Impact of metabolic disorders on the relation between overweight/obesity and incident myocardial infarction and ischaemic stroke in fertile women: a nationwide cohort study.

AIMS: Whether overweight is a risk factor for cardiovascular disease in the absence of metabolic disorders remains under debate and is largely unexamined in young women. We evaluated the risk of myocardial infarction and ischaemic stroke in fertile women conditional on time-dependent presence of metabolic disorders. MATERIALS AND METHODS: From nationwide registers we identified all normal weight (body mass index [BMI] ≥ 18.5 to <25 kg m(-2) and overweight (BMI ≥ 25 kg m(-2)) Danish women giving birth from 2004 to 2009. Using multivariable Poisson regression models adjusted for age, calendar year and smoking, the risk of the composite outcome of myocardial infarction and ischaemic stroke was assessed with metabolic disorders (i.e. hypertensive conditions, abnormal glucose metabolism and/or dyslipidaemia) included as time-dependent variables. RESULTS: The population comprised 261,489 women with median age of 30.5 years (interquartile range = [27.3, 33.8]). Median follow-up was 5.6 years (interquartile range = [4.0, 6.8]). Compared with normal weight women without metabolic disorders (with an incidence rate [IR] of 17.0 [95% confidence interval {CI} = 14.5-20.0] events per 100,000 person-years), overweight women without metabolic disorders had no significantly increased risk, IR 22.6 (CI = 18.3-27.8), adjusted incidence rate ratio (IRR), 1.26 (CI = 0.97-1.65). For women with metabolic disorders, IR was 30.2 (CI = 18.8-48.6) and adjusted IRR 1.77 (CI = 1.07-2.93) in normal weight, while IR was 87.1 (CI = 67.6-112.2) and IRR 4.24 (CI = 5 3.11-5.79) in overweight. CONCLUSIONS: The risk of myocardial infarction and ischaemic stroke was more strongly associated with the presence of metabolic disorders than with overweight per se in fertile women. Targeting prevention of metabolic disorders might be beneficial to reduce cardiovascular disease in overweight/obese young women.

Endothelial nitric oxide synthase phosphorylation at Threonine 495 and mitochondrial reactive oxygen species formation in response to a high H2O2 concentration.

BACKGROUND: Hydrogen peroxide (H2O2) is produced in vessels during ischemia/reperfusion and during inflammation, both leading to vascular dysfunction. We investigated cellular pathways involved in endothelial nitric oxide synthase (eNOS) phosphorylation at Threonine 495 (Thr(495)) in human umbilical vein endothelial cells (HUVECs) exposed to H2O2. METHODS: HUVECs were exposed to 400 µM H2O2 for 30 min. Phosphorylation at Thr(495) was assessed by Western blotting and reactive oxygen species (ROS) monitored by flow cytometry. Protein kinase C (PKC) pathways were investigated by pretreatment with PKC-ß inhibitor ruboxistaurin or pan-PKC inhibitor GF109203X. In addition, we investigated ROCK and ERK pathways by MEKK1/2 inhibitor U0126 and ROCK inhibitor Y27632. RESULTS: H2O2 increased eNOS phosphorylation at Thr(495) (to 176% vs. control (100%), p < 0.001) along with increased mitochondrial ROS formation (from 19.7 to 45.3%, p < 0.01). This rise in phosphorylation could be prevented by U0126 and Y27632 in a dose-dependent manner, but did not result in lowered mitochondrial ROS formation. Conversely, addition of the antioxidant N-acetyl-L-cysteine only prevented mitochondrial ROS formation but did not prevent phosphorylation of eNOS Thr(495). CONCLUSION: H2O2-mediated phosphorylation of eNOS Thr(495) is mediated by ROCK and ERK activity, but not by PKC, and is uncoupled from mitochondrial ROS signaling. Furthermore, ERK inhibition increased mitochondrial ROS formation.

[Angiotensin-converting enzyme inhibitors after AMI]. / Angiotensinkonverterende enzym efter AMI.

The purpose of this study was to calculate the improvement in life expectancy by treating patients with left ventricular dysfunction after a myocardial infarction with an ACE inhibitor. Life expectancy was estimated as median lifetime and follow up in the TRACE study was prolonged until median lifetime could be calculated in both treatment groups. Median lifetime was reached in the placebo group after 4.6 years. In the trandolapril group median lifetime was increased by 15.3 months or 27% (7-51%). We conclude that the increase in lifetime by treatment of patients with left ventricular dysfunction after a myocardial infarction is substantial.

Improving the reproducibility of QT dispersion measures.

BACKGROUND: The low reproducibility of the QT dispersion (QTD) method is a major reason why it is not used in clinics. The purpose of this study was to develop QT dispersion parameters with better reproducibility and identification of patients with a high risk of ventricular arrhythmia or death. METHODS AND RESULTS: Three institutions using different methods for measuring QT intervals provided QT databases, which included more than 3500 twelve-lead surface ECGs. The data represented low and high risk subjects from the following groups: the normal population EpiSet (survivors vs dead from cardiovascular causes), acute myocardial infarction patients AmiSet (survivors vs dead) and remote myocardial infarction patients ArrSet (with vs without a history of ventricular arrhythmia). The EpiSet, AmiSet, and the ArrSet contributed with N = 122, 0, and 110 ECGs for reproducibility analysis, and 3244, 446, and 100 ECGs for the analysis of prognostic accuracy. The prognostic accuracy was measured as the area under the Receiver Operator Curve. The QT intervals were divided into six QT pairs; the longest pair consisted of the longest and the shortest QT intervals etc. The QT dispersion trend (QTDT) was defined as the slope of the linear regression of the N longest QT pairs after estimation of missing QT intervals by interpolation of measured QT intervals. The QTMAD and the QTSTD methods were defined as twice the mean absolute deviation and the standard deviation of the N longest QT pairs. The reproducibility was improved by 27% and 19% in the EpiSet and the ArrSet relative to the reproducibility of QTD. The accuracy improved for the EpiSet and the ArrSet and was maintained for the AmiSet. CONCLUSIONS: By using the three longest and the three shortest QT intervals in QTDT, QTMAD, or QTSTD, the reproducibility improved significantly while maintaining or improving the prognostic accuracy compared to QTD.

Dofetilide in patients with congestive heart failure and left ventricular dysfunction: safety aspects and effect on atrial fibrillation. The Danish Investigators of Arrhythmia and Mortality on Dofetilide (DIAMOND) Study Group.

INTRODUCTION. Atrial fibrillation is a frequent cause of worsening of symptoms in patients with congestive heart failure. The drugs currently available for maintenance of sinus rhythm all have major side effects. METHODS. In 34 Danish coronary care units, 1518 patients with congestive heart failure and reduced left ventricular systolic function were randomized to receive either placebo or a new class III antiarrhythmic drug, dofetilide. The dose of dofetilide was adjusted according to the presence of atrial fibrillation, the length of the QT interval, and renal function. Patients were continuously monitored electrocardiographically for the first 3 days of the study. The primary end point was all-cause mortality and follow-up was for at least 1 year. RESULTS. In the dofetilide/placebo groups, 311/317 patients died (41%/42%). The hazard ratio for dofetilide treatment was 0.95 (95% confidence interval, 0.81-1.11). Treatment with dofetilide reduced worsening of heart failure significantly (hazard ratio, 0.75; 0.63-0.89). After 1 year, 61% of patients with atrial fibrillation at the start of the study had converted to sinus rhythm on dofetilide, vs. 33% in the placebo group. After conversion to sinus rhythm, 78%/43% of patients in the dofetilide/placebo groups remained in sinus rhythm for at least 1 year. There were 25 instances (3%) of torsade de pointes ventricular tachycardia in the dofetilide group and none in the placebo group. CONCLUSION. In patients with congestive heart failure, dofetilide can effectively convert atrial fibrillation to sinus rhythm and maintain sinus rhythm after conversion. Hospitalization for congestive heart failure is reduced. Dofetilide does not affect mortality. (c)2001 by CHF, Inc.

[Dofetilide to patients with heart failure and left ventricular dysfunction]. / Dofetilid til patienter med hjerteinsufficiens og dårligt fungerende venstre ventrikel.

INTRODUCTION: Dofetilide, a new class III antiarrhythmic drug, was tested for its ability to reduce mortality and morbidity in patients with congestive heart failure and left ventricular dysfunction. METHODS: In 34 Danish centers, 1518 patients with NYHA class III or IV heart failure and wall motion index of the left ventricle < or = 1.2 (ejection fraction < or = 35%) were randomized to receive dofetilide or placebo in a double blind study. The dose of dofetilide was adjusted to renal function and the QT interval. Patients were monitored continuously with ekg during the first three days in the study. Minimum follow up was one year. RESULTS: Dofetilide did not affect mortality. Hospitalizations for worsening of heart failure were reduced significantly, hazard ratio 0.75 (0.63-0.89) Dofetilide effectively converted atrial fibrillation to sinus rhythm. After one year, 61% of patients with atrial fibrillation had converted on dofetilide and 33% on placebo (p < 0.001). DISCUSSION: Dofetilide can be used to convert atrial fibrillation to sinus rhythm and to maintain sinus rhythm in patients with congestive heart failure and left ventricular dysfunction. Dofetilide does not affect mortality.

[Treatment of diabetic patients with ischaemic heart disease]. / Behandling af diabetespatienter med iskaemisk hjertesygdom.

Patients with diabetes constitute a large group among patients with ischaemic heart disease, and their risk of repeated cardiovascular events is large. Due to this, there is increasing focus on intervention against the increased risk of cardiac morbidity and mortality in patients with diabetes. Subgroup analyses of patients with diabetes from studies on patients with ischaemic heart disease show that intervention with thrombolysis, aspirin, beta blockers, ACE inhibitors and statins have similar relative benefit among patients with diabetes, but because of the greater risk in these patients, the absolute benefit is increased. In spite of this, intervention is less common among patients with diabetes, a fact that should be corrected. Direct intervention targeted at the metabolic disorder in ischaemic heart disease has only been investigated in the DIGAMI study, where glucose/insulin treatment followed by long term treatment with insulin was compared to conventional treatment. The mortality was lower in the insulin treated group after one to four years of follow up, a promising result which is currently being investigated in the DIGAMI-2 study.

[Delay from start of symptoms to hospital admission among 5.978 patients with acute myocardial infarction]. / Forsinkelse fra symptomdebut til ankomst på hospital blandt 5.978 patienter med akut myokardieinfarkt.

The aim of this study was to analyse the influence of patient characteristics on delay between onset of symptoms and hospital admission (patient delay) in acute myocardial infarction. A group of 6676 consecutive patients with AMI, admitted alive to 27 Danish hospitals from 1990 to 1992, were studied. Due to missing information on delay or in hospital acute myocardial infarction 698 patients were excluded. Mean patient delay was 9.1 hours, median delay 3.25 hours (5 to 95 percentiles: 0.67-40 hours). In multivariate logistic regression analysis patient delay was independently associated with male gender, increased age, diabetes mellitus, left ventricular systolic function (wall motion index), onset from midnight to 6 a.m., onset on a weekday, history of angina pectoris, chest pain as initial symptom, ventricular fibrillation or-tachycardia, Killip class > or = 3, presence of ST-elevation and ST-depressions. In conclusion, patient delay continues to be disappointingly long. This also applies to patients with a high risk of acute myocardial infarction (notably history of diabetes mellitus and angina pectoris).

Magnetic properties experiments on the Mars Pathfinder lander: preliminary results.

Many of the particles currently suspended in the martian atmosphere are magnetic, with an average saturation magnetization of about 4 A. m2/kg (amperes times square meters per kilogram). The particles appear to consist of claylike aggregates stained or cemented with ferric oxide (Fe2O3); at least some of the stain and cement is probably maghemite (gamma-Fe2O3). The presence of the gamma phase would imply that Fe2+ ions leached from the bedrock, passing through a state as free Fe2+ ions dissolved in liquid water. These particles could be a freeze-dried precipitate from ground water poured out on the surface. An alternative is that the magnetic particles are titanomagnetite occurring in palagonite and inherited directly from a basaltic precursor.

[Prevalence of left ventricular hypertrophy in Danish patients with hypertension]. / Forekomsten af venstresidig hjertehypertrofi hos danske personer med hypertension.

The aim of this investigation was to study the prevalence of left ventricular hypertrophy (LVH) in a hypertensive population with reference to a normotensive control group. From the general population, 3498 men and women aged 35, 45, 55 and 65 years old were invited to a health examination. Participants with blood pressure above 160 mmHg systolic and/or 95 mmHg diastolic or participants currently taking antihypertensive medication or having done so during the previous six months were asked to undergo an echocardiographic examination. Controls were randomly selected from the same population. Of 552 participants in the final study population, 194 were normotensive controls and 358 were in the hypertensive group. Echocardiographic measurements were made according to the "Penn" conventions and indexed for body surface. Cutoff values for LVH were 134 grams per m2 for males and 102 grams per m2 for women. Overall, we found that the prevalence of 1 VH was 14%/20% (men/women) in normotensives and 25%/26% in hypertensives (p < 0.01). By subdivision in age and sex groups we found that the relation between normotensives and hypertensives was significant in the age group of 65 years (p < 0.02 for males and p < 0.05 for females). The association between blood pressure and 1 VH in the general population is weak. 1 VH is only significantly more frequent among hypertensives as compared to normotensives in older people.

[The significance of trandelapril for mortality after AMI in patients with reduced left ventricular function. TRACE Study Group]. / Trandolaprils betydning for overlevelse efter AMI hos patienter med nedsat funktion af venstre ventrikel. TRACE Study Group.

Angiotensin converting-enzyme (ACE) inhibition reduces mortality among patients surviving an acute myocardial infarction, but whether to give ACE-inhibitors to all patients or target their use to selected patients is unclear. Seven thousand and one consecutive enzyme-confirmed myocardial infarctions were screened. One thousand seven hundred and forty-nine patients with echocardiographic signs of left ventricular dysfunction were randomized to oral trandolapril (876 patients) or placebo (873 patients) starting from days three to seven following the infarction. Average follow-up was 27 months. There were 304 deaths (34.7 percent) among patients on trandolapril vs. 369 deaths (42.3 percent) among patients on placebo (p = 0.0013). Relative risk (RR) of death in the trandolapril group was 0.78 (95% confidence interval (CD 0.67-0.91). Trandolapril reduced cardiovascular death (RR 0.75, CI 0.63-0.89) and sudden death (RR 0.76, CI 0.59-0.98). Progression to severe/resistant heart failure was reduced (RR 0.71, CI 0.56-0.90). Recurrent myocardial infarction (fatal or non-fatal) was not significantly reduced (RR 0.86, CI 0.66-1.13). It is concluded that long-term treatment with trandolapril in patients with reduced left ventricular function shortly after myocardial infarction significantly reduced total mortality. The substantial mortality risk reduction was obtained in 25% of consecutive patients screened for entry encouraging a selective use of ACE inhibition following myocardial infarction.

[Hypertension and left ventricular hypertrophy in patients with spontaneous subarachnoid hemorrhage]. / Hypertension og venstresidig ventrikelhypertrofi hos patienter med spontan subaraknoidal haemoragi.

One hundred and eighteen consecutive cases of spontaneous subarachnoid haemorrhage seen at one hospital during a three-year period were examined to assess the prevalence of hypertension and the correlation between the presence of hypertension and the risk of early death. Eighty-seven of the patients had intracranial aneurysms. The diagnosis of hypertension was determined by means of three complementary criteria: a history of treatment with antihypertensive drugs; systolic and/or diastolic blood pressure levels > or = 160 and 95 mmHg, respectively, measured by the general practitioners of the patients before the onset of the subarachnoid haemorrhage; and the presence of left ventricular hypertrophy determined by echocardiography and/or necropsy. The major findings were as follows: 1) hypertension was present in at least 41% of the patients; 2) in 37% of 51 patients with no history of hypertension before the haemorrhage, left ventricular hypertrophy was diagnosed; and 3) the frequency of hypertension was significantly higher in patients who died within 14 days after the bleeding episode compared with patients surviving this period.

[The optimal dose of bendroflumethiazide in hypertension. A randomized double-blind dose-response study]. / Optimal dosis af bendroflumetiazid ved hypertension. En randomiseret dobbeltblind dosis-responsundersøgelse.

The object of this study was to determine the clinically relevant dose of bendrofluazide for the treatment of arterial hypertension. A material of 257 male and female subjects, age 25-70 years, with sitting diastolic blood pressures between 100-120 mmHg after six weeks of placebo treatment participated in this randomized, double-blind placebo-controlled parallel group study. The patients were treated with either 0, 1.25, 2.5, 5.0 or 10 mg bendrofluazide daily for 12 weeks. Blood pressure was measured with a random zero sphygmomanometer and a Tricuff. Compliance was checked by tablet counts. The mean decreases in diastolic blood pressure were 3.5, 9.8, 10.8, 10.1 and 10.8 mmHg in the five treatment groups respectively. The heart rates were unchanged in all groups. Dose-effect relations were demonstrated for potassium, urate, glucose, cholesterol and apolipoprotein B. The lowest dose of bendrofluazide, 1.25 mg, affected only urate, whereas all of the mentioned biochemical variables were affected by the highest dose of 10 mg. It can be concluded that the optimal dose of bendrofluazide for aterial hypertension is 1.25 mg daily. Increase in the dose beyond this level only results in more pronounced adverse biochemical effects including the lipid-metabolism and subjective adverse events.

Oral administration of grass pollen to hay fever patients. An efficacy study in oral hyposensitization.

Oral hyposensitization is still widely used in the treatment of allergic diseases, but controlled studies proving a beneficial effect are lacking. Fifty-eight hay fever patients were admitted to a double-blind placebo efficacy study in oral hyposensitization. An enterosoluble tablet containing timothy whole pollen or placebo was taken daily. Preseasonally, the actively treated patients received 4,315,000 PNU (880,260 AUR) and totally for 6 months 8,915,000 PNU (1,818,660 AUR). Such high doses have never been tried in similar studies. A new principle has been used - "the pollen count interval method" - in the evaluation of symptom and medication score. The study failed to prove any beneficial effect of oral hyposensitization measured by symptom score, medication score, nasal provocation test or skin prick test. There was no change in timothy specific IgE and IgG which could be caused by the treatment. The possibility that oral hyposensitization might be an effective treatment of hay fever in the future is discussed, but it is concluded that the present regimens cannot be recommended.