Time course of rapid C-reactive protein reduction by pravastatin in patients with stable angina.

The evidence has indicated that rapid reduction of inflammatory marker, such as C-reactive protein (CRP) could be achieved by administration of a statin. However, limited information is available in evaluating the short-term time course of CRP reduction in patients with coronary artery disease by use of a statin. Forty-two patients with stable angina were randomly assigned to 20 mg/d or 40 mg/d group of pravastatin. Blood samples were drawn at days 0, 1, and 14 for measuring lipid profile, CRP levels, and hepatic enzymes in all patients. The results showed that both doses of pravastatin induced significant reductions in median CRP levels and in mean CRP levels, respectively, at day 1 (20% in the 20 mg/d group and 17.6% in the 40 mg/d group; 15% in the 20 mg/d group and 10% in the 40 mg/d group) as well as at day 14 (28.6% in the 20 mg/d group and 33.3% in the 40 mg/d group; 25% in the 20 mg/d group and 22.8% in the 40 mg/d group) compared with baseline data without a dose-dependent manner. In addition, no changes were found at day 1 regarding lipid profile; however, both doses of pravastatin induced significant reductions in total cholesterol (TC, 22% and 30%), and low-density lipoprotein (LDL) cholesterol (30% and 40%) compared with baseline at 14 days. The higher dose of pravastatin resulted in significantly greater reductions in TC and LDL cholesterol compared with the 20 mg/d dose (p = 0.05, p = 0.01, respectively). A less significant reduction was observed in triglycerides level (16% and 24%) compared with TC and LDL cholesterol. There was no significant difference in mean high-density lipoprotein (HDL) cholesterol levels compared with baseline in both groups. These data suggested that a common daily dose of pravastatin resulted in rapid reduction of CRP within 24 hours and of lipid profile within 2 weeks, and the benefit to the vascular endothelium might occur quickly by reduction of CRP levels, which may be clinically important for patients in a high-risk subgroup, such as acute coronary artery disease.

Effects of xuezhikang, an extract of cholestin, on lipid profile and C-reactive protein: a short-term time course study in patients with stable angina.

BACKGROUND: Reduction of cholesterol and inflammation can be achieved by administration of a statin. Xuezhikang, an extract of cholestin, available from Chinese red yeast rice, could effectively modify the lipid profile. However, limited information is available regarding rapid effects of Xuezhikang on plasma C-reactive protein (CRP) and the lipid profile in patients with stable angina. We evaluated the short-term time course effects of lipid profile and CRP by Xuezhikang in patients with stable angina. METHODS: Forty-eight consecutive patients with stable angina were randomly assigned to 1200 or 2400 mg/day of Xuezhikang. Blood samples were drawn at days 0, 1, 7 and 14 for lipid profile and CRP levels in all patients, and hepatic enzymes were also evaluated at days 0 and 14. RESULTS: Both doses of Xuezhikang induced significant reductions in median CRP levels and in mean CRP levels at day 1 (13.0% with 1200 and 16.6% with 2400 mg/day; 14.7% with 1200 and 18.4% with 2400 mg/day), and at day 7 (18.3% with 1200 and 20.2% with 2400 mg/day; 18.5% with 1200 and 22.6% with 2400 mg/day) as well as at day 14 (28.6% with 1200 and 30.4% with 2400 mg/day; 21.7% with 1200 and 24.8% with 2400 mg/day) compared with baseline without a dose-dependent effect but a time-dependent manner. In addition, no changes were found at days 1 and 7 regarding lipid profile. However, both doses of Xuezhikang induced significant reductions in total cholesterol (TC, 13% and 22%), and low-density lipoprotein (LDL) cholesterol (23% and 32%) compared with baseline at day 14. The higher dose of Xuezhikang (2400 mg/day) resulted in significantly greater reductions in TC and LDL cholesterol compared with 1200 mg/day group (p<0.05, p<0.01, respectively). A less significant reduction was observed in triglycerides (TG) level (13% and 23%) compared with TC and LDL cholesterol. There was no significant difference in mean high-density lipoprotein (HDL) cholesterol levels compared with baseline in both groups. CONCLUSIONS: Xuezhikang resulted in rapid reduction of CRP within 24 h and lipid profile within 2 weeks, which may be clinically important for patients with coronary artery disease.

Statin, like aspirin, should be given as early as possible in patients with acute coronary syndrome.

It is estimated that about 1 million patients are hospitalized for acute coronary events each years in the United States. An acceptable theory is that the acute coronary syndrome is caused by rupture of the atherosclerotic plaque with superimposed thrombus, which is a complex process and involving a number of different stages. Previous studies indicated that inflammation is one of the most important features of vulnerable plaque, and occurs in most vulnerable plaque, comprised of monocytes, macrophages, and lymphocytes in both the cap and in the adventitia. This is supported by evidence that reduction in serum inflammatory marker levels, such as C-reactive protein, significantly decreased coronary events in patients with acute coronary syndrome. A large number of investigations have demonstrated that administration of statin could modify C-reactive protein concentrations with a concurrent fall in cardiovascular events. Our recent data indicated that reduction of inflammatory markers could be achieved within 24 h following a single dose of statin administration after admission in patients with coronary artery disease. Based on the available evidence and in light of the new understanding that statins have pleiotropic effects, especially as a potent anti-inflammatory agent, the statins, like aspirin, should be clinically given as early as possible in patients with acute coronary syndrome.

Is hypertension an inflammatory disease?

Hypertension has been recognized as a multi-factorial trait resulting from the effect of a combination of environmental and genetic factors, including excess dietary salt or alcohol intake, stress, age, genetics and family history, obesity, physical inactivity, as well as high saturated fat diet. During the past few years, however, a large amount of information has been collected on the vascular inflammation, indicating that inflammation may involve in the initiation as well as development of hypertension and allowing us to reconsidering the pathogenic mechanisms of hypertension. Evidence from animal models as well as patients, have indicated that hypertension, an established major risk factor for coronary artery disease, has been suggested to exert pro-inflammatory actions through the increased expression of several mediators, including leukocyte adhesion molecules, chemokines, specific growth factors, heat shock proteins, endothelin-1, and angiotensin. The association between inflammation and hypertension recalls also a similar association between low-grade inflammation and other components of the metabolic syndrome, and endothelial dysfunction as well as increased serum levels of C-reactive protein in patients with hypertension. Is hypertension an inflammatory disease? This question has stimulated research on the role of vascular inflammation in hypertension. A better understanding of the inflammatory mechanism in hypertension may, therefore, contribute to novel therapeutic strategies to decrease the morbidity as well as mortality of hypertension, and alleviated hypertensive target organ damage.

Time course of inflammatory response after renal artery stenting in patients with atherosclerotic renal stenosis.

BACKGROUND: Inflammatory response has been demonstrated in patients with coronary artery disease after percutaneous coronary intervention (PCI). Such response following renal artery stenting has not yet been established, however, in patients with atherosclerotic renal artery stenosis. METHODS: A total of 44 patients were enrolled in this study. Of them, 22 patients with atherosclerotic renal artery stenosis received renal angioplasty with stent (group A, mean age 51+/-8 years), and 22 patients with age- and gender-matched underwent renal angiography for diagnostic purpose as a control group (group B, age 50+/-8 years). The peripheral blood samples were taken immediately before the procedure, 1, 6 and 24 h after the procedure in both groups. The concentrations of C-reactive protein (CRP) and interleukin-6 (IL-6) were measured using ELISA. RESULTS: The result showed that there was no difference in clinical characteristics and baseline levels of CRP and IL-6 between the groups. The IL-6 increased in the first hour (before: 5.8+/-3 pg/ml; 1 h: 8.6+/-5 pg/ml, p<0.01), lasted at 6 h (12.2+/-8 pg/ml), returned to baseline at 24 h (5.4+/-3 pg/ml) in group A. The CRP did not changed at the first hour after stenting, but mean CRP increased from 0.30+/-0.09 to 0.37+/-0.15 mg/dl at 6 h (p<0.05), and peaked at 24 h (0.43+/-0.18 mg/dl, p<0.001 compared with baseline and control) after stenting in group A, while no such changes were observed in group B (p>0.05 at different time points compared with baseline and group B, respectively). CONCLUSIONS: The data indicated that renal artery stenting could trigger inflammatory response by evidence of increased plasma levels of CRP and IL-6. IL-6, however, was an early initiator of inflammatory cytokine, and CRP was a later marker of systemic inflammatory response to renal artery stenting.

Increased C-reactive protein level after renal stent implantation in patients with atherosclerotic renal stenosis.

Elevated C-reactive protein (CRP) level has been demonstrated in patients with coronary artery disease after coronary stent implantation, but no data are available in patients with atherosclerotic renal artery stenosis concerning whether such changes of CRP also exist after renal artery stent implantation. The authors hypothesize that elevated CRP level may also be present in patients with atherosclerotic renal artery stenosis after stent implantation owing to mechanical disruption of atherosclerotic plaque. In total, 24 patients were enrolled in this study. Of these, 14 patients with atherosclerotic renal artery stenosis received renal angioplasty plus stent implantation (group A, mean age 51 +/- 8 years), and 14 age- and gender-matched patients underwent renal angiography for diagnostic purpose as a control group (group B, mean age 50 +/- 8 years). Peripheral blood samples were taken before the procedure and at 6 and 24 hours after the procedure in both groups. Plasma CRP concentration was measured by using immunoturbidimetry. The results showed that there was no difference in clinical characteristics or in baseline CRP levels between the 2 groups. However, median CRP level was found to increase significantly at 6 hours from 0.13 to 0.17 mg/dL (p < 0.05), and peaked at 24 hours (0.21 mg/dL) after renal artery stent implantation (p < 0.001). Mean CRP rose from 0.30 +/- 0.09 to 0.37 +/- 0.15 mg/dL at 6 hours (p < 0.05) and peaked at 24 hours (0.43 +/- 0.18 mg/dL) after renal artery stent implantation (p < 0.01), while no such changes were observed after renal angiography in group B (p > 0.05, respectively, at different time points). The results of the present study indicate, from evidence of increased plasma CRP concentrations, that renal artery stent implantation could trigger an inflammatory response due to mechanical disruption of atherosclerotic plaque of the renal artery, which is a pattern very similar to that of coronary stent implantation.

Atheroscleritis is a more rational term for the pathological entity currently known as atherosclerosis.

The term "atheroma", a Latin word was first used in 1755 by Albrecht von Halles to designate the plaque deposited on the innermost layer of systemic artery walls. In 1940, however, Félix Marchand suggested the word "atherosclerosis" should be better instead of "atheroma", which is derived from two Greek roots: athéré means gruel or porridge and sclerosis signifies hardening. It is obviously an improvement over the older designation arteriosclerosis. Atherosclerosis is still used up to data because it describes the two components of plaque: the lipid-filled core of atheroma encased in a shell of sclerosis or fibrosis, which presents the feature of atherosclerotic structure. Although atherosclerosis has been considered to be multi-factorial disease in which genetic, environmental, metabolic factors have been implicated, the gaps remain in our knowledge of the etiopathogenesis of atherosclerosis. More recently, there is mounting evidence that inflammation plays an important role in the initiation, development as well as evolution of atherosclerosis. The data from animals as well as humans indicated that an inflammatory process was involved in all stages of atherosclerosis appeared in different clinical settings, including atheromatous development, plaque rupture, restenotic process. The anti-inflammatory approach has been showed as one of the most promising strategies for atherosclerosis, such as statin intervention. Based on evidence and in light of the new understanding that inflammation is an intrinsic part of the process, we would like to propose a further change of nomenclature, call the disease atheroscleritis.

C-reactive protein is not only an inflammatory marker but also a direct cause of cardiovascular diseases.

Inflammatory processes play a pivotal role in the pathogenesis of atherosclerosis and mediate many of the stages of atheroma development from initial leukocyte recruitment to eventual rupture of the unstable atherosclerotic plaque. C-reactive protein (CRP), an acute phase reactant that reflects different degree of inflammation, has been indicated an independent risk factor in a variety of cardiovascular disease (CVD), especially in unstable coronary syndrome. Our data have showed that increased level of CRP in patients with unstable angina was associated with short-term clinical outcomes, response for conventional therapy, and activation of nuclear factor-kappa B (NF-kappaB), but it is not correlated to coronary artery stenosis as well as lipid profile. Traditionally, CRP has been thought of as a bystander marker of vascular inflammation, without playing a direct role in the CVD. More recently, accumulating evidence suggest that CRP may have direct proinflammatory effects, which is associated with all stages of atherosclerosis. In our recent study, the results demonstrate that monocytes exhibit an enhanced production of interleukin-6 (IL-6) in response to CRP, and this response is significantly inhibited by simvastatin in a dose-dependent manner. This may be of important interest in the connection between CVD and CRP. Based on those evidence, we hypothesis that CRP is not only an inflammatory marker but also a direct cause of CVD, and treatments that reduce CRP should be benefit for primary and secondary prevention of CVD. Administration of several agents, especially statin has been showed to modify CRP concentrations with a concurrent fall in cardiovascular events. Our clinical investigation suggested that treatment with a single high-dose or a short-term common dose of simvastatin could rapidly reduce CRP level. Those data indicated that the benefit to the vascular endothelium might occur quickly in patients with CVD, which is critical issue for high-risk subgroup. Other interventions, such as lifestyle changes, weight loss, and stop smoking are also warrant attention.

Activation of nuclear factor-kappaB and correlation with elevated plasma c-reactive protein in patients with unstable angina.

BACKGROUND: Unstable coronary syndromes are currently believed to be caused by rupture of an atherosclerotic plaque due to local events, which may be of general inflammatory etiology. There is increasing evidence that nuclear factor-kappaB (NF-kappaB) is a key transcription factor in controlling gene expression concerning inflammatory response, and that plasma concentrations of C-reactive protein (CRP) is a sensitive marker of inflammation in unstable coronary syndromes. However, whether NF-kappaB activation is associated with coronary heart disease (CHD) activity as well as plasma CRP level has been less well investigated. The aim of this study was to explore whether NF-kappaB activation was associated with CHD activity and plasma CRP elevation in patients with unstable angina (UA). METHODS: NF-kappaB activity derived from white blood cells circulating in 33 patients with CHD was determined by electrophoretic mobility shift assay. Of these, 16 had UA and were within 24h of the last episode of chest pain. The remaining 17 were being evaluated for stable angina (SA). The CRP was also evaluated in both groups using a high-sensitivity ELISA. RESULTS: There was marked NF-kappaB activation and elevated levels of CRP in UA group compared with SA group (4.02+/-0.71 AU versus 1.24+/-0.23 AU and 5.0+/-0.7mg/l versus 1.4+/-0.4mg/l, respectively, P<0.01), no NF-kappaB signal was observed in normal subjects (n=10). The NF-kappaB activation had a positive correlation with levels of CRP in patients with UA (n=11, gamma=0.771, P<0.01), but had no relationship between other clinical characteristics and the status of NF-kappaB activation. CONCLUSIONS: Our data suggest that inflammation is an important feature of unstable coronary artery disease, and both NF-kappaB and CRP are useful markers for the detection of UA or vulnerable plaques.

Rapid effects of simvastatin on lipid profile and C-reactive protein in patients with hypercholesterolemia.

BACKGROUND: Rapid lowering of low-density lipoprotein (LDL) cholesterol levels as well as C-reactive protein (CRP) by administration of drugs may produce early benefit to the coronary endothelium in patients with coronary heart disease and reduce angina and coronary events after revascularization. Limited information has been available in evaluating a potentially effective first 2-week therapeutic approach for the treatment of patients with hypercholesterolemia using a statin. HYPOTHESIS: The study was undertaken to investigate whether a rapid LDL cholesterol and CRP reduction can be achieved by 2-week simvastatin therapy using a common lipid-lowering protocol in patients with hypercholesterolemia. METHODS: Forty-two patients were randomly assigned to 20 or 40 mg/day of simvastatin. Blood samples were drawn at Day 0 and at Day 14 for measuring lipid profile, CRP levels, and hepatic enzymes in all patients. RESULTS: The results showed that both doses of simvastatin (20 and 40 mg) induced significant reductions in total cholesterol (TC, 25 and 38%) and LDL cholesterol (31 and 46%) compared with baseline. However, the highest dose of simvastatin (40 mg) resulted in significantly greater reductions in TC and LDL cholesterol (p = 0.04, p = 0.02, respectively) compared with the group receiving 20 mg (p < 0.04, p < 0.02, respectively). A less significant reduction was observed in mean triglycerides (TG) level (16 and 25%) compared with TC and LDL cholesterol. There was no significant difference in mean high-density lipoprotein (HDL) cholesterol levels compared with baseline in either group. In addition, both doses of simvastatin induced significant reductions in mean CRP levels on Day 14 (22.3 and 23.1%) in a non dose-dependent manner (p < 0.001, respectively. CONCLUSIONS: Our data suggest that a common daily dose of simvastatin, especially 40 mg, is an effective 2-week therapy for patients with hypercholesterolemia, and benefit to the vascular endothelium can be derived quickly by reduction of CRP levels.

Ischemic preconditioning detected by treadmill exercise tests in patients with stable angina.

The aim of this study was to explore the ischemic preconditioning (IP) phenomenon in patients with chronic stable angina (SA) by using treadmill exercise tests (TETs). Twenty-nine patients with SA were divided into 2 groups: group A (n = 15) and group B (n = 14). There was no difference between the 2 groups in both clinical characteristics and extent of coronary stenosis. Group A was subjected to 2 TETs at a 10-minute interval, but group B had a 60-minute interval according to Bruce protocol. The occurrence and time of chest pain, maximal value, duration of ST segment depression, and arrhythmias that occurred during TETs were analyzed for differences in the 2 tests in the 2 groups. In group A, 9 patients (60.0%) complained of chest pain in the first test, whereas only 4 (26.7%) did in the second test (p < 0.01); The time of occurrence of chest pain during exercise was 1.88 +/- 0.2 min in the first test, 2.3 +/- 0.4 min in the second test (p < 0.05); The maximal value of ST segment depression decreased from 0.21 +/- 0.09 mV in the first test to 0.14 +/- 0.05 mV in the second (p < 0.01); the duration of ST segment depression decreased from 7.12 +/- 0.9 min in the first test to 4.42 +/- 0.3 min in the second (p < 0.01). The incidence of arrhythmia decreased from 40.0% in the first test to 13.3% in the second (p < 0.05). However, no significant difference was observed in the multiple parameters, mentioned above, in group B. In conclusion, the first ischemic event could induce the IP phenomenon and protect the heart from more serious damage at a 10-minute interval. However, this effect disappeared when the second test was done at a 60-minute interval.

Circadian variation in ischemic threshold in patients with stable angina: relation to plasma endothelin-1.

To investigate circadian variation in ischemic threshold in chronic coronary heart disease (CHD) and its relation to plasma endothelin-1 (ET-1), 21 patients with stable angina underwent treadmill exercise tests twice within a day, performed at 8-9 AM for the first test and at 3-4 PM for the second one. Ischemic threshold was defined as the heart rate at the onset of 1 mm ST segment depression during exercise tests. Blood samples were taken at 5 minutes before each exercise test, and plasma ET-1 was measured for determining the possible relation to ischemic threshold in patients with CHD. The results showed that the heart rate-ischemic threshold in individual patients varied by 10 +/- 1% (range, 2-15%) in the morning and 9 +/- 1% (range, 2-14%) in the afternoon, while there was a mean (11.2%) reduction in the ischemic threshold between 2 time points, with the ischemic threshold being significantly lower in the morning compared with that in the afternoon (115 +/- 22 bpm vs 128 +/- 31 bpm p<0.04). ET-1 values were 6.20 +/- 2.44 ng/L in the morning hours and 4.02 +/- 1.61 ng/L in the afternoon hours, with a statistical significant difference (p<0.01). In conclusion, the present study indicated that circadian variation of plasma levels of ET-1 was likely to be one of the most likely mechanisms involved in reduction in the ischemic threshold in the morning hours.

Elevated level of plasma C-reactive protein in patients with unstable angina: its relations with coronary stenosis and lipid profile.

C-reactive protein (CRP) is a sensitive marker of inflammation, and elevated levels have been associated with future risk of cardiovascular events. To explore the role and relationship of CRP and coronary stenosis in the development of unstable angina (UA), plasma levels of CRP were determined on admission in 45 patients with UA, and in 42 patients with stable angina (SA) using high-sensitivity ELISA. Coronary angiography was performed in all patients with coronary heart disease (CHD), and severity of coronary stenosis was evaluated by a quantitative analysis. Lipid measurement was performed using automatic biochemical analyzer. Data available from patients with CHD were compared with those of 41 control subjects. The results showed that plasma levels of CRP are significantly higher in patients with UA than those in patients with SA and control subjects (5.1 +/- 1.4 mg/L vs 1.7 +/- 0.4 mg/L and 1.3 +/- 0.2 mg/L, p<0.01, respectively) with no difference between the latter two groups (p>0.05); the total incidence of clinical events during in-hospital follow-up was higher in the group A (p<0.01); the scores of coronary stenosis are significantly higher in patients with SA than those in patients with UA (4.9 +/- 2.1 vs 3.4 +/- 1.4, p<0.05); there is no correlation between plasma levels of CRP and serum total cholesterol (TC) as well as high-density lipoprotein cholesterol (HDL-C) in both groups (p>0.05 respectively); there was no correlation between plasma levels of CRP and severity of coronary stenosis was found in patients with UA (p>0.05) but a significant positive association in patients with SA (p<0.001); and the patients with persistent, severe, treatment-unresponsive UA had significantly higher CRP levels as well as incidence of clinical events than patients with treatment-responsive UA (7.4 +/- 1.8 mg/L vs 2.6 +/- 1.3 mg/L, p<0.01; 0 vs 22.2%, p<0.05). The present data suggested that inflammation may play an important role in the pathogenesis of UA, and the plasma levels of CRP might have a higher prognostic value than the severity of coronary stenosis correlated with the clinical outcome of instability despite of lipid profile status.