Lars Stavenow

Lung Function and Cardiovascular Risk Relationship With Inflammation-Sensitive Plasma Proteins

Background—The inverse relationship between pulmonary function and incidence of cardiovascular disease remains largely unexplained. This prospective study explored the hypothesis of a relationship with inflammation-sensitive plasma proteins. Methods and Results—Forced vital capacity (FVC) and plasma levels of fibrinogen, &agr; 1-antitrypsin, haptoglobin, ceruloplasmin, and orosomucoid were determined in 5064 healthy men aged 28 to 61 years. All-cause mortality, cardiovascular mortality, and incidence of myocardial infarction were monitored over a mean follow-up period of 18.4 years. Low FVC (fourth quartile) was associated with higher protein levels and with increased incidences of myocardial infarction and cardiovascular death. Adjustments for protein levels reduced the age-adjusted relative risks (RRs) for myocardial infarction (from 1.99, 95% CI 1.5 to 2.6, to 1.70, 95% CI 1.3 to 2.2) and cardiovascular death (from 2.71, 95% CI 1.9 to 3.9, to 2.28, 95% CI 1.6 to 3.3) among men with low FVC, corresponding to ≈25% of the excess risk. The risk factor–adjusted RRs were reduced from 1.45 (95% CI 1.1 to 1.9) to 1.38 (95% CI 1.1 to 1.8) and from 1.96 (95% CI 1.4 to 2.8) to 1.85 (95% CI 1.3 to 2.7) for myocardial infarction and cardiovascular death, respectively, corresponding to ≈10% to 15% of the excess risk. Among men with low FVC, the risk factor–adjusted RR for myocardial infarction was 2.5 (95% CI 1.7 to 3.6) for those with high protein levels (≥2 proteins in top quartile) and 1.7 (95% CI 1.1 to 2.4) for those with low protein levels (≤1 protein in top quartile; reference, top quartile of FVC and low protein levels). Conclusions—FVC is significantly and inversely associated with plasma levels of inflammation-sensitive plasma proteins. This relationship contributes to but cannot fully explain the increased cardiovascular risk among men with low FVC.

Orthostatic hypotension predicts all-cause mortality and coronary events in middle-aged individuals (The Malmö Preventive Project)

Aims Orthostatic hypotension (OH) has been linked to increased mortality and incidence of cardiovascular disease in various risk groups, but determinants and consequences of OH in the general population are poorly studied. Methods and results Prospective data of the Swedish ‘Malmö Preventive Project’ (n = 33 346, 67.3% men, mean age 45.7 ± 7.4 years, mean follow-up 22.7 ± 6.0 years) were analysed. Orthostatic hypotension was found in 6.2% of study participants and was associated with age, female gender, hypertension, antihypertensive treatment, increased heart rate, diabetes, low BMI, and current smoking. In Cox regression analysis, individuals with OH had significantly increased all-cause mortality (in particular those aged less than 42 years) and coronary event (CE) risk. Mortality and CE risk were distinctly higher in those with systolic blood pressure (BP) fall ≥30 mmHg [hazard ratio (HR): 1.6, 95% CI 1.3–1.9, P < 0.0001 and 1.6, 95% CI 1.2–2.1, P = 0.001] and diastolic BP fall ≥15 mmHg (HR: 1.4, 95% CI 1.1–1.9, P = 0.024 and 1.7, 95% CI 1.1–2.5, P = 0.01). In addition, impaired diastolic BP response had relatively greater impact (per mmHg) on CE incidence than systolic reaction. Conclusion Orthostatic hypotension can be detected in ∼6% of middle-aged individuals and is often associated with such comorbidities as hypertension or diabetes. Presence of OH increases mortality and CE risk, independently of traditional risk factors. Although both impaired systolic and diastolic responses predict adverse events, the diastolic impairment shows stronger association with coronary disease.

Effects of Cholesterol and Inflammation-Sensitive Plasma Proteins on Incidence of Myocardial Infarction and Stroke in Men

Background—Although cholesterol is a major cardiovascular risk factor, its association with stroke remains controversial. This study explored whether the cholesterol-related incidence of stroke and myocardial infarction is modified by plasma markers of inflammation in a large, population-based cohort with a long follow-up. Methods and Results—Plasma cholesterol and 5 inflammation-sensitive plasma proteins (ISP) (fibrinogen, &agr;1-antitrypsin, haptoglobin, ceruloplasmin, and orosomucoid) were determined in 6063 healthy men, 28 to 61 years of age. The incidence of stroke, cardiac events (fatal and nonfatal), and cardiovascular deaths was compared between groups defined by levels of cholesterol and ISP. Mean follow-up was 18.7 years. High ISP level was defined as 2 to 5 ISP in the top quartile. High cholesterol was associated with higher levels of ISP. Hypercholesterolemia (≥6.5 mmol/L, 251 mg/dL) was associated with an increased incidence of ischemic stroke and cardiac events and with a reduced incidence of intracerebral hemorrhage. The ISP levels modified these associations. After risk factor adjustment, men with hypercholesterolemia and high ISP levels had a significantly higher risk of cardiovascular death (relative risk [RR]=2.4; CI, 1.8 to 3.3), cardiac events (RR=2.3; CI, 1.8 to 3.0), and ischemic stroke (RR=2.1; CI, 1.4 to 3.3) than men with normal cholesterol and low ISP levels. In the absence of high ISP levels, hypercholesterolemia was associated with a moderately higher risk of cardiovascular death (RR=1.4; CI, 1.0 to 2.0) and cardiac events (RR=1.5; CI, 1.2 to 1.9) but not significantly with ischemic stroke (RR=1.25; CI, 0.8 to 2.0). Conclusions—Hypercholesterolemia is associated with high plasma levels of ISP. These proteins increase the cholesterol-related incidence of cardiovascular diseases. In the absence of elevated ISP levels, no statistically confirmed association was found between hypercholesterolemia and ischemic stroke.

Cardiovascular risk groups and mortality in an urban Swedish male population: the Malmö Preventive Project

Objectives. To describe the size, overlap and mortality of four cardiovascular risk groups, in order to give a scientific background for the prevention of cardiovascular disease in a representative urban population.

Noninvasive quantification of atherosclerotic lesions. Reproducibility of ultrasonographic measurement of arterial wall thickness and plaque size.

A noninvasive method based on high-resolution B-mode ultrasonography and a computerized image-analyzing system were used for the quantification of early (thickening of the intima-media complex) and late (plaque) atherosclerosis in the carotid and the femoral artery. The difference between repeated measurements was assessed to estimate intraobserver and interobserver differences. The results were satisfactory, with a coefficient of variation for measurement of lumen diameter in the common carotid artery of 3.8 +/- 4.1% (r = 0.91) and for the femoral artery of 4.8 +/- 4.1% (r = 0.93). Corresponding figures for intima-media thickness in the common carotid artery and the femoral artery were 10.0 +/- 8.5% (r = 0.86) and 16.2 +/- 12.6% (r = 0.91), respectively. The coefficient of variation for measurements of maximal intima-media thickness at the site of the plaque was 14.6 +/- 10.5% (r = 0.88); for plaque base, 13.1 +/- 9.0% (r = 0.91); and for plaque area, 16.3 +/- 12.6% (r = 0.90). The method seems promising for the detection and quantification of early and late atherosclerotic lesions in the carotid and femoral arteries.

Conservative drug treatment in patients with moderately severe chronic occlusive peripheral arterial disease. Scandinavian Study Group

A double-blind, parallel group, multicenter clinical trial of pentoxifylline compared with placebo enrolled 150 patients with moderately severe chronic occlusive arterial disease (COAD) at three centers in Scandinavia. The study consisted of a 4-6 week single-blind, placebo-controlled run-in phase, during which the stabilization of the initial claudication distance of all patients was assessed before randomization to a 6-month double-blind observation period. The diagnosis of COAD was established by clinical findings, conventional angiography, and noninvasive peripheral Doppler pressure assessment at rest and after exercise. The results of the overall intention-to-treat analysis of the study population show statistically significant superiority of pentoxifylline over placebo for all absolute claudication distance summary and end point measures. By using two clinically relevant parameters, which are a resting ankle/arm pressure ratio 0.8 or less and a duration of COAD for greater than 1 year, a target population could be defined in whom trial results became highly significant. For nontarget patients with mild COAD, we conclude that basic therapeutic measures should include the treatment of risk factors and the initiation of physical training. For target patients, however, a multifactorial therapeutic approach, including the use of pentoxifylline, is justified.

Blood Pressure Increase and Incidence of Hypertension in Relation to Inflammation-Sensitive Plasma Proteins

Objective—The reasons for the relationship between inflammation-sensitive plasma proteins (ISPs) and incidence of cardiovascular diseases are poorly understood. This study explored the hypothesis that ISPs are associated with future hypertension and age-related blood pressure increase. Method and Results—Blood pressure and plasma levels of fibrinogen, &agr;1-antitrypsin, haptoglobin, ceruloplasmin, and orosomucoid were determined in 2262 healthy men aged 35 to 50 years, initially without treatment for hypertension. The cohort was re-examined after 15.7 (±2.2) years. Incidence of hypertension and blood pressure increase was studied in relation to number of elevated proteins (ie, in the top quartile) at baseline. Among men without treatment for hypertension at follow-up, mean (±SD) increase in systolic blood pressure was 18.8±17, 19.2±17, 19.3±17, and 22.1±18 mm Hg, respectively, for men with 0, 1, 2, and ≥3 elevated proteins (P for trend=0.02, adjusted for confounders). The corresponding values for pulse pressure increase was 15.5±14, 15.8±14, 17.4±14, and 17.8±15 mm Hg, respectively (P =0.02). Incidence of hypertension (≥160/95 mm Hg or treatment) and future blood pressure treatment showed similar associations with ISPs. Increase in diastolic blood pressure showed no association with ISPs. Conclusions—Plasma levels of ISPs are associated with a future increase in blood pressure. This could contribute to the relationship between ISP levels and cardiovascular disease.

Long-Term Effects of Inflammation-Sensitive Plasma Proteins and Systolic Blood Pressure on Incidence of Stroke

Background and Purpose— The present study investigated the relationships between inflammation-sensitive plasma proteins (ISPs) and systolic blood pressure (SBP), as well as the joint long-term effects of ISP and SBP on incidence of stroke. Methods— BP and 5 ISPs (fibrinogen, &agr;1-antitrypsin, haptoglobin, ceruloplasmin, orosomucoid) were assessed in 6071 healthy men 28 to 61 years of age. All-cause mortality and incidence of stroke were monitored over a mean follow-up of 18.7 years in men defined by SBP (<120, 120 to 139, ≥140 mm Hg) and ISP (0 to 1 or 2 to 5 ISPs in the top quartile). Results— SBP and diastolic BP were significantly and positively associated with the number of ISPs in the top quartile. As expected, elevated SBP was associated with an increased incidence of stroke. Among men with SBP ≥140 mm Hg, there were, however, significant differences between those with high and low ISP levels. After risk factor adjustment, men with SBP ≥140 mm Hg and high ISP levels had a relative risk of stroke of 4.3 (95% CI, 2.3 to 7.8) compared with men with SBP <120 mm Hg and low ISP levels. In the absence of high ISP levels, the risk associated with SBP ≥140 was 2.5 (95% CI,1.4 to 4.6). Men with high ISP levels had a significantly increased risk of stroke also after exclusion of the events from the first 10 years of follow-up. Conclusions— High ISP levels are associated with elevated BP. These proteins are associated with an increased risk of stroke among men with high BP and provide information on stroke risk even after many years of follow-up.

Incidence of Obesity-Associated Cardiovascular Disease Is Related to Inflammation-Sensitive Plasma Proteins A Population-Based Cohort Study

Background—Although obesity is associated with increased inflammation, it is unclear whether this accounts for the increased cardiovascular risk in obesity. This population-based study explored whether inflammation-sensitive plasma proteins (ISPs) modify the cardiovascular risk in overweight or obese men. Methods and Results—The ISPs (fibrinogen, orosomucoid, &agr;1-antitrypsin, haptoglobin, ceruloplasmin) were measured in 6075 healthy men, aged 28 to 61 years. The incidences of cardiovascular events (myocardial infarction, stroke, cardiovascular deaths), cardiac events (fatal or nonfatal myocardial infarction), and stroke were followed-up over 18±4 years. High ISPs were associated with an increased cardiovascular risk in all categories of body mass index (BMI). The age-adjusted relative risks for cardiovascular events in obese men (BMI >30) were 2.1 (95% CI, 1.4 to 3.4), 2.4 (CI, 1.5 to 3.7), 3.7 (CI, 2.3 to 6.0), and 4.5 (CI, 3.0 to 6.6), respectively, for those with 0, 1, 2, and ≥3 ISPs in the top quartile (trend P =0.002) (reference: BMI <25 and no elevated ISP). This trend persisted after adjustments for several potential confounders (P =0.02). Incidence of cardiac events showed similar relations with the number of elevated ISPs in obese men. Conclusion—The cardiovascular risk varies widely between obese or overweight men with high and low ISPs. Relationships with ISPs contribute to, but cannot fully explain, the increased cardiovascular risk in obese men.

Influence of Plasma Fibrinogen Levels on the Incidence of Myocardial Infarction and Death Is Modified by Other Inflammation-Sensitive Proteins A Long-Term Cohort Study

Abstract —Inflammation may play an important role in atherosclerotic disease. Plasma fibrinogen is an established predictor of cardiovascular events. The aim of this study was to evaluate whether other inflammation-sensitive plasma proteins modify this prediction. We studied the incidence of cardiac events and death in men in relation to fibrinogen levels alone and in combination with other proteins. The study was based on 6075 men, who were, on average, 46 years old at the time of the screening examination, which included the quantitative assessment of plasma levels of fibrinogen, orosomucoid, &agr;1-antitrypsin, haptoglobin, and ceruloplasmin. The concentration of each protein was divided into quartiles for each. This classification made it possible to identify 4 groups, ie, men in the first fibrinogen quartile and at the same time either not belonging to the fourth quartile of any of the other proteins (Q1/No group) or also belonging to the fourth quartile of ≥1 of the additional proteins (Q1/Yes group) and corresponding groups in the fourth fibrinogen quartile (Q4/No and Q4/Yes groups). During the follow-up, which occurred at an average of 16 years, 439 (7.2%) men experienced a cardiac event, and 653 (10.7%) died; 278 of these men died of cardiovascular diseases, with 206 deaths attributed to ischemic heart disease. From the lowest to the highest quartile, there was for each protein a stepwise increase in the incidence of cardiac events and mortality. All-cause mortality and cardiovascular mortality were significantly higher in the Q4/Yes group compared with the Q4/No group, but they were similar in the Q4/No and Q1/Yes groups. The incidence of cardiac events was significantly higher in the Q1/Yes and Q4/Yes groups compared with the Q1/No and Q4/No groups, respectively. The increased cardiovascular mortality and cardiac event rates remained after adjustment for several confounders when the Q4/Yes and Q4/No groups were compared. The results suggest that the incidence of cardiac events and death due to cardiovascular diseases in middle-aged men predicted by plasma levels of fibrinogen is modified by other inflammation-sensitive proteins.