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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtcvs.2006.11.034 Byline: Danny Ramzy (b), Vivek Rao (b), Laura C. Tumiati (b), Ning Xu (b), Rohit Sheshgiri (a), Jessica Jackman (a), Diego H. Delgado (c), Heather J. Ross (c) Abbreviations: CRP, C-reactive protein; eNOS, endothelial nitric oxide synthase; ET-1, endothelin-1; HSVEC, human saphenous vein endothelial cell; M/C, membrane-to-cytosolic (ratio); NO, nitric oxide; PKC, protein kinase C; PMA, phorbol 12-myristate 13-acetate Abstract: The proinflammatory marker C-reactive protein has been demonstrated to play a role in the development of atherosclerosis. Endothelin-1 and nitric oxide homeostasis is crucial for normal vasomotor function, limiting inflammatory activation and maintaining a nonthrombogenic endothelial surface. In addition to its vasoactive properties, endothelin-1 is also an inflammatory cytokine. We have previously demonstrated that C-reactive protein impairs endothelial cell nitric oxide production. Protein kinase C, an important signal transducer within the cell, is involved in several cellular responses to external stimuli. We therefore sought to determine whether endothelin-1 exposure modulates C-reactive protein's effects on nitric oxide production via protein kinase C. Author Affiliation: (a) Heart Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada (b) Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada (c) Division of Cardiology, University of Toronto, Toronto, Ontario, Canada. Article History: Received 28 April 2006; Revised 18 October 2006; Accepted 1 November 2006 Article Note: (footnote) Supported by the Heart and Stroke Foundation of Ontario (Grant # NA 5868), the Canadian Institutes for Health Research, the Thoracic Surgery Foundation for Research and Education, the Tailored Advanced Collaborative Training in Cardiovascular Science for Research Fellows, and the Physician Services Incorporated Foundation Grant for Research Fellows. D.R. is a Research Fellow of the TSFRE, PSI and TACTICS; V.R. is a CIHR New Investigator., Manuscript accepted for the C. Walton Lillehei Resident Forum Session at the Annual Meeting of the American Association for Thoracic Surgery.

Amyloidosis is a term used to describe a group of rare heterogeneous diseases that ultimately result in the deposition and accumulation of misfolded proteins. These misfolded proteins, known as amyloids, are associated with a variety of precursor proteins that have amyloidogenic potential. Ultimately, the specific type of amyloidosis is dependent on multiple factors including genetic variability of precursor proteins and the tissue or organ in which the amyloid accumulates. Several types of amyloid have a predilection for the heart and thus contribute to cardiac amyloidosis, a major cause of restrictive cardiomyopathy. Individuals with cardiac amyloidosis present clinically with heart failure with preserved ejection fraction. Although improved diagnostics and increased awareness of cardiac amyloidosis have led to a relative increase in diagnosis, cardiac amyloidosis remains an underrecognized and underdiagnosed cause of heart failure with preserved ejection fraction. It is essential to properly identify cases of cardiac amyloidosis and determine the pathology responsible for the formation of amyloid to appropriately provide management. This review aims to encourage physician awareness of cardiac amyloidosis by focusing on clinical presentation and the distinctions between types. Furthermore, epidemiology is central to understanding the affected demographics and sometimes hereditary nature of the disease. Improved understanding of cardiac amyloidosis will ideally lead to earlier diagnosis and interventions to improve patient outcomes.

In this update, we focus on selected topics of high clinical relevance for health care providers who treat patients with heart failure (HF), on the basis of clinical trials published after 2017. Our objective was to review the evidence, and provide recommendations and practical tips regarding the management of candidates for the following HF therapies: (1) transcatheter mitral valve repair in HF with reduced ejection fraction; (2) a novel treatment for transthyretin amyloidosis or transthyretin cardiac amyloidosis; (3) angiotensin receptor-neprilysin inhibition in patients with HF and preserved ejection fraction (HFpEF); and (4) sodium glucose cotransport inhibitors for the prevention and treatment of HF in patients with and without type 2 diabetes. We emphasize the roles of optimal guideline-directed medical therapy and of multidisciplinary teams when considering transcatheter mitral valve repair, to ensure excellent evaluation and care of those patients. In the presence of suggestive clinical indices, health care providers should consider the possibility of cardiac amyloidosis and proceed with proper investigation. Tafamidis is the first agent shown in a prospective study to alter outcomes in patients with transthyretin cardiac amyloidosis. Patient subgroups with HFpEF might benefit from use of sacubitril/valsartan, however, further data are needed to clarify the effect of this therapy in patients with HFpEF. Sodium glucose cotransport inhibitors reduce the risk of incident HF, HF-related hospitalizations, and cardiovascular death in patients with type 2 diabetes and cardiovascular disease. A large clinical trial recently showed that dapagliflozin provides significant outcome benefits in well treated patients with HF with reduced ejection fraction (left ventricular ejection fraction ≤ 40%), with or without type 2 diabetes.

Human leukocyte antigen‐G (HLA‐G) expression is modulated by immunosuppressant use and is associated with lower incidence of graft rejection and cardiac allograft vasculopathy (CAV). We examined whether everolimus induces HLA‐G expression and inhibits human coronary artery smooth muscle cell (HCASMC) proliferation, a critical event in CAV. Also, we examined whether TNFα‐stimulated neutrophil adhesion is inhibited by HLA‐G on human coronary artery endothelial cells (HCAECs). HLA‐G expression in HCASMCs following everolimus treatment was determined by western‐blot densitometric analysis. HCASMCs proliferation following incubation with recombinant HLA‐G was determined by automated cell counter detecting 2‐10 µm particles. Assessment of recombinant HLA‐G on neutrophil adhesion to HCAECs in response to TNF‐α induced‐injury was determined by nonstatic adhesion assays. HLA‐G expression was upregulated in HCASMCs following everolimus exposure (1000 ng/ml; P< .05). HLA‐G (500, 1000 ng/ml; both P< .05) reduced HCASMC proliferation and inhibited TNFα‐stimulated neutrophil adhesion to endothelial cells at all concentrations (0.1‐1 ng/ml; all P< .001). Our study reveals novel regulation of HLA‐G by everolimus, by demonstrating HLA‐G upregulation and subsequent inhibition of HCASMC proliferation. HLA‐G is a potent inhibitor of neutrophil adhesion to HCAECs. Findings support HLA‐G’s importance and potential use in heart transplantation for preventative therapy or as a marker to identify patients at high risk for developing CAV. The authors reveal novel effects of everolimus and HLA‐G by demonstrating HLA‐G upregulation and subsequent inhibition of proliferation, as well as potent inhibition of neutrophil adhesion.

Introduction:Hereditary amyloid transthyretin (hATTR, or ATTRv [variant]) amyloidosis is a progressive and fatal disease caused by alterations in the transthyretin (TTR) gene that result in the deposition of misfolded protein throughout the body, leading to multisystem dysfunction. The p.V142I and p.T80A pathogenic alterations typically manifest with a cardiac phenotype, and early diagnosis is crucial to achieving optimal patient outcomes. The hATTR Compass Program offers confidential genetic testing to patients suspected of having hATTR in the United States, Canada, and Puerto Rico.Methods:Patients were referred to Compass for genetic testing using a TTRsingle-gene analysis, a cardiovascular-focused 92-gene panel, or a neuropathy-focused 81-gene panel. All patient demographics were self-reported. This report analyzes patients with TTRalterations.Results:A total of 22,801 patients were referred for genetic testing; 1469 (6%) patients were positive for TTR. Of those, 1237 (84%) had the p.V142I alteration and 73 (5%) had the p.T80A alteration. Patients with p.V142I were predominantly Black (81%), while patients with p.T80A were predominantly White (86%). Most p.V142I patients were male (60%), while 48% of p.T80A patients were male. The average age at testing was earlier in patients with p.T80A (56 y) compared with p.V142I (67 y). The majority of p.T80A patients reported a family history of ATTR (64%), contrasting with only 23% of p.V142I patients. In patients with p.V142I and p.T80A who reported symptoms (1049 vs 42, respectively), most reported heart disease (90% vs 71%). Other symptoms included bilateral carpel tunnel syndrome (24% vs 31%), renal issues (22% vs 12%), and gastrointestinal issues (9% vs 31%). Patients with p.T80A reported a higher incidence of sensory (52%), motor (31%), and autonomic (29%) dysfunction compared with patients with p.V142I (31%, 18%, and 21%, respectively).Conclusions:Patients with p.V142I were mostly Black and were less likely to have a known family history of hATTR. Both p.V142I and p.T80A patients presented with mixed symptoms, including heart disease and polyneuropathies. Genetic testing may be an efficient path toward early diagnosis and treatment for this progressive and fatal disease.

The increasing prevalence of heart failure and its unpredictable trajectory highlight the need for patients to make their end-of-life care wishes known using advanced care directives (ACDs). The paucity of literature addressing heart failure patients' decision-making processes and knowledge of ACDs underscores the need for investigation. The purposes of this study were to (1) determine patients' awareness, comprehension, and utilization of ACDs and (2) determine their knowledge of the process of cardiopulmonary resuscitation and their current resuscitation preference.

Acute hemodynamic collapse resulting in cardiogenic shock and impending end-organ failure is usually associated with certain death. The introduction of short-term mechanical circulatory support (MCS) devices offers potential therapy to these critically ill patients. The BVS 5000 device (ABIOMED Inc, USA) is widely used in the United States, but rarely in Canada, where device reimbursement remains a barrier.

Implantation of a left ventricular assist device (LVAD) is an acceptable therapy for patients with advanced heart failure. LVADs may be used as a bridge to recovery, a bridge to transplantation or as destination therapy. Although the morbidity rate of individuals on device support remains high, experience suggests that patients who are discharged home have satisfactory outcomes during support and following heart transplantation.

Left ventricular assist devices (LVADs) are an important adjunct to the management of end-stage heart failure patients. Uncertainty remains regarding whether to remove an LVAD in a clinically stable, asymptomatic patient who displays signs of ventricular recovery.

Thromboembolism has been reported as a frequent complication after cardiac transplantation. Many risk factors for thrombosis may explain this, such as metabolic alterations and the use of cyclosporine. In the general population, two single nucleotide polymorphisms (SNPs), factor V Leiden and prothrombin G20210A (PT G20210A), have been associated with a significant increase in the risk of thrombosis. However, these mutations have not been analyzed in cardiac transplant patients. We describe the protracted history of recurrent thromboembolism in a rare case of homozygosity for the PT G20210A variant. This prompted us to analyze the entire cardiac transplant cohort for the incidence of thromboembolic events and their association with these genetic polymorphisms.