Biomedical subjects
Publications and source records attributed to J Kjekshus.
In patients participating in the Scandinavian Simvastatin Survival Study, cholesterol lowering with simvastatin reduced the incidence of carotid bruits and cerebrovascular events as well as new-onset or worsening of angina pectoris and intermittent claudication. These effects suggest that simvastatin may have a general antiatherosclerotic effect not limited to the coronary bed.
OBJECTIVE: Cardiac hypertrophy appears early after heart transplantation, and may represent a myocardial response to injury. Recent evidence suggests that angiotensin II (Ang II) may promote growth through the AT1 and inhibit growth through the AT2 receptor subtypes. We therefore asked whether hypertrophy after heart transplantation is characterized by alterations in Ang II receptor gene expression. METHODS: The expression of Ang II receptor subtypes. AT1 and AT2, was analyzed in right ventricular endomyocardial biopsies taken from 10 human donor hearts prior to implantation (controls) and from 17 heart transplant recipients, 11 studied during annual evaluation (> 1 year after transplantation) and 6 one week after transplantation. Competitive reverse transcription polymerase chain reaction (RT-PCR) was performed using synthetic RNA internal standards for both receptor subtypes. RESULTS: AT1 and AT2 receptor mRNAs were detected in all samples. AT1 receptor mRNA decreased 4.5 fold (p < 0.01) and AT2 receptor mRNA 4.2 fold (p < 0.001) in transplant patients compared with controls. In the subgroup of patients examined one week after surgery AT1 was reduced relative to AT2 receptor mRNA, resulting in an altered ratio of AT1 to AT2 early after transplantation. There was no correlation between Ang II receptor levels and left ventricular wall thickness, and the decrease in receptor level did not correlate with any hemodynamic parameters, cyclosporine blood levels, or plasma renin, Ang II or pANP, except for a negative correlation between AT2 mRNA and plasma renin (r = -0.49, p = 0.05). CONCLUSIONS: Contrary to our expectations, mRNA for both Ang II receptors was downregulated after heart transplantation. The cause of myocardial hypertrophy after heart transplantation is still unclear, but the hypertrophy does not appear to be driven by increased transcription of the AT1 receptor.
OBJECTIVES: This study assessed the long-term clinical outcome of stenting chronic occlusions. BACKGROUND: In the Stenting in Chronic Coronary Occlusion (SICCO) study, patients were randomized to additional stent implantation (n = 58) or not (n = 59) after successful recanalization and dilation of a chronic coronary occlusion. Palmaz-Schatz stents were used with full anticoagulation. The previously published 6-month angiographic follow-up results showed reduction of the restenosis rate from 74% to 32%. METHODS: The primary end point was the occurrence of major adverse cardiac events (cardiac death, lesion-related acute myocardial infarction, repeat lesion-related revascularization or angiographic documentation of reocclusion). RESULTS: Late clinical follow-up was obtained in all patients at 33 +/- 6 months. Major adverse cardiac events occurred in 14 patients (24.1%) in the stent group compared with 35 patients (59.3%) in the percutaneous transluminal coronary angioplasty (PTCA) group (odds ratio 0.22, 95% confidence interval 0.10 to 0.49, p = 0.0002). Target vessel revascularization (including failed PTCA attempts) was performed in 24% of the stent group and in 53% of the PTCA group (p = 0.002). There were no events in the stent group after 8 months, whereas events continued to occur in the PTCA group. By multivariate analysis, allocation to the PTCA group, left anterior descending coronary artery lesion and lesion length were significantly related to the development of major adverse cardiac events. CONCLUSIONS: These data demonstrate the long-term safety and clinical benefit of stenting recanalized chronic occlusions. There is a continued risk of late clinical events related to nonstented lesions. Implantation of an intracoronary stent should therefore be considered after successful opening of a chronic coronary occlusion.
UNLABELLED: Three-dimensional (3D) echocardiography may overcome the problems with inadequate accuracy and reproducibility of 2D volume measurements of the left ventricle. AIMS: To establish the in vitro accuracy and reproducibility of two new methods for 3D echocardiographic volume determination as compared to biplane measurements. METHODS: Validation of volume measurements by a multiplane 3D method was performed on asymmetric latex phantoms (n = 8, true volumes 45-304 ml) using rotational acquisition of 90 image planes. Porcine agarose-filled asymmetrical left ventricles (n = 7, true volumes 34-280 ml) were measured by the same multiplane 3D method based on images acquired by probe rotation axis perpendicular (A) and parallel (B) to the ventricular long axis. Ventricular volumes were also obtained by a simplified 3D system using only the three standard apical views (C) and by the ordinary biplane Simpson's method (D). RESULTS: On latex phantoms systematic deviation from true volumes by multiplane 3D was less than 2%, and 95% variability of individual measurements from this mean was +/- 4.9%. For accuracy on left ventricles, systematic bias was small with all the methods (< 5%), but 95% variability of individual measurements was +/- 9.0%, 15.4%, 18.8% and 41.3% of true volumes for methods A-D respectively. Corresponding results in the same range were obtained for inter- and intraobserver variability. CONCLUSION: Individual in vitro volume estimates of left ventricles are of similar quality using apical multiplane or apical triplane 3D echocardiography. Both methods were superior to the ordinary apical biplane method, but inferior to multiplane 3D method with the probe directed perpendicular to the ventricular long axis.
AIM: To assess differences in treatment of ischaemic heart disease in the Scandinavian countries. METHODS AND RESULTS: The Scandinavian Simvastatin Survival Study (4S) lasted 5.4 years and showed that death rates in 4444 patients with coronary heart disease were 30% lower in those treated with simvastatin to lower serum cholesterol than in those given placebo. Apart from this main result, the 4S provided detailed information on rates of death and other manifestations of coronary heart disease, as well as on use of non-lipid forms of therapy. There were substantial differences in 4S placebo group rates of mortality, coronary deaths and major coronary events between countries. Surgical and medical therapy varied importantly between countries. CONCLUSIONS: Major inter-country differences in rates of death and myocardial infarction in patients with coronary heart disease were likely to be due to a composite of differences in baseline characteristics including smoking. They occurred in a setting of very uneven exploitation of the potential for improving survival of patients with ischaemic heart disease.
OBJECTIVES: The aim of this study was to examine the responses to endothelium-dependent and -independent vasodilators on the peripheral microcirculation in heart transplant recipients in relation to exercise capacity compared with that in healthy controls. BACKGROUND: Impaired endothelium-dependent vasodilation of the microcirculation may play an important role in the limitation of exercise capacity after heart transplantation. METHODS: Microvascular perfusion responses to four graded levels of iontophoretically applied 1% acetylcholine (endothelium-dependent vasodilator) and 1% sodium nitroprusside (SNP) (endothelium-independent) in the forearm skin of 42 transplant recipients and 16 age-matched controls were determined by laser Doppler perfusion measurements. Maximal exercise capacity was assessed by peak oxygen uptake (peak VO2) during progressive, symptom-limited, upright bicycle exercise. RESULTS: With similar baseline perfusion levels in transplant recipients and controls (4.2 +/- 0.4 vs 4.6 +/- 0.6 arbitrary units [AU]), the increases in perfusion to acetylcholine, but not to SNP, were significantly attenuated in the transplant recipients: 7.0 +/- 1.0 vs 11.0 +/- 2.0, 12.7 +/- 1.5 vs 21.0 +/- 2.8, 21.0 +/- 1.9 vs 32.7 +/- 2.4, and 28.0 +/- 1.6 vs 39.2 +/- 2.4 AU, respectively (all p < 0.01). Peak VO2 was significantly lower in the transplant recipients (22.4 +/- 1.0 vs 38.0 +/- 2.9 ml/kg/min; p < 0.01). Furthermore, acetylcholine responses of the transplant recipients correlated closely to their peak VO2, irrespective of level of application (r = 0.63; p < 0.001, all four acetylcholine responses taken together), whereas no such correlation was found for SNP responses. In the control group, no relation was observed in acetylcholine/SNP responses to peak VO2. CONCLUSIONS: Exercise limitation in transplant recipients appears strongly associated with attenuated endothelium-dependent vasodilation of the peripheral microcirculation.
The use of cardiac peptide measurements as possible diagnostic tools in congestive heart failure has been extensively discussed in the recent literature. Therefore, the aim of this study was to establish a model of experimental chronic heart failure, and thereby perform a comparative study of secretion and circulating levels of the cardiac peptides atrial natriuretic peptide (ANP), N-terminal proatrial natriuretic peptide (N-terminal proANP) and brain natriuretic peptide (BNP) during evolving heart failure. Chronic heart failure was induced in seven pigs by rapid left atrial pacing for three weeks. The effects of failure induction were documented 24 h after pacemaker deactivation. Hemodynamic indices of cardiac preload, like pulmonary capillary wedge pressure (PCWP) and right atrial pressure (RAP), were all considerably increased compared to sham operated controls. Likewise, plasma endothelin-L, noradrenaline, renin activity, aldosterone and angiotensin II were all markedly increased. Heart failure was accompanied by significant increases in both estimated cardiac secretory rate and plasma concentrations of all three cardiac peptides, significantly correlated to the PCWP. The directional changes during evolving heart failure were similar, although the percentage increase in plasma BNP was much larger than for ANP and N-terminal proANP. In absolute molar terms, however, the BNP concentration changes were minor compared to those of the other two peptides. The larger percentage increase of BNP might indicate its superiority as a marker of heart failure development, provided a functional assay suitable for clinical use can be designed for a peptide circulating in this low concentration range.
BACKGROUND: The Scandinavian Simvastatin Survival Study (4S) demonstrated pronounced reductions in mortality and major coronary events in a cohort of patients with established coronary heart disease (CHD). The present study provides a detailed, post hoc assessment of the efficacy and safety of simvastatin therapy in the following subgroups of 4S patients: those > or = 65 years of age, those < 65 years of age, women, and men. METHODS AND RESULTS: The 4S cohort of 4444 CHD patients included 827 women and 1021 patients > or = 65 years of age. Total cholesterol at baseline was 5.5 to 8.0 mmol/L with triglycerides < or = 2.5 mmol/L. Patients were randomized to therapy with simvastatin 20 to 40 mg daily or placebo for a median follow-up period of 5.4 years. End points consisted of all-cause and CHD mortality, major coronary events (primarily CHD death and nonfatal myocardial infarction), other acute CHD and atherosclerotic events, hospitalizations for CHD and cardiovascular events, and coronary revascularization procedures. Mean changes in serum lipids were similar in the different subgroups. In patients > or = 65 years of age in the simvastatin group, relative risks (95% confidence intervals) for clinical events were as follows: all-cause mortality, 0.66 (0.48 to 0.90); CHD mortality, 0.57 (0.39 to 0.83); major coronary events, 0.66 (0.52 to 0.84); any atherosclerosis-related event, 0.67 (0.56 to 0.81); and revascularization procedures, 0.59 (0.41 to 0.84). In women, the corresponding figures were 1.16 (0.68 to 1.99); 0.86 (0.42 to 1.74), 0.66 (0.48 to 0.91), 0.71 (0.56 to 0.91), and 0.51 (0.30 to 0.86), respectively. CONCLUSIONS: Cholesterol lowering with simvastatin produced similar reductions in relative risk for major coronary events in women compared with men and in elderly (> or = 65 years of age) compared with younger patients. There were too few female deaths to assess the effects on mortality in women. Because mortality rates increased substantially with age, the absolute risk reduction for both all-cause and CHD mortality in simvastatin-treated subjects was approximately twice as great in the older patients.
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Patients with heart failure are particularly susceptible to the negative effects of calcium channel blockers because the failing heart demonstrates a defect in the delivery of calcium to the contractile proteins, and an attenuation of the normal sympathetic reflexes. Currently these drugs have no place in the treatment of heart failure caused by systolic dysfunction of the left ventricle. Calcium channel blockers should probably not be described for patients with coronary artery disease and left ventricular dysfunction. When the patient needs additional treatment for angina and beta-blockers or nitrates have not given satisfactory results, it may be appropriate to prescribe amlodipine or felodipine.
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Since 1975 several studies have indicated that treatment with beta-adrenergic blocking drugs has a positive effect on prognosis in patients with left ventricular dysfunction. After myocardial infarction, treatment with timolol and propranolol improves prognosis in patients with symptoms of cardiomegaly and heart failure. In patients with idiopathic dilated cardiomyopathy, treatment with metoprolol improves the left ventricular ejection fraction and symptoms of heart failure, and may have a positive effect on prognosis. Recent studies of patients with chronic congestive heart failure also indicate that carvedilol has a positive effect on mortality and morbidity. The authors review some relevant studies, to stimulate the use of beta-adrenergic blocking drugs to treat certain types of heart failure.
BACKGROUND: The Scandinavian Simvastatin Survival Study (4S) showed that lowering cholesterol levels with simvastatin reduces mortality and morbidity in patients with angina pectoris or previous acute myocardial infarction. Before the widespread use of cholesterol-lowering drugs in such patients is recommended, its cost effectiveness should be demonstrated. We estimated the cost effectiveness of simvastatin treatment to lower cholesterol levels in relation to the age, sex, and cholesterol level before treatment of patients with coronary heart disease. METHODS: We estimated the cost per year of life gained with simvastatin therapy. To model the increased life expectancy, hazard functions from 4S were used. The costs studied included those of the intervention and the direct and indirect costs associated with morbidity from coronary causes. We prepared separate estimates for men and women at various ages (from 35 to 70 years) and total cholesterol levels before treatment (213 to 309 mg per deciliter). RESULTS: In the analysis limited to direct costs, the cost of each year of life gained ranged from $3,800 for 70-year-old men with 309 mg of cholesterol per deciliter to $27,400 for 35-year-old women with 213 mg of cholesterol per deciliter. When we included indirect costs, the results ranged from a savings in the youngest patients to a cost of $13,300 per year of life gained in 70-year-old women with 213 mg of cholesterol per deciliter. CONCLUSIONS: In patients with coronary heart disease, simvastatin therapy is cost effective among both men and women at the ages and cholesterol levels studied.
The use of angiotensin-converting enzyme (ACE) inhibitors early after an acute myocardial infarction to reduce mortality has been studied in several trials with inconsistent results. Aspirin (ASA) has become a well-documented therapeutic adjunct in patients with coronary heart disease. Attention has recently been focused on a possible interaction between ASA and ACE inhibitors. We therefore reanalyzed data from the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II) to find any evidence of differential effects of the ACE inhibitor enalapril in subgroups defined by use of ASA at baseline. Logistic regression tested the multiplicative interaction. We used Rothman synergy index S, which would be equal to unity under additivity, and less than unity when suggesting antagonism, to examine the postulated interaction with departure from an additive model. Logistic regression showed that the enalapril-ASA interaction term was a significant predictor of mortality at the end of the study (p = 0.047), and was a borderline significant predictor of mortality 30 days after randomization (p = 0.085). The Rothman synergy index S was 0.66 (95% confidence interval 0.46 to 0.94) for mortality at the end of the study, and 0.68 ( 0.44 to 1.04) for 30-day mortality, indicating antagonism between enalapril and ASA with departure from an additive model. Thus, we found evidence of enalapril-ASA interaction. The effect of enalapril was less favorable among patients taking ASA than among patients not taking ASA at baseline.
This article argues that major risk factors such as diabetes or hypertension increase the risk of vascular disease principally by amplifying the malign interactions of low-density lipoprotein (LDL) particles with the arterial wall and, consequently, that LDL is the first and foremost factor in the pathogenesis of vascular disease. We conclude that marked reduction of the LDL particle number should be the cornerstone of therapy in those with vascular disease or in those at high risk of vascular disease.
BACKGROUND: The reproducibility of left ventricular (LV) mass measurement by two-dimensional (2-D) echocardiography is inadequate for individual assessments. HYPOTHESIS: This study was undertaken to evaluate the potential of LV mass determination with a new three-dimensional (3-D) echocardiographic method compared with 2-D measurements. METHODS: Porcine agarose-filled left ventricles (n = 15, true mass 61-511 g) of different shapes were measured by a multiplane 3-D method based on 90 images acquired by probe rotation axis (1) perpendicular and (2) parallel to the ventricular long axis ["parasternal" (the left sternal border was not present as a reference point in this study) and apical views]. Mass was also obtained using (3) the biplane truncated ellipsoid and (4) area-length methods, as well as (5) the modified cube formula. Five hearts were not analyzed with the apical 3-D technique because of insufficient image quality. RESULTS: Systematic deviation from true mass was small with all methods (< 5.3%). Accuracy, expressed as 1 standard deviation of individual estimates around this systematic bias, was 7.7, 13.6, 8.2, 11.9, and 11.9% of true mass for the methods 1-5, respectively. Interobserver reproducibility, expressed as the coefficient of variation, was 4.7, 8.8, 8.1, 8.9, and 9.4% for the same methods. CONCLUSION: Limits for individual accuracy and reproducibility of LV mass estimates are nearly doubled using apical compared with "parasternal" 3-D echocardiography in vitro. A main advantage of "parasternal" 3-D compared with 2-D LV mass estimates is better reproducibility, but at the expense of greater time consumption. Apical 3-D technique is not superior to simpler 2-D methods based on "parasternal" short axis imaging.