Thamarasee Jeewandara

Biocompatibility of Coronary Stents

Cardiovascular disease is the dominant cause of mortality in developed countries, with coronary artery disease (CAD) a predominant contributor. The development of stents to treat CAD was a significant innovation, facilitating effective percutaneous coronary revascularization. Coronary stents have evolved from bare metal compositions, to incorporate advances in pharmacological therapy in what are now known as drug eluting stents (DES). Deployment of a stent overcomes some limitations of balloon angioplasty alone, but provides an acute stimulus for thrombus formation and promotes neointimal hyperplasia. First generation DES effectively reduced in-stent restenosis, but profoundly delay healing and are susceptible to late stent thrombosis, leading to significant clinical complications in the long term. This review characterizes the development of coronary stents, detailing the incremental improvements, which aim to attenuate the major clinical complications of thrombosis and restenosis. Despite these enhancements, coronary stents remain fundamentally incompatible with the vasculature, an issue which has largely gone unaddressed. We highlight the latest modifications and research directions that promise to more holistically design coronary implants that are truly biocompatible.

Protective cardiorenal effects of spironolactone in a rodent model of polycystic kidney disease

Studies were performed to examine the contribution of aldosterone to the pathogenesis of cardiovascular and renal disease in a rodent model of genetic kidney disease. Spironolactone (20 mg/kg per day) was administered in water to mixed sex Lewis Polycystic Kidney (LPK) rats (n = 20) and control Lewis rats (n = 27) from 4 to 12 weeks of age. At 12 weeks of age, hypertension was reduced in female LPK rats; systolic blood pressure declined from 226.4 ± 26.8 mmHg in untreated rats and to 179.2 ± 3.2 mmHg in treated rats (P = 0.018). No similar effect on male or control rats was found. Water consumption and urine volume were significantly greater in LPK animals than in Lewis rats, and treatment reduced both variables by ~30% in LPK animals (P < 0.05). Proteinuria and the urinary protein‐to‐creatinine ratio were normalized in treated LPK relative to Lewis controls, and plasma creatinine levels were significantly reduced by treatment in LPK rats. Spironolactone did not alter kidney morphology in LPK rats (fibrosis or cyst size). Aortic vascular responses to noradrenaline and acetylcholine were sensitized and impaired in the LPK (P < 0.01). Aldosterone antagonism did not alter these responses or indicators of aortic structural remodelling. There was no treatment effect on left ventricular hypertrophy or elevated cardiac messenger RNA for β‐myosin‐heavy chain and brain natriuretic peptide in the LPK rats. However, perivascular fibrosis and messenger RNA for α‐cardiac actin were normalized by spironolactone in LPK animals relative to Lewis controls. In conclusion, we have shown an important blood pressure independent effect whereby inhibition of aldosterone via spironolactone was able to retard both renal and cardiac disease progression in a rodent model of polycystic kidney disease.

Bioengineering cobalt chromium cardiovascular stent biomaterial for biofunctionalization

Suboptimal biocompatibility of cardiovascular stents manifest as non-compliance at stent-artery interface in vivo. We optimized a plasma-activated coating (PAC) technology to modify cobalt chromium alloy L605 (PAC-L605) surface of an implantable coronary stent material, for improved biofunctionalization. The PAC-L605 surfaces displayed covalent binding capacity of a protein candidate tropoelastin (TE) by retaining 70.3% of TE after SDS detergent washing. Human coronary artery endothelial cell (HCAEC) proliferation visualized with crystal violet staining, did not vary significantly among the biomaterials at 3 or 5 days. Anchorage of cell cytoskeleton visualized with immunofluorescence and scanning electron microscopy (SEM), showed homogenous cell morphology on PAC/TE (with TE) surfaces. Surface hemocompatibility was assessed with static and flow blood assays, the hydrophilic PAC-L605 displayed lower clot formation compared to L605. Area of surface fibrinogen deposited was significantly lower on PAC-L605 vs. L605. Selected ISO 10993-4 tests for biological evaluation of medical devices in contact with blood indicated significantly lowered plasma markers of thrombin-antithrombin complex (TAT), beta-thromboglobulin (β-TG), soluble P-selectin and soluble terminal complement complex (SC5b-9) on PAC-L605 vs. L605. There was no significant difference for plasma biomarkers of polymorphonuclear elastase (PMN elastase) on PAC-L605 vs. L605. Improved surface biofunctionalization of implantable cardiovascular materials could be achieved by plasma-activated coating (PAC).

1037 INHIBITION OF THE RENIN ANGIOTENSIN ALDOSTERONE SYSTEM AND ITS IMPACT ON KIDNEY OXIDATIVE STRESS, RENAL FUNCTION AND HYPERTENSION IN POLYCYSTIC KIDNEY DISEASE

Background: The renin angiotensin aldosterone system (RAAS) regulates blood pressure (BP), and is a target for treatment of hypertension in chronic renal failure (CRF). Both angiotensin II (AngII) and aldosterone can have local effects, including production of reactive oxygen species (ROS), which are detrimental to tissue function. We examined if angiotensin converting enzyme or aldosterone receptor inhibition can reduce renal ROS pathway gene expression in the Lewis Polycystic Kidney (LPK) model of CRF. Methods: Rats were treated with perindopril (n = 12, 3 mg/kg/day p.o.) or spironolactone (n = 12, 20 mg/kg/day p.o.) from age 4-12 weeks. BP was measured, and urine & blood assessed for protein, urea and creatinine. Quantitative RT-PCR was used to determine renal expression of markers of oxidative stress hypoxia-inducible factor-1&agr;, vascular-endothelial growth factor, hemeoxygenase-1, p47phox, gp91phox and superoxide dismutase-1. Results: Perindopril treatment caused a significant reduction in SBP in LPK (164 ± 13 mmHg vs. 226 ± 10 mmHg, treated vs. untreated, P < 0.0001). In contrast spironolactone did not have a significant impact on SBP. Serum and urine markers of kidney dysfunction were unchanged after perindopril treatment, however a significant reduction in urinary protein (0.4 ± 0.2 vs. 1.02 ± 0.25 g/L) was seen after spironolactone (P < 0.0001). Intra-renal levels of ROS genes were largely unchanged after both treatments. Conclusions: Spironolactone significantly reduced proteinuria, independent of any impact on BP. In contrast, perindopril was effective in ameliorating hypertension, but had no impact on renal function. Neither treatment had an impact on markers of oxidative stress, suggesting this does not contribute to their mechanism of action.