The influence of clinical characteristics, laboratory and inflammatory markers on 'high on-treatment platelet reactivity' as measured with different platelet function tests.

High on-clopidogrel platelet reactivity (HCPR) and high on-aspirin platelet reactivity (HAPR) are independently associated with an increased risk of atherothrombotic events. However, despite this positive correlation, the definitions of both HCPR and HAPR vary largely throughout studies and between different platelet function assays. The aim of the present study was to explore clinical and laboratory parameters that are associated with HCPR and HAPR as measured with different platelet function tests. 530 clopidogrel and aspirin pre-treated patients undergoing elective PCI (percutaneous coronary intervention) were enrolled. Platelet function measurements were performed with: optical aggregometry, the VerifyNow device and PFA-100 cartridges (including the novel INNOVANCE P2Y assay). HCPR as measured with Adenosin-Di-Phospate-induced (ADP) aggregation based tests was associated with clinical factors such as older age, female gender and Diabetes mellitus (DM). The VerifyNow P2Y12 assay was significantly influenced by haemoglobin and haematocrit levels. HAPR as measured with aggregation based tests was significantly influenced by the presence of malignancy, BMI (Body-Mass Index), older age and increased levels of hsCRP (high sensitivity c-reactive proteine). The PFA-100 COL/EPI (collagen-epinephrine) and COL/ADP (collagen-ADP) cartridges were significantly influenced by monocyte count, hs-CRP, MPV (mean platelet volume), vWF-antigen (von Willebrand factor) and vWF-activity. HCPR as measured with the novel INNOVANCE P2Y cartridge was associated with clinical determinants such as BMI, female gender, impaired LVEF (left ventricular ejection fraction), renal failure and dosing of clopidogrel. Laboratory markers that were associated with HCPR as measured with INNOVANCE P2Y were platelet count, white blood cells (WBC), hsCRP and fibrinogen. Both HCPR and HAPR are highly dependent on the type of platelet function assay. Each platelet function assay, in turn, is significantly influenced by distinct clinical and laboratory variables.

Plasma matrix metalloproteinase-9 and ACE-inhibitor-induced improvement of urinary albumin excretion in non-diabetic, microalbuminuric subjects.

INTRODUCTION: Elevated plasma matrix metalloproteinase-9 (MMP-9) levels have been suggested to precede the development of microalbuminuria. As angiotensin-converting enzyme (ACE) inhibitors effectively reduce urinary albumin excretion (UAE), in the present study we have investigated the potential association of plasma MMP-9 levels with UAE and treatment effects of ACE-inhibition. MATERIAL AND METHODS: In a placebo-controlled randomised trial we determined plasma MMP-9 levels at baseline and after three months of randomisation to either placebo (n=202) or fosinopril (20 mg/day, n=204) treatment. RESULTS: Baseline plasma MMP-9 levels were not related to baseline UAE (r=-0.008, p=0.871). Three months of fosinopril treatment effectively reduced UAE compared to placebo treatment (-10.4+/-2.4 vs. 1.8+/-1.3 mg/24 hours, p<0.001, respectively). However, fosinopril treatment failed to significantly change plasma MMP-9 levels compared to placebo (-0.47+/-7.68 vs. 0.06+/-9.20, p=0.646, respectively). In addition, the change in UAE was not related with change in MMP-9 levels. CONCLUSION: The effective reduction of UAE with fosinopril was not related to plasma MMP-9 levels.

Predictors of angiotensin-converting enzyme inhibitor-induced reduction of urinary albumin excretion in nondiabetic patients.

Urinary albumin excretion is a predictor for cardiovascular mortality and morbidity. We investigated which parameters determine baseline urinary albumin excretion in nondiabetic subjects, without renal disease. In addition, we evaluated the parameters that predict the albuminuria-lowering efficacy of an angiotensin-converting enzyme inhibitor. In this substudy of the Prevention of Renal and Vascular Endstage Disease Intervention Trial, 384 microalbuminuric patients were included. Patient and biochemical characteristics were obtained at baseline and after 3 months of double-blinded, randomized treatment (fosinopril 20 mg or placebo). Mean age was 51.1+/-11.5 years, and 65.6% were male. Median urinary albumin excretion was 22.2 mg per 24 hours. At baseline, mean arterial pressure (beta(standardized)=0.161; P=0.006), urinary sodium excretion (beta(standardized)=0.154; P=0.011), and estimated renal function were independently associated with albumin excretion. In these predominantly normotensive to prehypertensive subjects, fosinopril reduced albumin excretion by 18.5% versus a 6.1% increase on placebo after 3 months (P<0.001). Fosinopril use and blood pressure reduction independently predicted the change in urinary albumin excretion. Baseline urinary albumin excretion independently predicted the antialbuminuric effect of fosinopril (beta(standardized)=-0.303; P<0.001). In conclusion, at baseline, sodium intake and blood pressure were positively associated with urinary albumin excretion. Fosinopril reduced albuminuria more than might be expected from its blood pressure-lowering effect alone, and this effect was more outspoken in subjects with higher baseline albumin excretion. Based on our data, we hypothesize that angiotensin-converting enzyme inhibition may result in superior cardiovascular protection when compared with other blood pressure-lowering agents in subjects with higher baseline levels of albuminuria.

High prevalence of microalbuminuria in chronic heart failure patients.

BACKGROUND: Microalbuminuria is associated with increased risk for cardiovascular morbidity and mortality. However, the relation between microalbuminuria and chronic heart failure has not been well described yet. In this cross-sectional study, we aim to evaluate the prevalence of microalbuminuria and the association with neurohormonal parameters in severe chronic heart failure patients. METHODS AND RESULTS: We studied 94 stable chronic heart failure patients (New York Heart Association class III/IV) receiving therapy with angiotensin-converting enzyme (ACE) inhibitors for over three months. In all patients, renal function and neurohormonal status were evaluated and correlated with urinary albumin/creatinine ratio. The studied population consisted of 70 men and 21 women (mean age 69 +/- 12 years). Ischemia was the underlying cause of heart failure in 61 patients. Overall, 100% of the patients were treated with an ACE inhibitor, 72% with a beta-blocker, and 47% with spironolactone. In 32% (95% confidence interval 22-42) of the patients, microalbuminuria was present, which is significantly higher than in the general population. However, we found no significant association between the presence of microalbuminuria and renal function. Plasma NT-proBNP, active renin protein, angiotensin I, angiotensin II, and aldosterone did not differ significantly between groups with and without microalbuminuria. CONCLUSION: In 32% of the patients, microalbuminuria was present. No association was found with either renal or neurohormonal parameters.

Levels of hematopoiesis inhibitor N-acetyl-seryl-aspartyl-lysyl-proline partially explain the occurrence of anemia in heart failure.

BACKGROUND: Anemia is common in patients with chronic heart failure (CHF) and is associated with a poor prognosis. However, only a minority of patients with CHF have impaired renal function or underlying hematinic deficiencies. It has been shown that inhibition of the renin-angiotensin system is associated with the development of anemia. The aim of the present study was to determine possible mechanisms linking anemia to renin-angiotensin system activity in CHF patients. METHODS AND RESULTS: We initially evaluated 98 patients with advanced stable CHF who were treated with ACE inhibitors (left ventricular ejection fraction, 28+/-1%; age, 69+/-1 years; 80% male), 10 of whom had an unexplained anemia (normal hematinics and no renal failure). These 10 anemic patients were matched with 10 nonanemic patients in terms of age and left ventricular ejection fraction. Serum ACE activity was 73% lower in anemic CHF patients compared with nonanemic CHF patients (P=0.018). Moreover, serum of these patients inhibited in vitro the proliferation of bone marrow-derived erythropoietic progenitor cells of healthy donors by 17% (P=0.003). Levels of the hematopoiesis inhibitor N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), which is almost exclusively degraded by ACE, were significantly higher in anemic CHF patients and were clearly correlated to erythroid progenitor cell proliferation (r=-0.64, P=0.001). CONCLUSIONS: Serum ACE activity is markedly lower in anemic CHF patients, and serum of these patients inhibits hematopoiesis. The clear correlation between Ac-SDKP and proliferation of erythroid progenitor cells suggests an inhibitory role of Ac-SDKP on hematopoiesis in CHF patients, which may explain the observed anemia in patients treated with ACE inhibitors.

Addition of an angiotensin receptor blocker to full-dose ACE-inhibition: controversial or common sense?

Both angiotensin-converting enzyme (ACE)-inhibitors and angiotensin receptor blockers (ARBs) interfere with the activity of the renin-angiotensin system (RAS) in a different way. Theoretically, one might expect beneficial effects when they are used in combination, as a more complete suppression of the RAS can be achieved. But can this additional effect still be seen in patients on full-dose ACE-inhibition? Several controlled trials demonstrated that combination therapy can have additional benefits in hypertensive patients, in chronic heart failure patients, and in both diabetic and non-diabetic nephropathy patients. However, the clinical benefit was not always as pronounced as expected and not every patient will benefit from dual blockade of the RAS. There is some evidence of a less pronounced effect of combination therapy when a full dose of the ACE-inhibitor is given. However, it is well known that ACE-inhibitors cannot completely suppress the formation of angiotensin II, in particular, when the RAS is activated. Indeed, clinical trials indicated that add-on therapy with an ARB was especially of use when the RAS remained activated despite full-dose ACE-inhibitor treatment. In summary, combination of a full-dose ACE-inhibitor and an ARB can be a rational choice in selected patients.

Mild preoperative renal dysfunction as a predictor of long-term clinical outcome after coronary bypass surgery.

BACKGROUND: Renal dysfunction is a prognostic marker in patients with cardiovascular disease. However, no long-term follow-up studies on the influence of mild renal dysfunction on mortality in patients undergoing coronary bypass grafting have been reported. Therefore, we aimed to identify the significance of preoperative (mild) renal dysfunction as a long-term predictor of clinical outcome after coronary bypass surgery. METHODS: In 358 patients who underwent isolated saphenous vein aorta-coronary artery bypass grafting, estimated glomerular filtration rates were calculated with the Cockroft-Gault equation (GFRc). Patients were categorized into 2 groups (group 1, GFRc >71.1 mL x min (-1) x 1.73 m (-2) ; group 2, GFRc <71.1 mL x min (-1) x 1.73 m (-2) ). Multivariate Cox proportional hazard analyses were performed to determine the independent prognostic value of GFRc. RESULTS: During a median follow-up of 18.2 years, 233 patients (65.1%) died. Patients who died had lower GFRc and were older. Multivariate analysis demonstrated that total mortality in patients with lower GFRc was significantly increased (lower GFRc group vs normal GFRc group: hazard ratio, 1.44; P = .019). Lower GFRc was also an independent predictor of cardiac mortality (hazard ratio, 1.51; P = .032). No significant differences were observed between groups in the occurrence of myocardial infarction and the need for reintervention. CONCLUSIONS: Our study demonstrates that after long-term follow-up, preoperative mild renal dysfunction is an independent predictor of long-term (cardiac) mortality in patients who undergo coronary artery bypass grafting.