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.

Clr-f expression regulates kidney immune and metabolic homeostasis.

The C-type lectin-related protein, Clr-f, encoded by Clec2h in the mouse NK gene complex (NKC), is a member of a family of immune regulatory lectins that guide immune responses at distinct tissues of the body. Clr-f is highly expressed in the kidney; however, its activity in this organ is unknown. To assess the requirement for Clr-f in kidney health and function, we generated a Clr-f-deficient mouse (Clr-f-/-) by targeted deletions in the Clec2h gene. Mice lacking Clr-f exhibited glomerular and tubular lesions, immunoglobulin and C3 complement protein renal deposits, and significant abdominal and ectopic lipid accumulation. Whole kidney transcriptional profile analysis of Clr-f-/- mice at 7, 13, and 24 weeks of age revealed a dynamic dysregulation in lipid metabolic processes, stress responses, and inflammatory mediators. Examination of the immune contribution to the pathologies of Clr-f-/- mouse kidneys identified elevated IL-12 and IFNγ in cells of the tubulointerstitium, and an infiltrating population of neutrophils and T and B lymphocytes. The presence of these insults in a Rag1-/-Clr-f-/- background reveals that Clr-f-/- mice are susceptible to a T and B lymphocyte-independent renal pathogenesis. Our data reveal a role for Clr-f in the maintenance of kidney immune and metabolic homeostasis.

Autophagy Is Differentially Regulated in Leukocyte and Nonleukocyte Foam Cells During Atherosclerosis.

RATIONALE: Atherosclerosis is characterized by an accumulation of foam cells within the arterial wall, resulting from excess cholesterol uptake and buildup of cytosolic lipid droplets (LDs). Autophagy promotes LD clearance by freeing stored cholesterol for efflux, a process that has been shown to be atheroprotective. While the role of autophagy in LD catabolism has been studied in macrophage-derived foam cells, this has remained unexplored in vascular smooth muscle cell (VSMC)-derived foam cells that constitute a large fraction of foam cells within atherosclerotic lesions. OBJECTIVE: We performed a comparative analysis of autophagy flux in lipid-rich aortic intimal populations to determine whether VSMC-derived foam cells metabolize LDs similarly to their macrophage counterparts. METHODS AND RESULTS: Atherosclerosis was induced in GFP-LC3 (microtubule-associated proteins 1A/1B light chain 3) transgenic mice by PCSK9 (proprotein convertase subtilisin/kexin type 9)-adeno-associated viral injection and Western diet feeding. Using flow cytometry of aortic digests, we observed a significant increase in dysfunctional autophagy of VSMC-derived foam cells during atherogenesis relative to macrophage-derived foam cells. Using cell culture models of lipid-loaded VSMCs and macrophages, we show that autophagy-mediated cholesterol efflux from VSMC foam cells was poor relative to macrophage foam cells, and largely occurs when HDL (high-density lipoprotein) was used as a cholesterol acceptor, as opposed to apoA-1 (apolipoproteinA-1). This was associated with the predominant expression of ABCG1 in VSMC foam cells. Using metformin, an autophagy activator, cholesterol efflux to HDL was significantly increased in VSMC, but not in macrophage, foam cells. CONCLUSIONS: These data demonstrate that VSMC and macrophage foam cells perform cholesterol efflux by distinct mechanisms, and that autophagy flux is highly impaired in VSMC foam cells, but can be induced by pharmacological means. Further investigation is warranted into targeting autophagy specifically in VSMC foam cells, the predominant foam cell subtype of advanced atherosclerotic plaques, to promote reverse cholesterol transport and resolution of the atherosclerotic plaque.

Systematic Approach to the Calcified Mitral Valve Apparatus at Time of Mitral Valve Replacement.

Mitral annular calcification (MAC) represents a surgical challenge to mitral valve replacement. The presence of MAC at the time of mitral valve replacement is associated with perivalvular leak and atrial-ventricular groove injury. Although percutaneous and hybrid approaches may offer alternatives to surgical mitral valve replacement, the early and late results from these techniques remain unknown. As such, the surgical management of MAC remains relevant in the contemporary treatment of patients with MAC. Herein, we present a systematic approach to the management of MAC at the time of mitral valve replacement.

Comprehensive left ventricular outflow tract management beyond septal reduction to relieve obstruction.

The surgical management of patients with hypertrophic obstructive cardiomyopathy can be extremely challenging. Relieving the left ventricular outflow tract obstruction in these patients is often achieved by performing a septal myectomy. However, in many instances, septal reduction alone is not enough to relieve the obstruction. Interventions on the sub-valvular apparatus, including the anomalous chordae tendineae and the abnormal papillary muscles, are often required. In this review, we summarize the embryology and the pathophysiology of the different elements that may contribute to the left ventricular outflow tract obstruction in the setting of hypertrophic obstructive cardiomyopathy. In addition, we highlight the different surgical procedures that a surgeon may adopt to relieve the left ventricular outflow tract obstruction, beyond the septal myectomy.

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.

Conduits' Biology Regulates the Outcomes of Coronary Artery Bypass Grafting.

Coronary artery bypass graft (CABG) is the gold standard for coronary surgical revascularization. Retrospective, prospective, and meta-analysis studies looking into long-term outcomes of using different conduits have pointed to the superiority of arterial grafts over veins and have placed the internal mammary artery as the standard conduit of choice for CABG. The superiority of the internal mammary artery over other conduits could be attributable to its intrinsic characteristics; however, little is known regarding the features that render some conduits atherosclerosis-prone and others atherosclerosis-resistant. Here, an overview is provided of the available data on the most commonly used conduits in CABG (internal mammary artery, saphenous vein, radial artery, gastroepiploic artery), highlighting the differences in their cellular biology, mechanical, biochemical, and vasoconstrictive properties. This information should help in furthering our understanding of the clinical outcomes observed for each of these conduits.

Comparative Analysis Following Implementation of Two Types of Y-Composite Multiarterial Revascularization Strategies at a Single Academic Institution.

Background We compared early outcomes, at a single academic institution, of implementing full coronary revascularization in coronary artery bypass grafting using multiarterial Y-composite grafts with multiple sequential anastomoses. Methods and Results Clinical records of 425 consecutive patients who underwent coronary artery bypass grafting using Y-grafting with left internal mammary artery and radial artery (Y-RA group) or right internal mammary artery (Y-RIMA group) from 2015 to 2019, were reviewed. These were compared with the institutional experience of isolated coronary artery bypass grafting cases (in situ on pump/off pump) for the same period of time. When comparing the 4 groups, the Y-RIMA/RA groups revealed a higher number of distal anastomosis than the in situ on- or off-pump groups. When the number of distal arterial anastomosis was analyzed, there was a superiority of using the Y-configuration compared with the in situ approach. Moreover, there were no significant differences among groups for mortality and/or major adverse cardiac and cerebrovascular events in hospital or at 30-day follow-up. A subanalysis comparing the Y-RIMA group with the Y-RA group showed that complementary grafts to the Y-construct were required to accomplish full revascularization more frequently in the Y-RIMA group. Full-arterial revascularization was achieved in 92.2% of the Y-RA group and 72.0% of the Y-RIMA group (P<0.001). In 82.8% of the Y-RA group and 30.8% of the Y-RIMA group, revascularization was completed as an anaortic procedure (P<0.001). Conclusions The 2 types of arterial Y-composite grafting were able to be introduced in the routine practice of our institution showing comparable results to the established institutional practice. This procedure allowed for more arterial distal anastomosis to be performed safely without compromising outcomes.

GATA6 is a regulator of sinus node development and heart rhythm.

The sinus node (SAN) is the primary pacemaker of the human heart, and abnormalities in its structure or function cause sick sinus syndrome, the most common reason for electronic pacemaker implantation. Here we report that transcription factor GATA6, whose mutations in humans are linked to arrhythmia, is highly expressed in the SAN and its haploinsufficiency in mice results in hypoplastic SANs and rhythm abnormalities. Cell-specific deletion reveals a requirement for GATA6 in various SAN lineages. Mechanistically, GATA6 directly activates key regulators of the SAN genetic program in conduction and nonconduction cells, such as TBX3 and EDN1, respectively. The data identify GATA6 as an important regulator of the SAN and provide a molecular basis for understanding the conduction abnormalities associated with GATA6 mutations in humans. They also suggest that GATA6 may be a potential modifier of the cardiac pacemaker.

Cardiac Neural Crest Cells: Their Rhombomeric Specification, Migration, and Association with Heart and Great Vessel Anomalies.

Outflow tract abnormalities are the most frequent congenital heart defects. These are due to the absence or dysfunction of the two main cell types, i.e., neural crest cells and secondary heart field cells that migrate in opposite directions at the same stage of development. These cells directly govern aortic arch patterning and development, ascending aorta dilatation, semi-valvular and coronary artery development, aortopulmonary septation abnormalities, persistence of the ductus arteriosus, trunk and proximal pulmonary arteries, sub-valvular conal ventricular septal/rotational defects, and non-compaction of the left ventricle. In some cases, depending on the functional defects of these cells, additional malformations are found in the expected spatial migratory area of the cells, namely in the pharyngeal arch derivatives and cervico-facial structures. Associated non-cardiovascular anomalies are often underestimated, since the multipotency and functional alteration of these cells can result in the modification of multiple neural, epidermal, and cervical structures at different levels. In most cases, patients do not display the full phenotype of abnormalities, but congenital cardiac defects involving the ventricular outflow tract, ascending aorta, aortic arch and supra-aortic trunks should be considered as markers for possible impaired function of these cells. Neural crest cells should not be considered as a unique cell population but on the basis of their cervical rhombomere origins R3-R5 or R6-R7-R8 and specific migration patterns: R3-R4 towards arch II, R5-R6 arch III and R7-R8 arch IV and VI. A better understanding of their development may lead to the discovery of unknown associated abnormalities, thereby enabling potential improvements to be made to the therapeutic approach.

From embryogenesis to adulthood: Critical role for GATA factors in heart development and function.

Cardiac development is governed by a complex network of transcription factors (TFs) that regulate cell fates in a spatiotemporal manner. Among these, the GATA family of zinc finger TFs plays prominent roles in regulating the development of the myocardium, endocardium, and outflow tract. This family comprises six members three of which, GATA4, 5, and 6, are predominantly expressed in cardiac cells where they activate specific downstream gene targets via interactions with one another and with other TFs and signaling molecules. Their critical function in heart formation is evidenced by the phenotypes of animal models lacking these factors and by the broad spectrum of human congenital heart diseases associated with mutations in their genes. Similarly, in the postnatal heart, these proteins play significant and nonredundant roles in cardiac function, regulating adaptive stress responses including cardiomyocyte hypertrophy and survival, as well as endothelial homeostasis and angiogenesis. As such, decreased expression of either GATA4, 5, or 6 results in impaired cardiovascular homeostasis and increased risk of premature and serious cardiovascular events such as hypertension, arrhythmia, aortopathy, and heart failure. Although a great deal of progress has been made in understanding GATA-dependent regulatory processes in the heart, the molecular mechanisms underlying the specificity of GATA factors and their upstream regulation remain incompletely understood. The knowledge and tools developed since their discovery 25 years ago should accelerate progress toward further elucidation of their mechanisms of action in health and disease. This in turn will greatly improve diagnosis and care for the millions of individuals affected by congenital and acquired cardiac disease worldwide.

GATA6 Regulates Aortic Valve Remodeling, and Its Haploinsufficiency Leads to Right-Left Type Bicuspid Aortic Valve.

BACKGROUND: Bicuspid aortic valve (BAV), the most common congenital heart defect affecting 1% to 2% of the population, is a major risk factor for premature aortic valve disease and accounts for the majority of valve replacement. The genetic basis and mechanisms of BAV etiology and pathogenesis remain largely undefined. METHODS: Cardiac structure and function was assessed in mice lacking a Gata6 allele. Human GATA6 gene variants were analyzed in 452 BAV cases from the BAV consortium and 1849 controls from the Framingham GWAS (Genome Wide Association Study). GATA6 expression was determined in mice and human tissues using quantitative real-time polymerase chain reaction and immunohistochemistry. Mechanistic studies were carried out in cultured cells. RESULTS: Gata6 heterozygous mice have highly penetrant right-left (RL)-type BAV, the most frequent type in humans. GATA6 transcript levels are lower in human BAV compared with normal tricuspid valves. Mechanistically, Gata6 haploinsufficiency disrupts valve remodeling and extracellular matrix composition through dysregulation of important signaling molecules, including matrix metalloproteinase 9. Cell-specific inactivation of Gata6 reveals an essential role for GATA6 in secondary heart field myocytes because loss of 1 Gata6 allele from Isl- 1-positive cells-but not from endothelial or neural crest cells-recapitulates the phenotype of Gata6 heterozygous mice. CONCLUSIONS: The data identify a new cellular and molecular mechanism underlying BAV. The availability of an animal model for the most frequent human BAV opens the way for the elucidation of BAV pathogenesis and the development of much needed therapies.

Glutaredoxin-2 controls cardiac mitochondrial dynamics and energetics in mice, and protects against human cardiac pathologies.

Glutaredoxin 2 (GRX2), a mitochondrial glutathione-dependent oxidoreductase, is central to glutathione homeostasis and mitochondrial redox, which is crucial in highly metabolic tissues like the heart. Previous research showed that absence of Grx2, leads to impaired mitochondrial complex I function, hypertension and cardiac hypertrophy in mice but the impact on mitochondrial structure and function in intact cardiomyocytes and in humans has not been explored. We hypothesized that Grx2 controls cardiac mitochondrial dynamics and function in cellular and mouse models, and that low expression is associated with human cardiac dysfunction. Here we show that Grx2 absence impairs mitochondrial fusion, ultrastructure and energetics in primary cardiomyocytes and cardiac tissue. Moreover, provision of the glutathione precursor, N-acetylcysteine (NAC) to Grx2-/- mice did not restore glutathione redox or prevent impairments. Using genetic and histopathological data from the human Genotype-Tissue Expression consortium we demonstrate that low GRX2 is associated with fibrosis, hypertrophy, and infarct in the left ventricle. Altogether, GRX2 is important in the control of cardiac mitochondrial structure and function, and protects against human cardiac pathologies.

Inhibition of Cardiomyogenesis in Embryocarcinoma Cells Induced by Long-Term High Level of Glucose.

BACKGROUND/AIMS: Cardiac myocytes constitute the first differentiated cell type during mammalian heart formation with the ability to beat spontaneously and rhythmically. Hyperglycemia is a primary risk factor for cardiovascular disease in pre-gestational diabetes mellitus (PGDM). However, the impact that hyperglycemia has on cardiac progenitors or on precursors differentiation remains poorly understood. The aim of the present study is to investigate whether hyperglycemia affects cardiomyogenesis of embryocarcinoma cells. METHODS: P19CL6 cells differentiation induced by 1% DMSO was evaluated under either normal glucose (5.6 mmol/L) or high level of glucose concentrations (20 mmol/L or 40 mmol/L). To investigate the effect of long-term high level of glucose on cardiomyocytes differentiation, sarcomeric α-actinin, peroxisome proliferator-activated receptor coactivator-1 (PGC-1α), transcription factor GATA4 and Nkx2.5 were assessed by qRT-PCR analysis, western blot and immunofluorescence. RESULTS: We observed that long-term high level of glucose markedly reduced P19CL6 cells differentiation into cardiomyocytes. The change in PGC-1α expression was consistent with changes in cardiac muscle myosin expression after exposure to 20 mmol/L or 40 mmol/L of glucose. On the other hand, the high level of glucose concentration profoundly decreased both GATA4 and Nkx2-5 expressions from day 6 to day 12 after differentiation, which was induced by 1% DMSO. CONCLUSION: Our results elucidate that the effect resulting from the long-term exposure of cardiac progenitors to high level of glucose is associated with decreased expression of GATA4 and Nkx2.5, providing a novel mechanism by which high glucose is able to affect cell differentiation.

GATA5 mutation homozygosity linked to a double outlet right ventricle phenotype in a Lebanese patient.

BACKGROUND: GATA transcription factors are evolutionary conserved zinc finger proteins with multiple roles in cell differentiation/proliferation and organogenesis. GATA5 is only transiently expressed in the embryonic heart, and the inactivation of both Gata5 alleles results in a partially penetrant bicuspid aortic valve (BAV) phenotype in mice. We hypothesized that only biallelic mutations in GATA5 could be disease causing. METHODS: A total of 185 patients with different forms of congenital heart disease (CHD) were screened along 150 healthy individuals for GATA4, 5, and 6. All patients' phenotypes were diagnosed with echocardiography. RESULTS: Sequencing results revealed eight missense variants (three of which are novel) in cases with various conotruncal and septal defects. Out of these, two were inherited in recessive forms: the p.T67P variant, which was found both in patients and in healthy individuals, and the previously described p.Y142H variant which was only found in a patient with a double outlet right ventricle (DORV). We characterized the p.Y142H variant and showed that it significantly reduced the transcriptional activity of the protein over cardiac promoters by 30-40%. CONCLUSION: Our results do prove that p.Y142H is associated with DORV and suggests including GATA5 as a potential gene to be screened in patients with this phenotype.

GATA4 loss-of-function mutations underlie familial tetralogy of fallot.

Tetralogy of Fallot (TOF) represents the most common form of cyanotic congenital heart disease and accounts for significant morbidity and mortality in humans. Emerging evidence has implicated genetic defects in the pathogenesis of TOF. However, TOF is genetically heterogeneous and the genetic basis for TOF in most patients remains unclear. In this study, the GATA4 gene were sequenced in 52 probands with familial TOF, and three novel heterozygous mutations, including A9P and L51V both located in the putative first transactivational domain and N285S in the C-terminal zinc finger, were identified in three probands, respectively. Genetic analysis of the pedigrees demonstrated that in each family the mutation cosegregated with TOF with complete penetrance. The missense mutations were absent in 800 control chromosomes and the altered amino acids were highly conserved evolutionarily. Functional analysis showed that the GATA4 mutants were consistently associated with diminished DNA-binding affinity and decreased transcriptional activity. Furthermore, the N285S mutation completely disrupted the physical interaction between GATA4 and TBX5. To our knowledge, this report associates GATA4 loss-of-function mutations with familial TOF for the first time, providing novel insight into the molecular mechanism involved in TOF and suggesting potential implications for the early prophylaxis and allele-specific therapy of TOF.