Impact of Non-Diameter Aortic Indices on Surgical Eligibility: Results from the TITAN: SvS Randomized Controlled Trial.

OBJECTIVES: Traditional criteria for intervention on an asymptomatic ascending aortic aneurysm has been a maximal aortic diameter of ⩾5.5cm. The 2022 ACC/AHA aortic guidelines adopted cross-sectional aortic area/height ratio, aortic size index (ASI) and aortic height index (AHI) as alternate parameters for surgical intervention. The objective of this study was to evaluate the impact of using these newer indices on patient eligibility for surgical intervention in a prospective, multicenter cohort with moderate sized ascending aortic aneurysms between 5.0-5.4 cm. METHODS: Patients enrolled from 2018 to 2023 in the randomization or registry arms of the multicenter trial, TITAN: SvS, were included in the study. Clinical data was captured prospectively in an online database. Imaging data were derived from a core CT lab. RESULTS: Among the 329 included patients, 20% were female. Mean age was 65.0 ± 11.6 years and mean maximal aortic diameter was 50.8 ±3.9 mm. In the one third of all patients (n=109) who met any one of the three criteria (i.e., ASI ⩾ 3.08 cm/m2, AHI ⩾ 3.21 cm/m or cross-sectional aortic area/height ⩾ 10 cm2/m), their mean maximal aortic diameter was 52.5 ±0.52 mm. Alternate criteria were most commonly met in females compared to males: 20% versus 2% for ASI (p<0.001), 39% versus 5% for AHI (p<0.001) and 39% versus 21% for cross-sectional aortic area/height (p=0.002), respectively. CONCLUSIONS: One third of patients in Titan:SvS would meet criteria for surgical intervention based on novel parameters vs. the classic definition of diameter⩾5.5cm. Surgical thresholds for ASI, AHI or cross-sectional aortic area/height ratio are more likely to be met in female patients compared to male patients.

CCTA-based CABG SYNTAX Score: a tool to evaluate completeness of coronary segment revascularization after bypass surgery.

To describe the updated coronary computed tomographic angiography (CCTA)-based coronary artery bypass graft (CABG) anatomic SYNTAX Score (aSS) and assess its utility and reproducibility for assessing the completeness of revascularization after CABG. The CCTA-CABG aSS is a visual assessment using CCTA post-CABG which quantifies the failure in effectively grafting stenotic coronary segments, and therefore assesses the completeness of surgical revascularization. It is calculated by subtracting the aSS of successfully anastomosed coronary segments from the aSS of the native coronary tree. The inter-observer reproducibility of the CCTA-CABG aSS was evaluated in 45 consecutive patients with three-vessel disease with or without left main disease who underwent a CCTA 30 days (± 7 days) after CABG. The CCTA-CABG aSS was evaluated in 45 consecutive patients with 117 bypass grafts and 152 anastomoses. The median native coronary aSS was 35.0 [interquartile range (IQR) 27.0-41.0], whilst the median CCTA-CABG aSS was 13.0 (IQR 9.0-20.5). The inter-observer level of agreement for the native coronary aSS and the CCTA-CABG aSS were both substantial with respective Kappas of 0.67 and 0.61. The CCTA-CABG aSS was feasible in all patients who underwent CABG for complex coronary artery disease with substantial inter-observer reproducibility, and therefore can be used to quantify the completeness of revascularization after CABG.

Decreased serotonin transporter activity in the mitral valve contributes to progression of degenerative mitral regurgitation.

Degenerative mitral valve (MV) regurgitation (MR) is a highly prevalent heart disease that requires surgery in severe cases. Here, we show that a decrease in the activity of the serotonin transporter (SERT) accelerates MV remodeling and progression to MR. Through studies of a population of patients with MR, we show that selective serotonin reuptake inhibitor (SSRI) use and SERT promoter polymorphism 5-HTTLPR LL genotype were associated with MV surgery at younger age. Functional characterization of 122 human MV samples, in conjunction with in vivo studies in SERT-/- mice and wild-type mice treated with the SSRI fluoxetine, showed that diminished SERT activity in MV interstitial cells (MVICs) contributed to the pathophysiology of MR through enhanced serotonin receptor (HTR) signaling. SERT activity was decreased in LL MVICs partially because of diminished membrane localization of SERT. In mice, fluoxetine treatment or SERT knockdown resulted in thickened MV leaflets. Similarly, silencing of SERT in normal human MVICs led to up-regulation of transforming growth factor ß1 (TGFß1) and collagen (COL1A1) in the presence of serotonin. In addition, treatment of MVICs with fluoxetine not only directly inhibited SERT activity but also decreased SERT expression and increased HTR2B expression. Fluoxetine treatment and LL genotype were also associated with increased COL1A1 expression in the presence of serotonin in MVICs, and these effects were attenuated by HTR2B inhibition. These results suggest that assessment of both 5-HTTLPR genotype and SERT-inhibiting treatments may be useful tools to risk-stratify patients with MV disease to estimate the likelihood of rapid disease progression.

Extended Myectomy for Hypertrophic Cardiomyopathy: Early Outcomes From a Nascent Centre of Excellence in Canada.

Hypertrophic cardiomyopathy (HCM) is one of the commonest inherited cardiac abnormalities. The disorder is clinically and genetically heterogeneous and is characterized by left ventricular wall thickening that is not explained by abnormal loading conditions. HCM is estimated to affect between 1 in 200 and 1 in 500 people in the general population. In the majority of cases, HCM patients have a relatively benign course; however, if left untreated, this abnormality can lead to sudden cardiac death, especially in young adults and athletes. Therefore, early diagnosis is crucial to help implement the proper management for patients with HCM. In response to the growing need for more HCM centres of excellence in Canada, we developed one such centre at the University of Ottawa Heart Institute from the start of 2018. This centre will help in the early diagnosis and management of HCM patients, especially those with left ventricular outflow tract obstruction who might benefit from myectomy surgery. This paper describes our early experience with surgical myectomy in adult HCM patients between January 2018 and December 2020. We report the results of 27 patients with HCM who underwent myectomy surgery during the study period. All 27 patients survived to discharge, and all were still alive at 6 months postdischarge. Our experience highlights the crucial role that preoperative and perioperative imaging play in the management of this condition, in addition to the vital role of having a committed "heart team" of cardiologists, surgeons, and anesthesiologists.

La cardiomyopathie hypertrophique (CMH) est l'une des plus fréquentes anomalies cardiaques héréditaires. L'anomalie qui est cliniquement et génétiquement hétérogène est caractérisée par l'épaississement de la paroi du ventricule gauche qui n'est pas expliqué par des conditions de charge anormales. On estime que la CMH touche entre une personne sur 200 et une personne sur 500 dans la population générale. Dans la plupart des cas de CMH, l'évolution de la maladie est relativement bénigne. Toutefois, si cette anomalie n'est pas traitée, elle peut mener à la mort subite d'origine cardiaque, particulièrement chez les jeunes adultes et les athlètes. Par conséquent, le diagnostic précoce est crucial à la mise en œuvre d'une prise en charge adéquate des patients atteints de CMH. Pour répondre à la nécessité croissante d'un plus grand nombre de centres d'excellence sur la CMH au Canada, nous avons mis en place l'un de ces centres à l'Institut de cardiologie de l'Université d'Ottawa dès le début de 2018. Ce centre contribuera au diagnostic précoce et à la prise en charge des patients atteints de CMH, particulièrement des patients, dont la CMH est associée à une obstruction de la chambre de chasse du ventricule gauche, qui pourraient bénéficier d'une myectomie. Le présent article décrit nos premières expériences de myectomie chez les patients adultes atteints de CMH entre janvier 2018 et décembre 2020. Nous présentons les résultats de 27 patients atteints de CMH qui ont subi une myectomie durant la période étudiée. Les 27 patients ont survécu jusqu'à la sortie de l'hôpital, et étaient tous encore en vie six mois après. Notre expérience démontre le rôle crucial que joue l'imagerie en phase préopératoire et en phase périopératoire lors de la prise en charge de cette maladie, en plus du rôle essentiel de l'« équipe de cardiologie ¼ dévouée qui est composée de cardiologues, de chirurgiens et d'anesthésistes.

Severe Mitral Annular Calcification in Two Cases of Hypertrophic Obstructive Cardiomyopathy.

Management of patients with hypertrophic obstructive cardiomyopathy and severe mitral annular calcification can be challenging. Our cases highlight the importance of addressing all elements contributing to left ventricular outflow tract obstruction in cases of hypertrophic obstructive cardiomyopathy: hypertrophic basal interventricular septum, abnormal papillary muscles, and systolic anterior motion of the anterior mitral valve leaflet. Addressing mitral valve repair through aortotomy by performing a septal myectomy, papillary muscle realignment, and resection of aberrant chordae tendineae allows left ventricular outflow tract obstruction and systolic anterior motion to be successfully corrected. The success of these procedures depended on preoperative imaging and intraoperative provocation.

Surgical Techniques for the Treatment of Anomalous Origin of Right Coronary Artery From the Left Sinus: A Comparative Review.

The anomalous aortic origin of the right coronary artery (AAORCA) from the left sinus is a congenital anomaly affecting both the origin and course of the right coronary artery. AAORCA is nowadays easily and increasingly recognized by several cardiac imaging modalities. In most cases, patients remain asymptomatic; however, in some, and especially in young athletes, symptoms start to appear following exertion. A literature review was conducted on the surgical management of AAORCA by searching the Pubmed and Google Scholar databases. The inclusion criteria included manuscripts reporting surgical outcomes of AAORCA for ≥1 of the 3 techniques of interest (unroofing, reimplantation, and coronary artery bypass grafting) and manuscripts written in English and that were published between 2010 and 2020. The surgical management of AAORCA can be done through several techniques, most commonly the unroofing of the intramural segment of the AAORCA, the reimplantation of the native right coronary artery onto the right sinus of the aortic root, and coronary artery bypass grafting with either arterial or venous graft conduits with or without ligation of the proximal right coronary artery. Superiority of one surgical technique has not yet been formally proven because of the rare nature of this condition and the lack of any prospective randomized controlled trial or robust prospective observational studies.

Aortic Valve Regurgitation: Pathophysiology and Implications for Surgical Intervention in the Era of TAVR.

Aortic insufficiency (AI) or regurgitation is caused by the malcoaptation of the aortic valve (AV) cusps due to intrinsic abnormalities of the valve itself, a dilatation or geometric distortion of the aortic root, or by some combination thereof. In recent years, there has been an increase in the number of studies suggesting that AI is an active disease process caused by a combination of factors including but not limited to alteration of specific molecular pathways, genetic predisposition, and changes in the mechanotransductive properties of the AV apparatus. As the surgical management of AV disease continues to evolve, increasingly sophisticated surgical and percutaneous techniques for AV repair and replacement, including transcatheter aortic valve replacement (TAVR), have become more commonplace and will likely continue to expand as new devices are introduced. However, these techniques necessitate frequent reappraisal of the biological and mechanobiological mechanisms underlying AV regurgitation to better understand the risk factors for AI development and recurrence following surgical intervention as well as expand our limited knowledge on patient selection for such procedures. The aim of this review is to describe some of the putative mechanisms implicated in the development of AI, dissect some of the cross-talk among known and possible signaling pathways leading to valve remodeling, identify association between these pathways and pharmacological approaches, and discuss the implications for surgical and percutaneous approaches to AV repair in replacement in the TAVR era.

Circulating and tissue matricellular RNA and protein expression in calcific aortic valve disease.

Aortic valve sclerosis is a highly prevalent, poorly characterized asymptomatic manifestation of calcific aortic valve disease and may represent a therapeutic target for disease mitigation. Human aortic valve cusps and blood were obtained from 333 patients undergoing cardiac surgery (n = 236 for severe aortic stenosis, n = 35 for asymptomatic aortic valve sclerosis, n = 62 for no valvular disease), and a multiplex assay was used to evaluate protein expression across the spectrum of calcific aortic valve disease. A subset of six valvular tissue samples (n = 3 for asymptomatic aortic valve sclerosis, n = 3 for severe aortic stenosis) was used to create RNA sequencing profiles, which were subsequently organized into clinically relevant gene modules. RNA sequencing identified 182 protein-encoding, differentially expressed genes in aortic valve sclerosis vs. aortic stenosis; 85% and 89% of expressed genes overlapped in aortic stenosis and aortic valve sclerosis, respectively, which decreased to 55% and 84% when we targeted highly expressed genes. Bioinformatic analyses identified six differentially expressed genes encoding key extracellular matrix regulators: TBHS2, SPARC, COL1A2, COL1A1, SPP1, and CTGF. Differential expression of key circulating biomarkers of extracellular matrix reorganization was observed in control vs. aortic valve sclerosis (osteopontin), control vs. aortic stenosis (osteoprotegerin), and aortic valve sclerosis vs. aortic stenosis groups (MMP-2), which corresponded to valvular mRNA expression. We demonstrate distinct mRNA and protein expression underlying aortic valve sclerosis and aortic stenosis. We anticipate that extracellular matrix regulators can serve as circulating biomarkers of early calcific aortic valve disease and as novel targets for early disease mitigation, pending prospective clinical investigations.

Impact of preoperative fractional flow reserve on arterial bypass graft anastomotic function: the IMPAG trial.

AIMS: Visual estimation is the most commonly used method to evaluate the degree of coronary artery stenosis prior to coronary artery bypass grafting. In interventional cardiology, the use of fractional flow reserve (FFR) to guide revascularization decisions has become routine. We investigated whether the preoperative FFR measurement of coronary lesions is associated with anastomosis function 6 months after surgical revascularization using a multiarterial grafting strategy. METHODS AND RESULTS: In this prospective double-blind study, 67 patients were enrolled from two institutions in Europe and Canada. From these patients, 199 coronary lesions were assessed visually and with FFR at the time of the preoperative angiogram. All patients received coronary revascularization using multiple arterial grafts. A post-operative 6-month angiogram was performed to assess anastomosis functionality using a described angiographic method. The primary outcome was the association between preoperative FFR values and anastomosis function 6 months after surgery. Preoperative FFR was significantly associated with 6-months anastomotic function for all conduits and for all targets (P < 0.001). An FFR value of ≤0.78 was associated with an anastomotic occlusion rate of 3%. CONCLUSION: We found a significant association between the preoperative FFR measurement of the target vessel and the anastomotic functionality at 6 months, with a cut-off of 0.78. Integration of FFR measurement into the preoperative diagnostic workup before multiarterial coronary surgical revascularization leads to improved anastomotic graft function. CLINICAL TRIALS. GOV IDENTIFIER: NCT02527044.

Bilateral internal thoracic artery grafting: in situ or composite?

Bilateral internal thoracic artery (BITA) grafting is considered a superior choice for coronary artery bypass grafting (CABG). While the 10-year outcomes of BITA grafting from the recent Arterial Revascularization Trial (ART) are still pending, numerous observational studies have demonstrated the advantages of BITA grafting. These include better long-term graft patency and freedom from arteriosclerosis, in addition to higher survival rate compared to CABG using only the left internal thoracic artery (ITA). The different BITA configurations are in situ and composite-the choice of optimal grafting configuration is challenging. Patient factors such as coronary anatomy, presence of a diseased ascending aorta and the potential need for a future redo sternotomy will influence the choice of the grafting strategy. In situ BITA grafting is associated with excellent clinical outcomes and has been extensively described in the literature. However, uncertainties remain regarding the ideal in situ configuration and design. Composite BITA grafting is the other option that maximizes right ITA (RITA) utilization. In this configuration, the RITA is able to reach the distal circumflex and right coronary artery branches. This approach decreases the need for a third graft conduit.

Porphyrin-Based SOD Mimic MnTnBu OE -2-PyP5+ Inhibits Mechanisms of Aortic Valve Remodeling in Human and Murine Models of Aortic Valve Sclerosis.

Background Aortic valve sclerosis ( AVS c), the early asymptomatic presentation of calcific aortic valve (AV) disease, affects 25% to 30% of patients aged >65 years. In vitro and ex vivo experiments with antioxidant strategies and antagonists of osteogenic differentiation revealed that AVS c is reversible. In this study, we characterized the underlying changes in the extracellular matrix architecture and valve interstitial cell activation in AVSc and tested in vitro and in vivo the activity of a clinically approved SOD (superoxide dismutase) mimic and redox-active drug MnTnBu OE -2-PyP5+ ( BMX -001). Methods and Results After receiving informed consent, samples from patients with AVS c, AV stenosis, and controls were collected. Uniaxial mechanical stimulation and in vitro studies on human valve interstitial cells were performed. An angiotensin II chronic infusion model was used to impose AV thickening and remodeling. We characterized extracellular matrix structures by small-angle light scattering, scanning electron microscopy, histology, and mass spectrometry. Diseased human valves showed altered collagen fiber alignment and ultrastructural changes in AVS c, accumulation of oxidized cross-linking products in AV stenosis, and reversible expression of extracellular matrix regulators ex vivo. We demonstrated that MnTnBu OE -2-PyP5+ inhibits human valve interstitial cell activation and extracellular matrix remodeling in a murine model (C57 BL /6J) of AVS c by electron microscopy and histology. Conclusions AVS c is associated with architectural remodeling despite marginal effects on the mechanical properties in both human and mice. MnTnBu OE -2-PyP5+ controls AV thickening in a murine model of AVS c. Because this compound has been approved recently for clinical use, this work could shift the focus for the treatment of calcific AV disease, moving from AV stenosis to an earlier presentation ( AVS c) that could be more responsive to medical therapies.

Implications of coronary artery bypass grafting and percutaneous coronary intervention on disease progression and the resulting changes to the physiology and pathology of the native coronary arteries.

Myocardial revascularization can be achieved through 2 different methods: coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI). Clinical trials comparing PCI and CABG generally use the composite end points of death, stroke, myocardial infarction and target vessel revascularization to determine superiority. Other effects of these interventions, including the preservation of normal coronary physiology, the response of the coronary tree to stressors and the response of the vessel wall to the revascularization intervention, are not routinely considered, but these may have significant implications for patients in the medium and long term. For PCI, relatively small differences in clinical outcomes have been reported between bare metal and drug-eluting stents, and the latter seems to have inconsistent and somewhat unpredictable effects on the vascular biology of the coronary arteries. In coronary bypass, the use of arterial conduits is associated with superior clinical outcomes, better long-term patency and the preservation of essentially normal coronary function after intervention. This review assembles the clinical, physiological, angiographic and pathological literature currently available and attempts to provide a more complete picture of the effects of CABG and PCI on coronary arteries.

Serotonin receptor 2B signaling with interstitial cell activation and leaflet remodeling in degenerative mitral regurgitation.

AIMS: Mitral valve interstitial cells (MVIC) play an important role in the pathogenesis of degenerative mitral regurgitation (MR) due to mitral valve prolapse (MVP). Numerous clinical studies have observed serotonin (5HT) dysregulation in cardiac valvulopathies; however, the impact of 5HT-mediated signaling on MVIC activation and leaflet remodeling in MVP have been investigated to a limited extent. Here we test the hypothesis that 5HT receptors (5HTRs) signaling contributes to MVP pathophysiology. METHODS AND RESULTS: Diseased human MV leaflets were obtained during cardiac surgery for MVP; normal MV leaflets were obtained from heart transplants. MV RNA was used for microarray analysis of MVP patients versus control, highlighting genes that indicate the involvement of 5HTR pathways and extracellular matrix remodeling in MVP. Human MV leaflets were also studied in vitro and ex vivo with biomechanical testing to assess remodeling in the presence of a 5HTR2B antagonist (LY272015). MVP leaflets from Cavalier King Charles Spaniels were used as a naturally acquired in vivo model of MVP. These canine MVP leaflets (N=5/group) showed 5HTR2B upregulation. This study also utilized CB57.1ML/6 mice in order to determine the effect of Angiotensin II infusion on MV remodeling. Histological analysis showed that MV thickening due to chronic Angiotensin II remodeling is mitigated by a 5HTR2B antagonist (LY272015) but not by 5HTR2A inhibitors. CONCLUSION: In humans, MVP is associated with an upregulation in 5HTR2B expression and increased 5HT receptor signaling in the leaflets. Antagonism of 5HTR2B mitigates MVIC activation in vitro and MV remodeling in vivo. These observations support the view that 5HTR signaling is involved not only in previously reported 5HT-related valvulopathies, but it is also involved in the pathological remodeling of MVP.

Serotonin and catecholamines in the development and progression of heart valve diseases.

Heart valve diseases (HVDs) arise from a number of different processes that affect both the structure and function of the valve apparatus. Despite diverse aetiologies, treatments for HVDs are limited to percutaneous or surgical interventions. The search for medical therapies to prevent or slow the progression of HVDs has been hampered by our poor understanding of the progression from subclinical to symptomatic phases, and our limited knowledge of the molecular signals that control the susceptibility of valve interstitial cells to pathological remodeling. Clinical evidence has suggested a link between certain neurotransmitters and valvular diseases of the heart. The fenfluramine-phentermine appetite suppressants popular in the 1980s were linked to mitral valve dysfunction, and ergot-derived dopamine agonists for Parkinson's disease have been associated with an increased risk of mitral and aortic valve regurgitation. The effect does not appear to be limited to medications, as valvular pathologies have also been observed in patients with carcinoid tumours of serotonin-producing enterochromaffin cells. The role of neurotransmitter molecules in valve pathology has not been adequately characterized and may represent a target for future medical therapies. Here we present current evidence from both clinical and basic science suggesting a link between neurotransmitters and HVDs, opening the door to future research in this area.

Percutaneous coronary intervention versus coronary artery bypass grafting: where are we after NOBLE and EXCEL?

PURPOSE OF REVIEW: The publication of the NOBLE and EXCEL trials, with seemingly conflicting results, brought into question whether percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) is better for low-risk patients with left main coronary artery stenosis (LMCAS). This review appraises the methods and results of NOBLE and EXCEL, contextualizes them within the literature, and determines how they may affect clinical practice. RECENT FINDINGS: We appraised the trials and describe differences in methodology and results. NOBLE recruited primarily isolated LMCAS, and found that CABG was superior to PCI. EXCEL's population included patients LMCAS in the context of multivessel CAD, and found PCI and CABG were comparable. Both trials enrolled young patients with few comorbidities, and there was more protocol-mandated consistency in the procedural techniques and medical therapy of patients receiving PCI. SUMMARY: The generalizability of these trials is limited by the use of young, healthy patients at highly skilled centres that rarely reflect typical clinical practice. If these studies are to maintain relevance, trialists must address the lack of protocolization of surgical interventions and inconsistent medical therapies. Unfortunately, the limitations of NOBLE and EXCEL mean that we are no closer to answering the question of what is the optimal treatment for patients with LMCAS.