Guidelines on CHD prevention have placed emphasis on identifying and treating suitable individuals with statin therapy and have set cholesterol goals to be attained. Absolute risk is based on modifiable and non-modifiable factors including age.  By failing to initiate statin treatment in high risk patients at a younger age, a large proportion of cardiovascular risk will accumulate.  Modifiable risk identifies individuals in addition to the patients selected using absolute risk.  The additional patients identified were younger with similar modifiable risk factors.  Modifiable risk is cost effective but by initiating treatment at a younger age the benefits would increase as the number of event free years would increase. It is recommended total cholesterol should be reduced to <5.0mmol/l.  In this study 54.6% failed this goal and this group had a greater proportion of females, primary prevention, were younger, greater TC but with lower efficacy.  43% of those who failed target responded appropriately.  The remaining 57% did not respond sufficiently to the statin dose. Only 56.0% claimed in a questionnaire to fully comply with their statin.  Those who admitted to poor compliance were younger and had a reduced TC efficacy.  Of the study population 13.4% did not have a detectable level of simvastatin or simvastatin acid in their plasma and this was supported by the difference in TC reduction observed. It has been proposed that CYP2D6 is involved in the metabolism of simvastatin acid.  Five individuals were found to carry more than one copy of the CYP2D6 gene and were fast metabolisers.  This did not correlate with a reduced efficacy therefore it is unlikely CYP2D6 metabolises simvastatin acid. This study has identified factors which contribute to the failure of over half of patients prescribed statin to achieve target and by doing so treatment can be tailored to achieve maximal cholesterol lowering efficacy.

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Inflammation has incompletely characterized effects on cardiopulmonary vascular reactivity. Sepsis is a major inflammatory disease characterized by two main vasomotor complications, generalized vasodilation with hyporesponsiveness to vasoconstrictors and pulmonary hypertension. The main aim of this study is to examine the molecular mechanisms involved in cardiopulmonary vascular reactivity changes induced by the powerful inflammatory stimulus lipopolysaccharide (LPS). Pulmonary and aortic rings from male Wistar rats (250-300g) were isolated and incubated for 20 h in culture medium (DMEM+10% FBS) with or without LPS (E. coli O55:B5, 10 μg.ml⁻¹). The effect of organ culture and LPS type, concentration and incubation time in addition to tissue contraction to endothelin-1 (ET-1), phenylephrine, 80 mM KCl, and U46619; and relaxation responses to ACh, sodium nitroprusside (SNP), 8-pCPT-cGMP, BAY 41-2272, T-0156, nifedipine, SKF-96365, Ro-31-8425, and Y-27632 were measured by standard organ bath techniques. Nitric oxide (NO) production was measured by the Griess method and SNP-induced cGMP production was measured by ELISA. mRNAs expression levels of eNOS, iNOS, ET-1, ETA and ETB were measured by qRT-PCR and the expression levels of PKC, sGCα₁, sGCβ₁ and PDE5 and phosphorylation of MLC₂₀, ROKα, CPI-17 and MYPT1 were measured by immunoblotting. The effect of endothelium removal, indomethacin, trolox, external Ca²⁺ removal, 1400W, ODQ, glibenclamide, iberiotoxin and cycloheximide in addition to changes in intracellular Ca²⁺ ([Ca²⁺]i) in aortic vascular smooth muscle cells (VSMCs) induced by ET-1 were also measured. LPS selectively induced vascular hyporeactivity to different vasoconstrictors in rat aorta but not in the pulmonary artery, which is not due to organ culturing and is not affected by changing the LPS type, but is enhanced by increasing LPS concentration or the incubation time. This aortic hypocontractility to ET-1 is largely mediated by NO-independent activation of sGC and depends on external Ca²⁺ influx through non-VOCCs, but not on ET-1 receptor expression or Ca²⁺ sensitization. In addition, this aortic hyporeactivity to ET-1 is dependent on protein synthesis. The pulmonary artery is not affected because LPS induces a desensitization of the sGC/cGMP dependent pathway by decreasing protein expression levels of sGCβ₁, and hence sGC activity, and increasing PDE5 activity. Neither the endothelium, cyclooxygenase, reactive oxygen species nor K⁺ channels are involved in these LPS effects. Therefore, it is likely that both Ca²⁺ homeostasis and the sGC/cGMP pathway play important roles in vasomotor complications in sepsis. sGC and/or PDE5-selective inhibitors, together with manipulating VSMC [Ca²⁺]i, could be important in controlling systemic and pulmonary vasomotor complications in sepsis.