Christian Torp-Pedersen

Risk of Myocardial Infarction and Death Associated With the Use of Nonsteroidal Anti‐Inflammatory Drugs (NSAIDs) Among Healthy Individuals: A Nationwide Cohort Study

Use of some nonsteroidal anti‐inflammatory drugs (NSAIDs) is associated with increased cardiovascular risk in several patient groups, but whether this excess risk exists in apparently healthy individuals has not been clarified. Using a historical cohort design, we estimated the risk of death and myocardial infarction associated with the use of NSAIDs. Participants in the study were selected from the Danish population and were defined as healthy according to a history of no hospital admissions and no concomitant selected pharmacotherapy. The source population consisted of 4,614,807 individuals, of whom 1,028,437 were included in the study after applying selection criteria. Compared to no NSAID use, hazard ratios (95% confidence limits) for death/myocardial infarction were 1.01 (0.96–1.07) for ibuprofen, 1.63 (1.52–1.76) for diclofenac, 0.97 (0.83–1.12) for naproxen, 2.13 (1.89–2.41) for rofecoxib, and 2.01 (1.78–2.27) for celecoxib. A dose‐dependent increase in cardiovascular risk was seen for selective COX‐2 inhibitors and diclofenac. Caution should be exercised in NSAID use in all individuals, and particularly high doses should be avoided if possible.

Cardiogenic shock complicating acute myocardial infarction; prognostic impact of early and late shock development.

AIMS Cardiogenic shock accounts for the majority of deaths following acute myocardial infarction. The majority of outcome data on this issue are, however, derived from single hospitals, referral centers or selected patients in randomized studies. The purpose of this study was to investigate incidence, outcome and prognostic significance of cardiogenic shock in 6676 consecutive patients with acute myocardial infarction. METHODS AND RESULTS Demographic and clinical data including the presence of cardiogenic shock were prospectively collected in 6676 non-invasively managed patients with myocardial infarction consecutively admitted to 27 different hospitals during a 2-year period. Six-year mortality data were collected in 99.9% of the population. Cardiogenic shock developed in 444 patients (6.7%). In 59% of these patients cardiogenic shock developed within 48 h, 11% developed shock during days 3 and 4 and 30% later than 4 days after the infarction. Thirty-day and 6-year mortality was 62 and 88% among shock patients compared to 9 and 45% in non-shock patients. Patients with early shock development (days 1-2) had a significantly lower 30-day mortality (45%) than those with intermediate or late shock development (>80%) (P<0.05). In 30-day survivors, survival the following years was lower than in patients without cardiogenic shock but with post-infarction heart failure. CONCLUSIONS In this nationwide prospectively collected registry, non-invasively managed consecutive myocardial infarct patients with cardiogenic shock had an extremely reduced life expectancy. Every attempt to improve treatment, prevention and identification of patients at risk of shock development should be strongly encouraged.

Gene Expression in Skeletal Muscle Biopsies from People with Type 2 Diabetes and Relatives: Differential Regulation of Insulin Signaling Pathways

Background Gene expression alterations have previously been associated with type 2 diabetes, however whether these changes are primary causes or secondary effects of type 2 diabetes is not known. As healthy first degree relatives of people with type 2 diabetes have an increased risk of developing type 2 diabetes, they provide a good model in the search for primary causes of the disease. Methods/Principal Findings We determined gene expression profiles in skeletal muscle biopsies from Caucasian males with type 2 diabetes, healthy first degree relatives, and healthy controls. Gene expression was measured using Affymetrix Human Genome U133 Plus 2.0 Arrays covering the entire human genome. These arrays have not previously been used for this type of study. We show for the first time that genes involved in insulin signaling are significantly upregulated in first degree relatives and significantly downregulated in people with type 2 diabetes. On the individual gene level, 11 genes showed altered expression levels in first degree relatives compared to controls, among others KIF1B and GDF8 (myostatin). LDHB was found to have a decreased expression in both groups compared to controls. Conclusions/Significance We hypothesize that increased expression of insulin signaling molecules in first degree relatives of people with type 2 diabetes, work in concert with increased levels of insulin as a compensatory mechanism, counter-acting otherwise reduced insulin signaling activity, protecting these individuals from severe insulin resistance. This compensation is lost in people with type 2 diabetes where expression of insulin signaling molecules is reduced.

Independent prognostic value of the ambulatory arterial stiffness index and aortic pulse wave velocity in a general population

Independent prognostic value of the ambulatory arterial stiffness index and aortic pulse wave velocity in a general population

Does Conversion and Prevention of Atrial Fibrillation Enhance Survival in Patients with Left Ventricular Dysfunction? Evidence from the Danish Investigations of Arrhythmia and Mortality ON Dofetilide/(DIAMOND) Study

BACKGROUND Atrial fibrillation is a common arrhythmia in patients with left ventricular dysfunction associated with increased morbidity and mortality. The present study investigated the potential of dofetilide to restore and maintain sinus rhythm in patients with left ventricular dysfunction, which might reduce mortality and hospitalizations. METHODS AND RESULTS In the Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) studies, 506 patients were in atrial fibrillation (AF) or atrial flutter (AFl) at baseline. Over the course of study, cardioversion occurred in 148 (59%) dofetilide- and 86 (34%) placebo-treated patients. In these patients, the probability of maintaining sinus rhythm for 1 year was 79% with dofetilide versus 42% with placebo ( P < 0.001). Dofetilide had no effect on all-cause mortality, but restoration and maintenance of sinusrhythm (independent of study treatment) was associated with a significant reduction in mortality (risk ratio [RR], 0.44; 95% CI, 0.30 to 0.64; P < 0.0001). In addition, dofetilide therapy was associated with a significantly lower risk ratio versus placebo for either all-cause (RR, 0.70; 95% CI, 0.56 to 0.89; P < or = 0.005) or congestive heart failure (RR, 0.69; 95% CI, 0.51 to 0.93; P < or = 0.02) rehospitalization. CONCLUSIONS Dofetilide is safe and increases the probability of obtaining and maintaining sinus rhythm in patients with structural heart disease. The present study suggests that restoration of sinus rhythm--on placebo or dofetilide--is associated with improved survival.

Anaemia is an independent predictor of mortality in patients with left ventricular systolic dysfunction following acute myocardial infarction

In patients with chronic heart failure (HF), mortality is inversely related to haemoglobin (hgb) concentration. We investigated the prognostic importance of anaemia in patients with acute myocardial infarction (AMI) and left ventricular systolic dysfunction (LVSD) with and without HF.

Is digoxin an independent risk factor for long-term mortality after acute myocardial infarction?

The safety of treatment with digoxin in patients with acute myocardial infarction (MI) was investigated in 584 hospital survivors of MI. All patients were examined by radionuclide ventriculography, with determination of left ventricular ejection fraction (LVEF), close to the time of discharge. Clinical data were collected on admission. All patients were followed up with regard to death (median 6·2 years, range 3·9–7·8 years). Patients treated with digoxin (N=172(29%)) were older (median 66 vs 59 years; (P<0·001), had a higher incidence of diabetes (13% vs 7%, P=0·025) and a lower LVEF (0·33 vs 0·49; P<0·001). As expected, clinical heart failure was more frequent among them (84% vs 14%, P<0·001), than in patients not receiving digoxin. The 1- and 5-year mortality of patients treated with digoxin was 38% and 74% compared to 8% and 26% in patients not receiving digoxin (P<0·001). The increased risk associated with digoxin therapy remained statistically sign cant when patients were stratified according to the presence or absence of heart failure or atrial fibrillationlflutter during hospitalization, or to LVEF above or below 0·45 at discharge. In a proportional hazard model including age, LVEF, diabetes mellitus, heart failure, arrial fibrillation or flutter, ventricular fibrillation, gender, dose of furosemide at discharge and calcium antagonists and digoxin treatment as covariates, digoxin was independently associated with an increased risk of death (relative risk 1·8 (95% confidence limit 1·2–2·5)). We conclude that administration of digoxin may be harmful in hospital survivors of MI.

Effects of Oral Glucose Load on Endothelial Function and on Insulin and Glucose Fluctuations in Healthy Individuals

Background/aims. Postprandial hyperglycemia, an independent risk factor for cardiovascular disease, is accompanied by endothelial dysfunction. We studied the effect of oral glucose load on insulin and glucose fluctuations, and on postprandial endothelial function in healthy individuals in order to better understand and cope with the postprandial state in insulin resistant individuals. Methods. We assessed post-oral glucose load endothelial function (flow mediated dilation), plasma insulin, and blood glucose in 9 healthy subjects. Results. The largest increases in delta FMD values (fasting FMD value subtracted from postprandial FMD value) occurred at 3 hours after both glucose or placebo load, respectively: 4.80 ± 1.41 (P = .009) and 2.34 ± 1.47 (P = .15). Glucose and insulin concentrations achieved maximum peaks at one hour post-glucose load. Conclusion. Oral glucose load does not induce endothelial dysfunction in healthy individuals with mean insulin and glucose values of 5.6 mmol/L and 27.2 mmol/L, respectively, 2 hours after glucose load.

Is blood pressure during the night more predictive of cardiovascular outcome than during the day

The objective of this study was to investigate the prognostic significance of the ambulatory blood pressure (BP) during night and day and of the night-to-day BP ratio (NDR). We studied 7458 participants (mean age 56.8 years; 45.8% women) enrolled in the International Database on Ambulatory BP in relation to Cardiovascular Outcome. Using Cox models, we calculated hazard ratios (HR) adjusted for cohort and cardiovascular risk factors. Over 9.6 years (median), 983 deaths and 943 cardiovascular events occurred. Nighttime BP predicted mortality outcomes (HR, 1.18–1.24; P<0.01) independent of daytime BP. Conversely, daytime systolic (HR, 0.84; P<0.01) and diastolic BP (HR, 0.88; P<0.05) predicted only noncardiovascular mortality after adjustment for nighttime BP. Both daytime BP and nighttime BP consistently predicted all cardiovascular events (HR, 1.11–1.33; P<0.05) and stroke (HR, 1.21–1.47; P<0.01). Daytime BP lost its prognostic significance for cardiovascular events in patients on antihypertensive treatment. Adjusted for the 24-h BP, NDR predicted mortality (P<0.05), but not fatal combined with nonfatal events. Participants with systolic NDR of at least 1 compared with participants with normal NDR (≥0.80 to <0.90) were older, at higher risk of death, but died at higher age. The predictive accuracy of the daytime and nighttime BP and the NDR depended on the disease outcome under study. The increased mortality in patients with higher NDR probably indicates reverse causality. Our findings support recording the ambulatory BP during the whole day.

New risk markers may change the HeartScore risk classification significantly in one-fifth of the population

The study aim was to determine whether urine albumin/creatinine ratio (UACR), high-sensitivity C-reactive protein (hsCRP) or N-terminal pro-brain natriuretic peptide (Nt-proBNP) added to risk prediction based on HeartScore and history of diabetes or cardiovascular disease. A Danish population sample of 2460 individuals was divided in three groups: 472 subjects receiving cardiovascular medication or having history of diabetes, prior myocardial infarction or stroke, 559 high-risk subjects with a 10-year risk of cardiovascular death above 5% as estimated by HeartScore, and 1429 low-moderate risk subjects with estimated risk below 5%. During the following 9.5 years the composite end point of cardiovascular death, non-fatal myocardial infarction or stroke (CEP) occurred in 204 subjects. CEP was predicted in all three groups by UACR (HRs: 2.1, 2.1 and 2.3 per 10-fold increase, all P<0.001) or by hsCRP (HRs: 1.9, 1.9 and 1.7 per 10-fold increase, all P<0.05), but not by Nt-proBNP (HRs: 1.1, 2.6 and 3.7 per 10-fold increase, last two P<0.001) (P<0.05 for interaction). In the low-moderate risk group, pre-specified gender adjusted (men/women) cutoff values of UACR⩾0.73/1.06 mg mmol−1 or hsCRP⩾6.0/7.3 mg l−1 identified a subgroup of 16% who experienced one-third of the CEPs. In the patient group, combined absence of high UACR and high Nt-proBNP⩾110/164 pg ml−1 (men/women) identified a subgroup of 52% who experienced only 15% of the CEPs. Additional use of UACR and hsCRP in subjects with low-moderate risk and UACR and Nt-proBNP in subjects with known diabetes of cardiovascular disease changed HeartScore risk classification significantly in 19% of the population.