Raja S.G.,Harefield Hospital
Recent Patents on Cardiovascular Drug Discovery | Year: 2012
Multiple cell types in the vascular wall rely upon the rho-kinase (ROCK) signaling pathway for homeostatic function and response to injury. These cell types include endothelial and vascular smooth muscle cells, inflammatory cells, and fibroblasts. Rho is a guanosine triphosphate binding protein that activates its downstream target rho-kinase, in response to activation of a variety of G-protein coupled receptors. When activated, ROCK inhibits myosin phosphatase and conversely upregulates the ezrin-radixin-moesin family of kinases. In vitro activation of these signaling cascades results in modulation of multiple cellular processes, including enhanced vasoconstriction, proliferation, impaired endothelial response to vasodilators, chronic pulmonary remodeling, and upregulation of vasoactive cytokines via the NF-κB transcription pathway. ROCK activity has also been linked specifically to a number of known effectors of pulmonary arterial hypertension (PAH), including endothelin-1, serotonin, and endothelial nitric oxide synthase, among others. Recently, elevated ROCK activity has been demonstrated in various animal models of PAH with ROCK inhibitors associated with pulmonary vasodilatation and regression of PAH. ROCK inhibitors are a new class of agents which may be beneficial in the treatment of PAH. Fasudil (Daiichi Chemical and Pharmacological Company, Ibaragi, Japan), a first generation ROCK inhibitor, has been widely studied. Emerging evidence from both animal and human studies suggests that fasudil can promote vasodilation independent of the mechanism that induces vasoconstriction and will be useful in conditions in which endothelial function is impaired including PAH. Several recent patents have described fasudil as a potential therapeutic option in PAH. This article provides an overview of the role of ROCK in the pathogenesis of PAH and discusses the clinical efficacy of fasudil as a therapeutic option for treating PAH. © 2012 Bentham Science Publishers.
Dronavalli V.B.,University of Birmingham |
Banner N.R.,Harefield Hospital |
Bonser R.S.,University of Birmingham
Journal of the American College of Cardiology | Year: 2010
Demand for donor hearts exceeds supply, and a significant number of patients die while awaiting transplantation. Within the pool of currently unused potential donor hearts, a proportion may be suitable for transplantation but are declined due to anticipated poor function. Despite current assessment methods, in some donor hearts accepted for transplantation early graft failure develops in the recipient. Current methods of assessment are inadequate, and there is a potential for biomarkers to improve identification of satisfactory hearts for transplantation or hearts destined to fail in the recipient. Biomarkers are routinely used to diagnose and risk-stratify myocardial infarction, acute coronary syndromes, and heart failure. Some of these might facilitate donor heart assessment. Cardiac troponins, cytokines, inflammatory markers, natriuretic peptides, and intracellular proteins may each have discriminant value. This review details the current status of biomarkers in the assessment of donor hearts. © 2010 American College of Cardiology Foundation.
Burke M.M.,Harefield Hospital
American Journal of Transplantation | Year: 2016
In heart transplantation, semiquantitative scoring schemes of structural and infl ammatory components of coronary allograft vasculopathy (CAV) identify a subset of recipients with CAV who also show concurrent or previous subclinical antibody-mediated rejection, of potential importance in CAV pathogenesis. See the article from Loupy et al on page 111. Copyright © 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.
Raja S.G.,Harefield Hospital
International Journal of Surgery | Year: 2015
Coronary artery disease (CAD) is a leading cause of mortality and morbidity in diabetics. Diabetics make up to 20%-35% of all patients undergoing coronary revascularization. Patients with diabetes represent a particularly difficult subset for revascularization due to increased short- and long-term mortality as well as a higher risk of repeat revascularization procedures. Potential factors contributing to the increased risk include co-morbid illnesses, small, diffusely diseased target vessels, progression of native CAD, hyperglycaemic endothelial dysfunction, and systemic inflammation. For diabetic patients with multi-vessel disease, revascularization by coronary artery bypass grafting (CABG) is regarded as the preferred option. There is increasing recognition that the use of arterial conduits for CABG is associated with improved outcomes compared to use of venous conduits. Amongst arterial conduits bilateral internal mammary arteries (BIMA) have emerged as the superior conduits due to better cardiac event-free survival. Consistent with its benefits in non-diabetic patients, BIMA grafting is presumed to offer similar benefits in diabetic patients. However, BIMA grafting remains underutilised in diabetics due to perceived increased risk of sternal wound infection. This review article provides an overview of BIMA grafting in diabetic patients focussing on outcomes, concerns, and controversies associated with BIMA usage in this high-risk group of patients. © 2014 IJS Publishing Group Limited.
Raja S.G.,Harefield Hospital
International Journal of Surgery | Year: 2012
Background: For the cardiac surgeon and patient the development of sternal wound infection is a serious post-operative complication associated with increased risk of death and also considerable morbidity. Methods: Nine publications were identified using the PubMed online database and search terms 'gentamicin-containing collagen implant' plus 'surgical site infection', 'wound infection' and 'cardiac surgery'. Results: Six out of eight studies demonstrated that prophylactic use of gentamicin-containing collagen implants (GCCI) significantly reduce the wound infection rate following cardiac surgery (via sternotomy) compared to standard treatment alone. The adjunctive use of GCCI is particularly beneficial in high-risk subjects e.g. diabetes and obese patients. GCCI significantly improve the morbidity associated with SSI following cardiac surgery by shortening the recovery phase and length of hospital stay; reducing the need for surgical revision and use of antibiotics. GCCI have been shown to be cost saving across a wide spectrum of patients. A further study has shown that GCCI may also have a therapeutic role to play in patients with deep sternal wounds. Conclusion: This review demonstrates that when used dry prior to insertion GCCI can be effective in reducing the rate of SSI following cardiac surgery. GCCI have also been shown to be cost saving as they reduce the substantial morbidity associated with deep SSI. The adjunctive use of GCCI is particularly beneficial in high-risk patients. GCCI may also have a role to play in the treatment of deep sternal wound infection. © 2012 Surgical Associates Ltd.