John Wikstrand

Effects of Controlled-Release Metoprolol on Total Mortality, Hospitalizations, and Well-being in Patients with Heart Failure: The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF)

Åke Hjalmarson, MD, PhD Sidney Goldstein, MD Björn Fagerberg, MD, PhD Hans Wedel, PhD Finn Waagstein, MD, PhD John Kjekshus, MD, PhD John Wikstrand, MD, PhD Dia El Allaf, MD Jirı́ Vı́tovec, MD, PhD Jan Aldershvile, MD, PhD Matti Halinen, MD, PhD Rainer Dietz, MD Karl-Ludwig Neuhaus, MD András Jánosi, MD, DSc Gudmundur Thorgeirsson, MD, PhD Peter H. J. M. Dunselman, MD, PhD Lars Gullestad, MD Jerzy Kuch, MD Johan Herlitz, MD, PhD Peter Rickenbacher, MD Stephen Ball, MD, PhD Stephen Gottlieb, MD Prakash Deedwania, MD for the MERIT-HF Study Group

A multiscale dynamic programming procedure for boundary detection in ultrasonic artery images

Ultrasonic measurements of human carotid and femoral artery walls are conventionally obtained by manually tracing interfaces between tissue layers. The drawbacks of this method are the interobserver variability and inefficiency. Here, the authors present a new automated method which reduces these problems. By applying a multiscale dynamic programming (DP) algorithm, approximate vessel wall positions are first estimated in a coarse-scale image, which then guide the detection of the boundaries in a fine-scale image. In both cases, DP is used for finding a global optimum for a cost function. The cost function is a weighted sum of terms, in fuzzy expression forms, representing image features and geometrical characteristics of the vessel interfaces. The weights are adjusted by a training procedure using human expert tracings. Operator interventions, if needed, also take effect under the framework of global optimality. This reduces the amount of human intervention and, hence, variability due to subjectiveness. By incorporating human knowledge and experience, the algorithm becomes more robust. A thorough evaluation of the method in the clinical environment shows that interobserver variability is evidently decreased and so is the overall analysis time. The authors conclude that the automated procedure can replace the manual procedure and leads to an improved performance.

Arterial wall thickness in familial hypercholesterolemia. Ultrasound measurement of intima-media thickness in the common carotid artery.

B-mode ultrasound was used to noninvasively determine wall thickness and lumen diameter in the common carotid artery in patients with familial hypercholesterolemia (n = 53) and in a control group (n = 53). The controls were matched for sex, age, height, and weight, and all had a serum cholesterol level below 6.5 mmol/l. The study was performed to evaluate whether the patients had a thicker arterial wall compared with that of the control group. Wall thickness was determined as the combined intima-media thickness of the far wall and is presented as the mean and maximum thickness of a 10-mm-long section of the common carotid artery. The difference between the groups was 0.13 mm in mean wall thickness (p less than 0.001; 95% confidence interval, 0.07-0.18 mm) and 0.20 mm in maximum wall thickness (p less than 0.001; 95% confidence interval, 0.09-0.23 mm). Fifty of the subjects were examined twice to estimate the interobserver variability. The coefficients of variation for mean and maximum wall thickness were 10.2% and 8.9%, respectively. The two study groups were well matched and differed only in lipid levels. Thus, there is reason to believe that the difference in wall thickness can be explained by the background of familial hypercholesterolemia and the increased cholesterol levels.

Atherosclerotic changes in the femoral and carotid arteries in familial hypercholesterolemia. Ultrasonographic assessment of intima-media thickness and plaque occurrence.

B-mode ultrasound is increasingly used in clinical research to study the atherosclerotic process in the carotid arteries. The present investigation evaluated the feasibility of measuring intima-media thickness in the common femoral artery and assessed whether such measurement might provide further information on the extent of the atherosclerotic process in patients with familial hypercholesterolemia. A further aim was to study the relationship between the intima-media thickness of the common carotid artery and the occurrence of plaque in the carotid and femoral arteries. The results showed an increased intima-media thickness in the far wall of the common femoral artery in patients with familial hypercholesterolemia compared with the control subjects (P < .01). The results also showed a clear relationship between the thickness of the intima-media complex in the common carotid artery and the prevalence of plaque in the carotid and femoral arteries. This may be interpreted as an indication that an increase in intima-media thickness in the common carotid artery at least partly expresses a generalized atherosclerotic process. The atherosclerotic changes appeared to be more advanced in the femoral artery compared with the carotid artery. In future studies, therefore, valuable information on different stages of atherosclerotic changes may be achieved by combining information from B-mode recordings from both the carotid and femoral arteries.

Atherosclerotic Changes in the Carotid Artery Bulb as Measured by B-Mode Ultrasound Are Associated With the Extent of Coronary Atherosclerosis

BACKGROUND AND PURPOSE Ultrasound is increasingly used to measure atherosclerotic development in carotid and femoral arteries. The aim of this study was to investigate the relationship between coronary atherosclerosis as measured by quantitative angiography and peripheral atherosclerosis as measured by ultrasound in three different arterial regions. METHODS Patients (n = 32) with at least two coronary segments with visible signs of atherosclerosis as defined in a computer-assisted analysis of coronary angiograms were also examined with B-mode ultrasound. The extent of coronary atherosclerosis was expressed as the average diameter stenosis of coronary segments, and peripheral atherosclerosis was defined as intima-media thickness (IMT) and plaque occurrence in the common carotid artery, the carotid bulb, and the common femoral artery. RESULTS The results showed a significant correlation between the ultrasound measurement of IMT of the carotid bulb and diameter stenosis of the included coronary segments (r = .68, P = .01) and of carotid plaques and diameter stenosis (P < .001). The correlation between common carotid IMT and diameter stenosis of included coronary segments was not statistically significant (r = .31, NS). There were no significant relationships between common femoral IMT or femoral plaques and diameter stenosis of included coronary segments. CONCLUSIONS Although this study is small, it points to a very important aspect of ultrasound measurements of atherosclerosis: measurements performed in the common carotid artery or the femoral artery may not relate to coronary atherosclerosis in the same way as measurements performed in the carotid bulb. The findings underline the importance of measuring IMT not only in the common carotid artery but also in the carotid bulb and present data separately. These results have to be confirmed in a larger-scale study.

Plasma concentration of amino-terminal pro-brain natriuretic peptide in chronic heart failure: prediction of cardiovascular events and interaction with the effects of rosuvastatin: a report from CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure).

OBJECTIVES We investigated whether plasma amino-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of cardiac dysfunction and prognosis measured in CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure), could be used to identify the severity of heart failure at which statins become ineffective. BACKGROUND Statins reduce cardiovascular morbidity and mortality in many patients with ischemic heart disease but not, overall, those with heart failure. There must be a transition point at which treatment with a statin becomes futile. METHODS In CORONA, patients with heart failure, reduced left ventricular ejection fraction, and ischemic heart disease were randomly assigned to 10 mg/day rosuvastatin or placebo. The primary composite outcome was cardiovascular death, nonfatal myocardial infarction, or stroke. RESULTS Of 5,011 patients enrolled, NT-proBNP was measured in 3,664 (73%). The midtertile included values between 103 pmol/l (868 pg/ml) and 277 pmol/l (2,348 pg/ml). Log NT-proBNP was the strongest predictor (per log unit) of every outcome assessed but was strongest for death from worsening heart failure (hazard ratio [HR]: 1.99; 95% confidence interval [CI]: 1.71 to 2.30), was weaker for sudden death (HR: 1.69; 95% CI: 1.52 to 1.88), and was weakest for atherothrombotic events (HR: 1.24; 95% CI: 1.10 to 1.40). Patients in the lowest tertile of NT-proBNP had the best prognosis and, if assigned to rosuvastatin rather than placebo, had a greater reduction in the primary end point (HR: 0.65; 95% CI: 0.47 to 0.88) than patients in the other tertiles (heterogeneity test, p = 0.0192). This reflected fewer atherothrombotic events and sudden deaths with rosuvastatin. CONCLUSIONS Patients with heart failure due to ischemic heart disease who have NT-proBNP values <103 pmol/l (868 pg/ml) may benefit from rosuvastatin.

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.

Coronary heart-disease after treatment of hypertension.

Abstract Within a group of 1026 men aged 47-54, cause-specific death-rates and the incidence of non-fatal myocardial infarction and stroke in a treatment group of 635 hypertensive men (casual systolic B.P. >175 or diastolic B.P. >115 mm Hg on two occasions) treated at a hypertension clinic were compared with those in a control group of 391 men (casual systolic B.P. >175 or diastolic >115 mm Hg on only one occasion) who remained mainly untreated during their 4·3 years of follow-up. The predicted risk of coronary heart-disease (C.H.D.) at entry, calculated by a multiple logistic function, was slightly higher in the treatment group. Total death-rate during follow-up was significantly lower in the treatment group (3·3%) than in the control group (6·1%). The difference in death-rate for C.H.D. was of the same relative order (0·8% versus 1·5%), as was the incidence of non-fatal myocardial infarction (2·8% versus 5·4%), although none of the differences reached statistical significance. However, the pooled incidence of fatal and non-fatal C.H.D. was significantly lower in the treatment group (3·6%) than in the control group (6·9%). The results suggest that antihypertensive treatment might be effective in preventing or postponing C.H.D. in middle-aged men.

Effects of Statin Therapy According to Plasma High-Sensitivity C-Reactive Protein Concentration in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) A Retrospective Analysis

Background— We examined whether the antiinflammatory action of statins may be of benefit in heart failure, a state characterized by inflammation in which low cholesterol is associated with worse outcomes. Methods and Results— We compared 10 mg rosuvastatin daily with placebo in patients with ischemic systolic heart failure according to baseline high sensitivity-C reactive protein (hs-CRP) <2.0 mg/L (placebo, n=779; rosuvastatin, n=777) or ≥2.0 mg/L (placebo, n=1694; rosuvastatin, n=1711). The primary outcome was cardiovascular death, myocardial infarction, or stroke. Baseline low-density lipoprotein was the same, and rosuvastatin reduced low-density lipoprotein by 47% in both hs-CRP groups. Median hs-CRP was 1.10 mg/L in the lower and 5.60 mg/L in the higher hs-CRP group, with higher hs-CRP associated with worse outcomes. The change in hs-CRP with rosuvastatin from baseline to 3 months was −6% in the low hs-CRP group (27% with placebo) and −33.3% in the high hs-CRP group (−11.1% with placebo). In the high hs-CRP group, 548 placebo-treated (14.0 per 100 patient-years of follow-up) and 498 rosuvastatin-treated (12.2 per 100 patient-years of follow-up) patients had a primary end point (hazard ratio of placebo to rosuvastatin, 0.87; 95% confidence interval, 0.77 to 0.98; P=0.024). In the low hs-CRP group, 175 placebo-treated (8.9 per 100 patient-years of follow-up) and 188 rosuvastatin-treated (9.8 per 100 patient-years of follow-up) patients experienced this outcome (hazard ratio, 1.09; 95% confidence interval, 0.89 to 1.34; P>0.2; P for interaction=0.062). The numbers of deaths were as follows: 581 placebo-treated (14.1 per 100 patient-years of follow-up) and 532 rosuvastatin-treated (12.6 per 100 patient-years) patients in the high hs-CRP group (hazard ratio, 0.89; 95% confidence interval, 0.79 to 1.00; P=0.050) and 170 placebo-treated (8.3 per 100 patient-years) and 192 rosuvastatin-treated (9.7 per 100 patient-years) patients in the low hs-CRP group (hazard ratio, 1.17; 95% confidence interval, 0.95 to 1.43; P=0.14; P for interaction=0.026). Conclusion— In this retrospective hypothesis-generating study, we found a significant interaction between hs-CRP and the effect of rosuvastatin for most end points whereby rosuvastatin treatment was associated with better outcomes in patients with hs-CRP ≥2.0 mg/L. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00206310.

Predictors of cardiovascular morbidity in treated hypertension: results from the primary preventive trial in Göteborg, Sweden.

Prognostic factors for cardiovascular disease (CVD) were studied in treated, middle-aged male hypertensives, derived from a random population sample and followed for more than 10 years. In multivariate analysis diastolic blood pressure, smoking, serum cholesterol, proteinuria, angina pectoris and previous stroke were found to be independent predictors of CVD morbidity (non-fatal myocardial infarction (MI), non-fatal stroke, or CVD death). Multivariate analyses for coronary heart disease (CHD), stroke and CVD mortality were also performed and the results are given. Life-table analyses showed a three times higher CVD incidence among smokers than amongst non-smokers and a doubled incidence for subjects with a serum cholesterol in the highest quartile, i.e. above 7.3 mmol/l, compared with those with levels below, and a three times higher incidence for subjects with proteinuria than those without. Non-smokers with a serum cholesterol below 7.3 mmol/l and free of any hypertensive organ manifestation at entry did not differ significantly in CVD morbidity from a normotensive comparison group that was derived from the same population sample. These findings in a well-defined population sample show that in spite of treatment for hypertension the CVD risk is still substantial if organ damage or other risk factors are present. These findings underline the importance of multiple risk intervention.