Prevention of cardiovascular disease in rheumatoid arthritis.

The increased risk of cardiovascular disease (CVD) in rheumatoid arthritis (RA) has been recognized for many years. However, although the characteristics of CVD and its burden resemble those in diabetes, the focus on cardiovascular (CV) prevention in RA has lagged behind, both in the clinical and research settings. Similar to diabetes, the clinical picture of CVD in RA may be atypical, even asymptomatic. Therefore, a proactive screening for subclinical CVD in RA is warranted. Because of the lack of clinical trials, the ideal CVD prevention (CVP) in RA has not yet been defined. In this article, we focus on challenges and controversies in the CVP in RA (such as thresholds for statin therapy), and propose recommendations based on the current evidence. Due to the significant contribution of non-traditional, RA-related CV risk factors, the CV risk calculators developed for the general population underestimate the true risk in RA. Thus, there is an enormous need to develop adequate CV risk stratification tools and to identify the optimal CVP strategies in RA. While awaiting results from randomized controlled trials in RA, clinicians are largely dependent on the use of common sense, and extrapolation of data from studies on other patient populations. The CVP in RA should be based on an individualized evaluation of a broad spectrum of risk factors, and include: 1) reduction of inflammation, preferably with drugs decreasing CV risk, 2) management of factors associated with increased CV risk (e.g., smoking, hypertension, hyperglycemia, dyslipidemia, kidney disease, depression, periodontitis, hypothyroidism, vitamin D deficiency and sleep apnea), and promotion of healthy life style (smoking cessation, healthy diet, adjusted physical activity, stress management, weight control), 3) aspirin and influenza and pneumococcus vaccines according to current guidelines, and 4) limiting use of drugs that increase CV risk. Rheumatologists should take responsibility for the education of health care providers and RA patients regarding CVP in RA. It is immensely important to incorporate CV outcomes in testing of anti-rheumatic drugs.

Oral antiplatelet agents in ACS: from pharmacology to clinical differences.

Antiplatelet agents play an essential role in the treatment of acute coronary syndrome (ACS). Numerous clinical trials have established the value of antiplatelet therapies for ACS. Aspirin (ASA), thienopyridines and GP IIb/IIIa antagonists comprise the major classes of antiplatelet therapies demonstrated to be of benefit in the treatment of ACS. Thienopyridines are a class of drugs that function via inhibition of the adenosine diphosphate (ADP) P2Y12 platelet receptors. Currently, clopidogrel, a second generation thienopyridine, is the main drug of choice and the combination of aspirin and clopidogrel is administered orally for the treatment of ACS. Recently, a third generation of thienopyridines has been introduced represented by prasugrel that has demonstrated promising results in ACS patients treated with percutaneous coronary intervention (PCI). A number of nonthienopyridine oral antiplatelet drugs are under development, and one of them, ticagrelor has already been tested in a major phase III clinical trial, PLATO, with the inclusion of a broad spectrum of patients with ACS. The present review aims to discuss the present knowledge about the safety and efficacy of oral antiplatelet treatment of patients with ACS.

Association between AMPD1 gene polymorphism and coagulation factors in patients with coronary heart disease.

The aim of this study was to investigate whether the C34T and G468T variations in the adenosine monophosphate deaminase-1 (AMPD1) gene were associated with intima-media thickness of the carotid and brachial artery, endothelial function of the brachial artery, glucose metabolism, haemostatic variables and cardiac hypertrophy in patients (n = 109) with coronary heart disease. The plasminogen activator inhibitor-1 activity and the von Willebrand factor were higher in the CC homozygote group compared to the CT/TT group (p < 0.05). There were no differences between the groups regarding intima-media complex of the carotid and brachial artery, presence of plaque in the carotid region, flow-mediated dilatation, ejection fraction or dimensions of the heart. In conclusion, there were no differences between the mutant AMPD1 allele carriers and CC homozygotes regarding surrogate values for atherosclerosis, endothelial function, dimensions and ejection fraction of the heart, glucose tolerance and other well-known cardiovascular risk factors, whereas plasminogen activator inhibitor-1 activity and von Willebrand levels were lower in the mutant AMPD1 allele carriers.

Oral snuff impairs endothelial function in healthy snuff users.

AIMS: Oral snuff is a less dangerous drug and therefore a good substitute for cigarette smoking. The aim of this study was to determine whether oral moist snuff induces acute endothelial dysfunction. Previous studies have shown that endothelial dysfunction predicts cardiovascular morbidity. METHODS AND RESULTS: Twenty healthy middle-aged snuff users underwent ultrasound assessment of endothelial-dependent flow-mediated dilatation (FMD) of the brachial artery. FMD measurements were performed in duplicate at baseline and then 20 and 35 min after the administration of 1 g portion-bag-packed moist snuff or placebo. Ten of the subjects were examined twice according to a randomized cross-over procedure, once with snuff and once with placebo. All images were arbitrarily analysed off-line by a single blinded observer. FMD values declined significantly from 3.4 +/- 2.0% to 2.3 +/- 1.3% (P < 0.05) 35 min after the administration of 1 g oral moist snuff. Heart rate, systolic and diastolic blood pressure increased significantly (P < 0.05) after snuff administration. All parameters remained unchanged after placebo. CONCLUSIONS: Oral moist snuff significantly impaired FMD of the brachial artery. As endothelial dysfunction predicts cardiovascular morbidity, use of oral snuff should be discouraged.

Smoking and use of smokeless tobacco in treated hypertensive men at high coronary risk: utility of urinary cotinine determination.

Guidelines for the treatment of hypertension underline the central importance of strenuous efforts to reduce the prevalence of smoking, as epidemiological studies consistently have demonstrated that smoking increases the risk of cardiovascular disease and death by some two- or three-fold. Accuracy of a questionnaire is examined against the ability of urinary cotinine determination to distinguish between men exposed to tobacco (94 smokers [25%], 30 snuff users [8%]) and men not exposed (n = 257), all of whom where treated hypertensives and were associated with at least one of the following factors: smoking, diabetes mellitus, serum cholesterol > or = 6.5 mmol/L. Main outcome variables in this cross-sectional study of 381 men were cotinine concentration and cotinine:creatinine ratio in overnight urine samples (decision limits: 2 mumol/L and 1.0 mmol/mol, respectively); tobacco use according to questionnaire; and follow-up examination by questionnaire of alleged non-smokers with high urinary cotinine levels. Questionnaire sensitivity was 85%, whereas the urinary cotinine assay showed 98% sensitivity and 99% specificity. Fourteen (15%) out of 94 patients may have used tobacco without reporting it in the questionnaire. In conclusion, cotinine measurement substantially improved the discrimination between smokers and non-smokers in men with multiple risk factors for cardiovascular disease.

Multiple risk intervention trial in high risk hypertensive men: comparison of ultrasound intima-media thickness and clinical outcome during 6 years of follow-up.

OBJECTIVES: The objective was to analyse whether a favourable change in risk factors, caused by a comprehensive risk factor modification programme, affected intima-media thickness (IMT) in the common carotid artery, and whether any such change was associated with a change in cardiovascular events during a 6-year follow-up. DESIGN: Patients were randomized 1 : 1 to special intervention or usual care. SETTING: Hypertension Unit at university hospital. SUBJECTS: A total of 164 patients were randomized. Inclusion criteria were male, aged 50-72 years (at randomization) and one or more of the following: Serum cholesterol level > 6.5 mmol L(-1), smoking or diabetes mellitus. All patients were prescribed antihypertensive treatment since many years. In 142 men good quality ultrasound recording of the common carotid IMT were achieved at baseline, 119 were re-examined after 3.3 years, and 97 patients were available for examination after mean follow-up time of 6.2 years. Cardiovascular events were available for all randomized patients. INTERVENTIONS: The nonpharmacological special intervention programme was based on one information meeting followed by five weekly 2-h sessions with participation of patients and spouses. The diet recommendations were similar to established guidelines. Overweight patients were instructed to lose weight, and diabetic patients were systematically taught self-monitoring of blood glucose. Smokers were invited to a smoking cessation programme with five weekly meetings. Follow-up visits were thereafter scheduled every 6 months. Lipid lowering drugs were recommended in the intervention group if the treatment goals using nonpharmacological measures were not achieved. Patients in the usual care group were told to quit smoking and to lower their consumption of fat and glucose. Antihypertensive treatment (i.e., selection of drugs) was on purpose kept similar in the two groups. MAIN OUTCOME MEASURES: The IMT of the common carotid artery as measured by ultrasound. Cardiovascular events during follow-up. RESULTS: Significant net reductions were seen for serum cholesterol, triglycerides, fasting glucose and smoking. No difference in change in IMT was observed during follow-up between the two randomization groups. The explanation was that patients with positive plaque status at baseline had a much larger increase in IMT over time than patients with negative plaque status, and that patients with positive plaque status more often survived and were available for re-examination after 6 years in the intervention group than in the usual care group. Total mortality was lower in the intervention group, compared with the usual care group, 13 and 29%, respectively (P=0.028). CONCLUSIONS: In high risk populations, long-term studies with surrogate endpoints may be misleading because of missing data in patients where a large increase in IMT would have been observed, had they been re-examined. Another important conclusion from our study was that the gloomy prognosis for this patient category may be improved by a dedicated risk factor intervention programme. The improved prognosis was observed mainly in those patients at highest risk judged from history of cardiovascular disease or positive ultrasound plaque status at baseline.

Should we do an oral glucose tolerance test in hypertensive men with normal fasting blood-glucose?

The objective of this study was to examine, using the new WHO criteria for diabetes mellitus, whether insulin and glucose before and after an oral glucose tolerance test would predict cardiovascular mortality in hypertensive men with normal fasting blood glucose. A standard oral glucose challenge was performed after an overnight fast in 113 hypertensive men with either hypercholesterolaemia or smoking. These patients were recruited from an on-going risk factor intervention study. The mean observation time was 6.3 years. During follow-up there were 10 cardiovascular deaths. The Cox regression analyses showed an independent and significant association (P < 0.05) between blood glucose 120 min after the glucose ingestion and cardiovascular death during follow-up. Fasting glucose, fasting insulin and insulin 120 min after glucose ingestion was not related to cardiovascular death during follow-up. In conclusion, this is the first study using the current definition of diabetes mellitus showing that hyperglycaemia following an oral glucose load is an independent risk factor for cardiovascular death in hypertensive men with a normal fasting glucose. In this type of hypertensive patient with normal fasting glucose, an oral glucose tolerance test may help to identify subjects at high cardiovascular risk. Journal of Human Hypertension (2001) 15, 71-74

Chlamydia pneumoniae seropositivity is associated with carotid artery intima-media thickness.

BACKGROUND AND PURPOSE: Infection may both augment the atherosclerotic process and contribute to later manifestations of overt clinical disease. Chlamydia pneumoniae elementary bodies have been detected in atherosclerotic lesions. The aim of the present study was to investigate whether elevated titers of antibodies and circulating immune complexes to C pneumoniae were associated with ultrasound findings indicating presence of atherosclerosis in the carotid artery. METHODS: Serum titers of antibodies to C pneumoniae (IgM, IgA, IgG, and circulating immune complex) were related to intima-media thickness (IMT) and plaque status measured by B-mode ultrasound in the carotid artery in 113 men with treated hypertension and at least 1 of the following risk factors: hypercholesterolemia, smoking, or diabetes. RESULTS: Any of the titers was elevated in 56 (50%) men, and common carotid artery IMT was thicker in this group compared with the 57 men without any elevated titers (1.00 versus 0.92 mm, P<0.05). There were no accompanying differences in blood pressure, lipid levels, blood glucose, or smoking. Elevation of separate antibody types and circulation immune complex were also associated with increased IMT. In the latter group, systolic blood pressure was higher among seropositive patients compared with those who had no circulating immune complex. Seropositivity was not related to plaque status. CONCLUSIONS: Seropositivity for C pneumoniae was associated with an increased intima-media thickness in the common carotid artery but not plaque status in hypertensive men at high risk for cardiovascular disease.

Insulin sensitivity and haemostatic factors in men at high and low cardiovascular risk. The Risk Factor Intervention Study Group.

OBJECTIVE: To investigate the relationship between variables of the coagulation and fibrinolysis system and insulin sensitivity in non-diabetic men at high and low risk of cardiovascular disease. DESIGN: Cross-sectional study. SETTING: Outpatient clinic in city hospital. PATIENTS: Thirty-five men at high risk for atherosclerotic disease (hypertension and at least one the following factors: hypercholesterolaemia and smoking) and an age-matched low-risk group (n = 23) with no cardiovascular risk factors. MAIN OUTCOME MEASURES: Insulin-mediated glucose disposal (hyperinsulinaemic euglycaemic clamp) adjusted for lean body mass and fibrinogen, von Willebrand factor, prothrombin fragment 1 + 2, thrombin/antithrombin complex and plasminogen activator inhibitor activity were determined. RESULTS: Insulin-mediated glucose disposal adjusted for lean body mass was significantly lower in the high-risk group than in the low-risk group. Glucose disposal was significantly negatively associated with plasminogen activator inhibitor activity (PAI) in the high-risk group and with von Willebrand factor in the low-risk group. In the whole study group, fibrinogen and PAI were significantly associated with glucose disposal. After adjusting for confounding factors, glucose disposal was independently negatively associated with PAI in the high-risk group (P < 0.001) and in the whole group (P < 0.001). CONCLUSIONS: High-risk men were significantly more insulin-resistant than the low-risk group. Glucose disposal adjusted for lean body mass was associated with an impaired fibrinolytic activity in the high-risk group. Fibrinogen was associated with insulin resistance in the whole study group. The negative relationship between von Willebrand factor levels and glucose disposal in the low-risk group may indicate that insulin resistance can induce an endothelial dysfunction even in non-diabetic subjects.

Chlamydia pneumoniae but not cytomegalovirus antibodies are associated with future risk of stroke and cardiovascular disease: a prospective study in middle-aged to elderly men with treated hypertension.

BACKGROUND AND PURPOSE: Several cross-sectional and prospective studies have indicated that high titers of antibodies to Chlamydia pneumoniae and cytomegalovirus (CMV) are associated with coronary heart disease. The aim of the present study was to examine whether elevated titers of antibodies to these pathogens are predictive of not only coronary but also cerebrovascular disease. METHODS: Serum titers of antibodies to C pneumoniae (IgM, IgG, IgA, IgG immune complex) and CMV (IgG) were determined at baseline (n=130) and after 3.5 years (n=111) in a total sample of 152 men. All individuals had treated hypertension and at least 1 additional risk factor for cardiovascular disease (hypercholesterolemia, smoking, or diabetes mellitus) and constituted 93% of a randomly selected subgroup (n=164) of patients participating in a multiple risk factor intervention study. RESULTS: Elevations of any or both of the IgA or IgG titers to C pneumoniae at entry or after 3.5 years were found in 84 cases (55%). Of those with high titers at entry, 97% remained high at the 3.5 year reexamination. After 6.5 years of follow-up, high titers to C pneumoniae at entry were associated with an increased risk for future stroke (relative risk [RR], 8.58; P=0.043; 95% CI, 1.07 to 68.82) and for any cardiovascular event (RR, 2.69; P=0.042; 95% CI, 1.04 to 6.97). A high serum titer of antibodies to CMV was found in 125 cases (85%), and this was not associated with an increased risk of future cardiovascular events. CONCLUSIONS: Seropositivity for C pneumoniae, but not for CMV, was associated with an increased risk for future cardiovascular disease and, in particular, stroke.

Stroke was predicted by dimensions of quality of life in treated hypertensive men.

BACKGROUND AND PURPOSE: Psychosocial factors have been suggested as risk factors for atherosclerotic disease. The purpose of the present study was to examine whether quality of life predicted strokes and acute coronary events in a prospective study. METHODS: The study included 412 treated hypertensive men, aged 50 to 72 years, with >/=1 of the following: serum cholesterol >/=6.5 mmol/L, smoking, or diabetes mellitus. The Minor Symptoms Evaluation Profile (MSEP) was used to estimate quality of life at entry. Incidences of stroke and acute coronary events were recorded during follow-up. The median follow-up time was 6.6 years. RESULTS: Sixty-four patients had an acute coronary event, and 37 had a stroke during the follow-up period. The Cox regression analyses revealed that the 3 dimensions of MSEP at entry were significant predictors of stroke. The relationship between low contentment at entry and the incidence of stroke during follow-up remained significant (relative risk=1.04; 95% CI, 1.01 to 1.06; P=0.003) even after adjustment for other potential cardiovascular risk factors. Vitality also remained an independent predictor for stroke after adjustment for these potential cardiovascular risk factors (relative risk=1.04; 95% CI, 1. 02 to 1.06; P<0.0001). There was no relationship between MSEP score at entry and myocardial infarction during follow-up. CONCLUSIONS: An independent and significant association between reduced well-being at entry and future stroke was observed in hypertensive men at high cardiovascular risk. The causal relationship is not known, however.

Prothrombin fragment 1+2 is a risk factor for myocardial infarction in treated hypertensive men.

BACKGROUND: Haemostatic factors may play a part in the development of acute coronary heart disease. OBJECTIVE: To evaluate as predictors of major coronary events (fatal and non-fatal myocardial infarctions and sudden death) levels of fibrinogen, von Willebrand factor, prothrombin fragment 1+2, thrombin-antithrombin complex, plasminogen activator inhibitor activity and C-reactive protein. METHODS: We studied 131 men, aged 56-77 years, with treated hypertension and at least one additional cardiovascular risk factor (hypercholesterolaemia, diabetes mellitus or smoking). These patients were recruited from a continuing risk factor intervention study. The mean observation time was 3.0 years. RESULTS: Fourteen patients died and 16 had a major coronary event during the follow-up period. After adjustments for other risk factors, levels of prothrombin fragment 1+2 and C-reactive protein were independent predictors of major coronary events. The other measured haemostatic variables were not significantly associated with major coronary events during follow-up. Fibrinogen and prothrombin fragment 1+2 levels were independent predictors for mortality. CONCLUSIONS: Among treated hypertensive men, levels of prothrombin fragment 1+2 and C-reactive protein were independent predictors of major coronary events.

Mortality rates in treated hypertensive men with additional risk factors are high but can be reduced: a randomized intervention study.

The aim was to examine the feasibility and efficacy of a multifactorial risk factor intervention program in hypertensive patients at high cardiovascular risk. Treated hypertensive men, aged 50 to 72 years, with at least one of the following: serum cholesterol concentration > or = 6.5 mmol/L, diabetes mellitus, or smoking were randomized to multifactorial risk factor intervention (n = 253) or usual care (n = 255). The specific intervention was based on group meetings to encourage a lipid lowering diet and smoking cessation. Cholestyramine, nicotinic acid, fibrates, and later statins were used either as single drug therapy or in combination, following agreed guidelines in patients in whom the nonpharmacological intervention was judged to be insufficient. Usual care was given according to clinical practice. The median follow-up time was 6.6 years. Sixty-four patients (25.1%) died in the usual care group, compared with 41 patients (16.2%) in the intervention group (P = .016; 95% confidence interval, relative risk 0.42 to 0.92). The overall risk for fatal and nonfatal cardiovascular events was 29% lower in the intervention group than in the usual care group (P = .041). Relative to usual care, the intervention program lowered mean in-trial serum concentrations of total cholesterol (6.3%, P < .0001), LDL cholesterol (9.1%, P < .0001), and blood glucose (0.2 mmol/L, P < .05). Among smokers, at entry, cotinine-adjusted quit rates were 28% in the intervention group and 11% in the usual care group (P = .012) after 3 years. This study illustrates the very high cardiovascular risk in hypertensive patients 50 to 72 years of age with additional risk factors. The results indicate, however, that the gloomy prognosis may be improved by a dedicated risk factor intervention program.

Usefulness of microalbuminuria in predicting cardiovascular mortality in treated hypertensive men with and without diabetes mellitus. Risk Factor Intervention Study Group.

In the present study we report on the predictive power of microalbuminuria for total and cardiovascular mortality in a prospective study (mean follow up 6.3 years) of treated hypertensive men, aged 50 to 72 years, with (n = 94) and without (n = 345) maturity onset diabetes mellitus. Thirty-three (35.1%) of the hypertensive patients with diabetes mellitus died during the follow-up period compared with 57 patients (16.5%) in the hypertensive group without diabetes mellitus (p <0.0002). In those with diabetes mellitus and hypertension, a log-rank test revealed a lower cardiovascular mortality in the normoalbuminuric group compared with both the microalbuminuric (p = 0.035) and the macroalbuminuric group (p = 0.002). The logarithm of urinary albumin excretion was a predictor of both total (p = 0.009) and cardiovascular (p = 0.001) mortality during the follow-up period using Cox regression analysis. This relation remained significant even after adjustment for other risk factors. HbA1c was also an independent predictor of total and cardiovascular mortality. In patients without diabetes mellitus, the small group of patients with macroalbuminuria had a markedly increased cardiovascular mortality compared with both the microalbuminuric (p <0.0001) and the normoalbuminuric groups (p <0.0001). No difference was observed between the normoalbuminuric and the microalbuminuric groups. Smoking at entry and concomitant cardiovascular disease at entry were independent predictors of cardiovascular mortality in these patients. We conclude that microalbuminuria was an independent predictor for cardiovascular mortality in treated hypertensive men with maturity onset diabetes mellitus. Macroalbuminuria, but not microalbuminuria, predicted cardiovascular mortality in nondiabetic treated hypertensive men.

Multifactorial treatment of hypertensive men at high cardiovascular risk and low-density lipoprotein cholesterol affinity to human arterial proteoglycans.

The purpose of this work was to examine in an open, randomized parallel-group study whether an intervention programme directed towards hypercholesterolaemia, smoking and diabetes mellitus in treated hypertensive men was associated with less complex formation between low-density lipoprotein (LDL) and human arterial proteoglycans than was the case with usual care. The intervention consisted mainly of non-pharmacological treatment, but drug therapy could be instituted to achieve the treatment goals in the intervention group. The intervention programme was associated with a significant reduction in body mass index, and 46% of the patients were on lipid-lowering medication at the follow-up examination. The net differences were (intervention--usual care): change in serum LDL-cholesterol, -0.48 mmol L-1 (95% confidence interval -0.84 to -0.11 mmol L-1), precipitated LDL-cholesterol, -5.5 micrograms (95% CI -9.0 to -1.1 micrograms). The latter remained after adjustment for the difference in serum LDL-cholesterol between groups. Our conclusion is that the multifactorial risk factor treatment programme was associated with a reduced tendency of LDL to form complexes with human arterial proteoglycans.

Risk factors that predict development of microalbuminuria in treated hypertensive men. The Risk Factor Intervention Study Group.

The aim of this prospective study was to investigate the risk factors for development of microalbuminuria in treated hypertensive men with and without diabetes mellitus. Two hundred and ninety-seven treated hypertensive men, aged fifty to seventy-two years, with at least one of the following: serum cholesterol > or = 6.5 mmol/L, smoking, or diabetes mellitus, were included in the study. Patients with elevated overnight urinary albumin excretion (> 17 mg/12 hr) were excluded. Urinary albumin excretion (UAE), blood pressure, and various well-established risk factor levels were measured. Two hundred thirteen nondiabetic patients and 40 patients with diabetes mellitus completed the three-year follow-up. Development of microalbuminuria was more prevalent in those with diabetes mellitus at baseline compared with the group without diabetes mellitus, 25% and 10.3%, respectively (P = 0.02). Nondiabetic patients who developed microalbuminuria had higher UAE. 10.2 mg +/- 3.7 and 5.7 +/- 3.2, respectively (P < 0.0001), and higher systolic blood pressure 160 mm Hg +/- 27 and 152 +/- 17, respectively (P = 0.043), at baseline compared with whose who remained normoalbuminuric. In the group with diabetes mellitus, a higher UAE, 9.8 +/- 2.7 and 7.1 +/- 3.6, respectively (P = 0.036), at baseline was observed in whose who developed microalbuminuria compared with whose who remained normoalbuminuric. In conclusion, concomitant diabetes mellitus significantly increased the risk for development of microalbuminuria during the three-year follow-up in treated hypertensive men. Patients who progressed to microalbuminuria had higher UAE at baseline, but still within the normoalbuminuric range, compared with thosewho remained normoalbuminuric. Systolic blood pressure at baseline was higher in those who progressed to microalbuminuria, although reaching statistically significance only in the larger nondiabetic group.