemashield (+30%, +9%), and CorMatrix (+13%, +32%). CONCLUSIONS The present study has shown that postrepair left ventricular work did not increase despite a decrease in geometric orifice areas in the Hemashield and CorMatrix groups. The autologous porcine pericardium and St Jude Medical pericardial patch had the closest profile to normal AVs; therefore, either biomaterial might be best suited. Finally, the increased stresses found in the bovine pericardial patch, Hemashield, and CorMatrix groups might, after prolonged tensile exposure, be associated with late repair failure.

Endovascular treatment for cerebral septic embolic stroke.

This case demonstrates an alternative approach to cerebral revascularization by performing both intravascular mechanical thrombectomy and local injection of thrombolytics that may reduce mortality, bleeding, and the diminished quality of life experienced by patients following an acute septic embolic stroke.

Contemporary Midterm Echocardiographic Outcomes of Bentall Procedure and Aortic Valve Sparing Root Replacement

BACKGROUND Valve sparing root replacement (VSRR) and aortic valve repair (AVr) is an attractive treatment option compared with composite valve and root replacement (Bentall procedure) for patients with aortic root dilatation with or without aortic valve disease. While aortic valve preservation reduces the risk of valve-related complications, little is known about echocardiographic differences at follow-up between these 2 strategies. METHODS Consecutive nonemergent patients undergoing VSRR and AVr (n=68) were compared with contemporary historical controls undergoing the Bentall procedure for aortic root pathology with or without mixed aortic valve disease (insufficiency or stenosis) (n=96). The VSRR was performed preferentially using the reimplantation technique. Bentall procedure utilized a mechanical valve in 65% of patients, a biologic prosthesis in 22%, and a homograft in 13%. Clinical and echocardiographic data were obtained at baseline and at follow-up (median=30 months). RESULTS The 2 cohorts were similar with respect to all preoperative characteristics with the exception of disease etiology. The Bentall group had a higher proportion of degenerative valve and root disease (47.8% vs 27.9%) and a lower proportion of bicuspid aortic valve disease (22.8% vs 51.5%) as compared with the VSRR group (p=0.007). Postoperative echocardiographic outcomes were comparable between groups with the exception of higher peak (23.37±11.80 vs 18.0±12.04; p=0.02) and mean (13.07±7.53 vs 9.56±6.49; p=0.01) transvalvular aortic gradients in the Bentall group. Persistence of left ventricular dysfunction (8.4% vs 6.1%; p=0.61), presence of greater than moderate aortic valve (AV) insufficiency (3% vs 4.6%; p=0.32), and left ventricular mass (213.24±72.36 vs 207.38±63.07, p=0.61) were comparable between the Bentall and VSRR group, respectively. Finally, survival (p=0.21) and freedom from valve-related events (p=0.74) were similar between groups. CONCLUSIONS Valve sparing root replacement with AV repair provides similar mid-term echocardiographic and clinical outcomes compared with the Bentall.

An update on mechanical circulatory support for heart failure therapy.

Purpose of review This article aims to review contemporary studies that utilized mechanical circulatory support (MCS) in the treatment of heart failure and to elaborate on prospective mechanical alternatives. Recent findings There is a growing need for a well-tolerated, durable and effective MCS option in patients with refractory heart failure. In previous years, the primary indication for MCS therapy supported bridge to transplantation. These early left ventricular assist devices (LVADs) suffered significant adverse events, thereby limiting their prolonged use. With the introduction of newer continuous flow LVADs, with lower morbidity, neurological events, pump failure and the expanded indication use (i.e. destination therapy), the overall number of implanted patients has grown. Summary There has been a dramatic advancement of durability found in the second and third-generation, continuous flow LVADs, along with improved survival rates in patients receiving these devices for destination therapy. MCS may soon become the treatment option of choice in refractory heart failure patients, especially with further evolution of less invasive approaches, smaller designs, and energy sources.