Objectives. The aim of the study was to investigate whether the use of the antifolate antibiotic trimethoprim during the 12 weeks before conception was associated with congenital malformations. Methods. We conducted a nationwide register-based cohort study including all Danish women giving birth from 1997 to 2004. All women with at least one prescription of trimethoprim dispensed during the 12 weeks before conception were identified. Results. There was a doubling of congenital malformations in offspring to women exposed to trimethoprim in the 12 weeks before conception. The adjusted odds ratio (OR) of major congenital malformation was 1.87, 95% confidence interval (CI) 1.25–2.81. There was a significant increase in major malformations of the heart (OR = 2.49; 1.18–5.26) and limbs (OR = 2.18; 1.13–4.23). Conclusions. In this study, we found an association between exposure to trimethoprim during the 12 weeks before conception and an increased risk of heart and limb defects.

Background

Non steroidal anti-inflammatory drugs (NSAIDs) increase mortality and morbidity after myocardial infarction (MI). We examined cause-specific mortality and morbidity associated with NSAIDs in a nationwide cohort of MI patients.

Methods and Results

By individual-level linkage of nationwide registries of hospitalization and drug dispensing from pharmacies in Denmark, patients aged >30 years admitted with first-time MI during 1997–2009 and their subsequent NSAID use were identified. The risk of three cardiovascular specific endpoints: cardiovascular death, the composite of coronary death and nonfatal MI, and the composite of fatal and nonfatal stroke, associated with NSAID use was analyzed by Cox proportional hazard analyses. Of 97,698 patients included 44.0% received NSAIDs during follow-up. Overall use of NSAIDs was associated with an increased risk of cardiovascular death (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.36–1.49). In particular use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with increased risk of cardiovascular death (HR 1.96 [1.79–2.15] and HR1.66 [1.44–1.91], respectively) with a dose dependent increase in risk. Use of ibuprofen was associated with increased risk of cardiovascular death (HR 1.34[1.26–1.44]), whereas naproxen was associated with the lowest risk of (e.g., HR 1.27[1.01–1.59].

Conclusion

Use of individual NSAIDs is associated with different cause-specific cardiovascular risk and in particular rofecoxib and diclofenac were associated with increased cardiovascular morbidity and mortality. These results support caution with use of all NSAIDs in patients with prior MI.

In hypertrophic cardiomyopathy (HC), ECG changes have been postulated to be an early marker of disease, detectable in sarcomere mutation carriers when LV wall thickness is still normal However, the ECG features of mutation carriers have not been fully characterized. Therefore, we systematically analyzed ECG’s in a genotyped HC population to: 1. Characterize ECG findings in mutation carriers (G+) with and without echocardiographic left ventricular hypertrophy (LVH), and 2. Evaluate the accuracy of the ECG to differentiate at- risk mutation carriers from genetically unaffected relatives during family screening. ECGs and echocardiograms were analyzed in 213 genotyped subjects (76 G+/LVH−, 57 G+/LVH+ overt HC, 80 genetically unaffected controls). Cardiac magnetic resonance imaging (CMR) was available on a subset. Q waves and repolarization abnormalities (QST) were highly specific (98%) markers for LVH− mutation carriers, present in 25% of G+/LVH− subjects and 3% of controls (p<0.001). QST ECG abnormalities remained independently predictive of carrying a sarcomere mutation after adjusting for age and impaired relaxation, another distinguishing feature of G+/LVH− subjects (OR 8.4, p=0.007). Myocardial scar or perfusion abnormalities were not detected on CMR in any G+/LVH− subjects, irrespective of ECG features. In overt HC, 75% had Q waves and/or repolarization changes but <25% demonstrated common isolated voltage criteria for LVH. In conclusion, Q waves and repolarization abnormalities are the most discriminating ECG features of sarcomere mutation carriers with and without LVH. However, due to the limited sensitivity of ECG and echocardiographic screening, genetic testing is required to definitively identify at-risk family members.

OBJECTIVE

This study was performed to understand how left ventricular function modulates the prognostic importance of diabetes after myocardial infarction (MI).

RESEARCH DESIGN AND METHODS

Consecutively hospitalized MI patients screened for three clinical trials were followed for a median of 7 years. Multivariable Cox regression models were used to assess the risk of mortality associated with diabetes, and the importance of diabetes was examined independently within defined left ventricular ejection fraction (LVEF) subgroups.

RESULTS

A total of 16,912 patients were included; 1,819 (11%) had diabetes. Diabetes and 15% unit depression in LVEF were of similar prognostic importance: hazard ratios (HRs) were 1.45 (95% CI 1.37–1.54) and 1.41 (1.37–1.45) for diabetes and LVEF depression, respectively. LVEF modified the outcomes associated with diabetes, with HRs being 1.29 (1.19–1.40) and 1.61 (1.49–1.74) in patients with LVEF <40% and LVEF ≥40%, respectively (P = 0.03).

CONCLUSIONS

Patients within the higher LVEF categories have a greater mortality risk attributable to diabetes than patients within the lower LVEF categories.

Objectives

To study the association between exposures to glucose-lowering therapy and risk of cancer using the nationwide administrative registers in Denmark.

Design

Nationwide cohort study.

Setting

All hospitals in Denmark.

Participants

All individuals aged ≥35 years in 1998–2009 who were naive to glucose-lowering treatment and had no history of cancer. Primary measures outcomes: first cancer diagnosis between 1998 and 2009. The RR of cancer as dependent on exposure to individual glucose-lowering agents was assessed by multivariable Poisson regression models.

Results

Of 159 894 patients that initiated treatment with glucose-lowering agents, 12 789 developed cancer, incidence rate 17.4/1000 person-years. Of the remaining 3 447 904 individuals not using glucose-lowering agents, 293 878 developed cancer, incidence rate 7.9/1000 person-years. Use of different types of glucose-lowering agents including human insulin, insulin analogues, as well as sulfonylureas were associated with a quantitatively similar and significantly increased RR of cancer of 1.2–1.3 compared with unexposed individuals after multivariable adjustment. For the majority of agents, the authors identified the highest RR of cancer during the first 30 treatment days with a subsequent decline of risk approaching the cancer risk of the background population only 6–12 months after initiation of treatments.

Conclusions

Use of most glucose-lowering agents including sulfonylureas was associated with a comparable increased risk of cancer shortly after initiation of treatment and subsequently a decline to the risk of the background population. This suggests that the relation is not causal.

Article summary

Article focus

Several observational studies have suggested that insulin therapy may increase the risk of cancer. If insulin therapy causes/enhances cancer development, the RR would be expected to increase with longer treatment duration.

The present study investigated the association between treatment duration with individual glucose-lowering agents and the RR of developing cancer in 3.6 million individuals.

Key messages

Use of human insulin, insulin analogues and sulfonylureas were associated with a significantly increased RR of cancer of 1.2–1.3 compared with unexposed individuals.

For all agents, the highest RR of cancer was found during the first 30 days of treatment. Hereafter, the RR declined rapidly, reaching a RR of cancer comparable to unexposed individuals after only 6–12 months of therapy for most agents.

This strongly suggests that a previously reported association between use of glucose-lowering agents and increased risk of cancer is not causal.

Strengths and limitations of this study

This study was based on complete and nationwide administrative registers, thereby reducing selection bias.

Data on measurements on body mass index, glucose regulation and family cancer history were lacking.

Background

Hypertension is a common comorbidity in patients with heart failure and may contribute to development and course of disease, but the importance of a history of hypertension in patients with prevalent heart failure remains uncertain.

Methods

3078 consecutively hospitalized heart failure patients (NYHA classes II-IV) were screened for the EchoCardiography and Heart Outcome Study (ECHOS). The left ventricular ejection fraction (LVEF) was estimated by 2 dimensional transthoracic echocardiography in all patients and a subgroup of 878 patients had additional data on pulsed wave Doppler assessment of transmitral flow available. A restrictive filling (RF) was defined as a mitral inflow deceleration time ≤140 ms. Patients were followed for a median of 6.8 (Inter Quartile Range 6.6-7.0) years and multivariable Cox regression models were used to assess the risk of all-cause mortality associated with hypertension.

Results

The study population had a mean age of 73 ± 11 years. 39% were female, 27% had a history of hypertension and 48% had a RF. Over the study period, 64% of the population died. Hypertension was not associated with increased risk of mortality, hazard ratio (HR) 0.95 (0.85-1.05). LVEF did not modify this relationship (p for interaction = 0.7), but RF pattern substantially influenced the outcomes associated with hypertension (p for interaction < 0.001); HR 0.75 (0.57-0.99) and 1.41 (1.08-1.84) in patients without and with RF, respectively.

Conclusions

In patients with symptomatic heart failure, a history of hypertension is associated with a substantially increased relative risk of mortality among patients with a restrictive transmitral filling pattern.

5′-adenosine monophosphate-activated protein kinase (AMPK) is considered central in regulation of energy status and substrate utilization within cells. In heart failure the energetic state is compromised and substrate metabolism is altered. We hypothesized that this could be linked to changes in AMPK activity and we therefore investigated mitochondrial oxidative phosphorylation capacity from the oxidation of long- and medium-chain fatty acids (LCFA and MCFA) in cardiomyocytes from young and old mice expressing a dominant negative AMPKα2 (AMPKα2-KD) construct and their wildtype (WT) littermates. We found a 35–45% (P < 0.05) lower mitochondrial capacity for oxidizing MCFA in AMPKα2-KD of both age-groups, compared to WT. This coincided with marked decreases in protein expression (19/29%, P < 0.05) and activity (14/21%, P < 0.05) of 3-hydroxyacyl-CoA-dehydrogenase (HAD), in young and old AMPKα2-KD mice, respectively, compared to WT. Maximal LCFA oxidation capacity was similar in AMPKα2-KD and WT mice independently of age implying that LCFA-transport into the mitochondria was unaffected by loss of AMPK activity or progressing age. Expression of regulatory proteins of glycolysis and glycogen breakdown showed equivocal effects of age and genotype. These results illustrate that AMPK is necessary for normal mitochondrial function in the heart and that decreased AMPK activity may lead to an altered energetic state as a consequence of reduced capacity to oxidize MCFA. We did not identify any clear aging effects on mitochondrial function.

Aim

Chronic heart failure is associated with endothelial dysfunction and insulin resistance. The aim of this investigation was to study insulin-stimulated endothelial function and glucose uptake in skeletal muscles in patients with heart failure in comparison to patients with type 2 diabetes.

Methods

Twenty-three patients with systolic heart failure and no history of diabetes, seven patients with both systolic heart failure and type 2 diabetes, 19 patients with type 2 diabetes, and ten healthy controls were included in the study. Endothelial function was studied by venous occlusion plethysmography. Insulin-stimulated endothelial function was assessed after intra-arterial infusion of insulin followed by co-infusion with serotonin in three different dosages. Forearm glucose uptake was measured during the insulin infusion.

Results

Patients with systolic heart failure had impaired insulin-stimulated endothelial function. The percentage increase in blood flow during co-infusion with insulin and serotonin dose response study was 24.74% ± 6.16%, 23.50% ± 8.32%, and 22.29% ± 10.77% at the three doses respectively, compared to the healthy control group 45.96% ± 11.56%, 67.40% ± 18.11% and 84.57% ± 25.73% (P = 0.01). Insulin-stimulated endothelial function was similar in heart failure patients and patients with type 2 diabetes, while it was further deteriorated in patients suffering from both heart failure and diabetes with a percentage increase in blood flow of 19.15% ± 7.81%, −2.35% ± 11.76%, and 5.82% ± 17.70% at the three doses of serotonin, respectively. Forearm glucose uptake was impaired in patients with heart failure compared to healthy controls (P = 0.03) and tended to be further impaired by co-existence of diabetes (P = 0.08).

Conclusion

Systolic heart failure and type 2 diabetes result in similar vascular insulin resistance and reduced muscular insulin-stimulated glucose uptake. The effects of systolic heart failure and type 2 diabetes appear to be additive.

Background

Carvedilol has been shown to be superior to metoprolol tartrate to improve clinical outcomes in patients with heart failure (HF), yet the mechanisms responsible for these differences remain unclear. We examined if there were differences in endothelial function, insulin stimulated endothelial function, 24 hour ambulatory blood pressure and heart rate during treatment with carvedilol, metoprolol tartrate and metoprolol succinate in patients with HF.

Methods

Twenty-seven patients with mild HF, all initially treated with carvedilol, were randomized to a two-month treatment with carvedilol, metoprolol tartrate or metoprolol succinate. Venous occlusion plethysmography, 24-hour blood pressure and heart rate measurements were done before and after a two-month treatment period.

Results

Endothelium-dependent vasodilatation was not affected by changing from carvedilol to either metoprolol tartrate or metoprolol succinate. The relative forearm blood flow at the highest dose of serotonin was 2.42 ± 0.33 in the carvedilol group at baseline and 2.14 ± 0.24 after two months continuation of carvedilol (P = 0.34); 2.57 ± 0.33 before metoprolol tartrate treatment and 2.42 ± 0.55 after treatment (p = 0.74) and in the metoprolol succinate group 1.82 ± 0.29 and 2.10 ± 0.37 before and after treatment, respectively (p = 0.27). Diurnal blood pressures as well as heart rate were also unchanged by changing from carvedilol to metoprolol tartrate or metoprolol succinate.

Conclusion

Endothelial function remained unchanged when switching the beta blocker treatment from carvedilol to either metoprolol tartrate or metoprolol succinate in this study, where blood pressure and heart rate also remained unchanged in patients with mild HF.

Trial registration

Current Controlled Trials NCT00497003

Background

We examined the incidence of new-onset atrial fibrillation in patients with left ventricular dysfunction. Patients either had a recent myocardial infarction (with or without clinical heart failure) or symptomatic heart failure (without a recent MI). Patients were with and without treatment with the class III antiarrhythmic drug dofetilide over 36 months.

Methods

The Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) studies included 2627 patients without atrial fibrillation at baseline, who were randomised to treatment with either dofetilide or placebo.

Results

The competing risk analyses estimated the cumulative incidences of atrial fibrillation during the 42 months of follow-up to be 9.6% in the placebo-treated heart failure-group, and 2.9% in the placebo-treated myocardial infarction-group.

Cox proportional hazard regression found a 42% significant reduction in the incidence of new-onset AF when assigned to dofetilide compared to placebo (hazard ratio 0.58, 95% confidence interval 0.40-0.82) and there was no interaction with study (p = 0.89).

In the heart failure-group, the incidence of atrial fibrillation was significantly reduced to 5.6% in the dofetilide-treated patients (hazard ratio 0.57, 95% confidence interval 0.38-0.86).

In the myocardial infarction-group the incidence of atrial fibrillation was reduced to 1.7% with the administration of dofetilide. This reduction was however not significant (hazard ratio 0.61, 95% confidence interval 0.30-1.24).

Conclusion

In patients with left ventricular dysfunction the incidence of AF in 42 months was 9.6% in patients with heart failure and 2.9% in patients with a recent MI. Dofetilide significantly reduced the risk of developing atrial fibrillation compared to placebo in the entire study group and in the subgroup of patients with heart failure. The reduction in the subgroup with recent MI was not statistically significant, but the hazard ratio was similar to the hazard ratio for the heart failure patients, and there was no difference between the effect in the two studies (p = 0.89 for interaction).

Objective To examine the effect of proton pump inhibitors on adverse cardiovascular events in aspirin treated patients with first time myocardial infarction.

Design Retrospective nationwide propensity score matched study based on administrative data.

Setting All hospitals in Denmark.

Participants All aspirin treated patients surviving 30 days after a first myocardial infarction from 1997 to 2006, with follow-up for one year. Patients treated with clopidogrel were excluded.

Main outcome measures The risk of the combined end point of cardiovascular death, myocardial infarction, or stroke associated with use of proton pump inhibitors was analysed using Kaplan-Meier analysis, Cox proportional hazard models, and propensity score matched Cox proportional hazard models.

Results 3366 of 19 925 (16.9%) aspirin treated patients experienced recurrent myocardial infarction, stroke, or cardiovascular death. The hazard ratio for the combined end point in patients receiving proton pump inhibitors based on the time dependent Cox proportional hazard model was 1.46 (1.33 to 1.61; P<0.001) and for the propensity score matched model based on 8318 patients it was 1.61 (1.45 to 1.79; P<0.001). A sensitivity analysis showed no increase in risk related to use of H2 receptor blockers (1.04, 0.79 to 1.38; P=0.78).

Conclusion In aspirin treated patients with first time myocardial infarction, treatment with proton pump inhibitors was associated with an increased risk of adverse cardiovascular events.

Background

Type 2 diabetes is a well-established risk factor for cardiovascular disease and is common among patients with acute myocardial infarction (MI). The extent to which patients with first-time MI develop diabetes requiring glucose-lowering medications (GLM) is largely unknown. The aim of the study was to investigate temporal trends in the initiation of GLM among patients discharged after first-time MI.

Methods

All Danish residents aged ≥ 30 years without prior diabetes hospitalized with first-time MI between 1997 and 2006 were identified by individual-level-linkage of nationwide registers. Initiation of GLM during follow-up was assessed by claimed prescriptions from pharmacies. Temporal trends in initiation of GLM were assessed by incidence rate calculations in the MI population as in the general population. Multivariable Cox proportional-hazard models were used to investigate the likelihood of initiating GLM within a year post-MI.

Results

The population comprised 66,788 patients. Among these patients 3962 patients initiated GLM, of whom 1567 started within one year post-MI. An increase in incidence rates of GLM initiation in the MI population from 19.6 per 1000 person years in 1997 to approximately 27.6 in 2001 was demonstrated. After 2001 the incidence rates stabilized. A similar trend was observed in the general population where the incidence rates increased from 2.8 in 1997 to 4.0 in 2004 and then stabilized.

Conclusion

Our study demonstrated an increase in incidence rates of GLM initiation within the first year post- MI. A similar trend was observed in the general population suggesting that the increase in GLM among MI patients was primarily the effect of a general increased awareness of diabetes. From a public heath perspective, this study underscores a continuous need for diagnostic and therapeutic improvement in the care of MI patients that develop diabetes.

Objective

To study the initiation of and long‐term refill persistency with statins and beta‐blockers after acute myocardial infarction (AMI) according to income and education.

Design and setting

Linkage of individuals through national registers of hospitalisations, drug dispensation, income and education.

Participants

30 078 patients aged 30–74 years surviving first hospitalisation for AMI in Denmark between 1995 and 2001.

Main outcome measures

Initiation of statin or beta‐blocker treatment (out‐patient claim of prescriptions within 6 months of discharge) and refill persistency (first break in treatment lasting at least 90 days, and re‐initiation of treatment after a break).

Results

When simultaneously estimating the effect of income and education on initiation of treatment, the effect of education attenuated and a clear income gradient remained for both drugs. Among patients aged 30–64 years, high income (adjusted hazard ratio (HR) 1.27; 95% confidence interval (CI) 1.19–1.35) and medium income (HR 1.13; 95% CI 1.06–1.20) was associated with initiation of statin treatment compared with low income. The risk of break in statin treatment was lower for patients with high (HR 0.73; 95% CI 0.66–0.82) and medium (HR 0.82; 95% CI 0.74–0.92) income compared with low income, whereas there was a trend in the opposite direction concerning a break in beta‐blocker treatment. There was no gradient in re‐initiation of treatment.

Conclusion

Patients with low compared with high income less frequently initiated preventive treatment post‐AMI, had worse long‐term persistency with statins, but tended to have better persistency with beta‐blockers. Low income by itself seems not to be associated with poor long‐term refill persistency post‐AMI.

Background

The use of mechanical/physical devices for applying mild therapeutic hypothermia is the only proven neuroprotective treatment for survivors of out of hospital cardiac arrest. However, this type of therapy is cumbersome and associated with several side-effects. We investigated the feasibility of using a transient receptor potential vanilloid type 1 (TRPV1) agonist for obtaining drug-induced sustainable mild hypothermia.

Methods

First, we screened a heterogeneous group of TRPV1 agonists and secondly we tested the hypothermic properties of a selected candidate by dose-response studies. Finally we tested the hypothermic properties in a large animal. The screening was in conscious rats, the dose-response experiments in conscious rats and in cynomologus monkeys, and the finally we tested the hypothermic properties in conscious young cattle (calves with a body weight as an adult human). The investigated TRPV1 agonists were administered by continuous intravenous infusion.

Results

Screening: Dihydrocapsaicin (DHC), a component of chili pepper, displayed a desirable hypothermic profile with regards to the duration, depth and control in conscious rats. Dose-response experiments: In both rats and cynomologus monkeys DHC caused a dose-dependent and immediate decrease in body temperature. Thus in rats, infusion of DHC at doses of 0.125, 0.25, 0.50, and 0.75 mg/kg/h caused a maximal ΔT (°C) as compared to vehicle control of -0.9, -1.5, -2.0, and -4.2 within approximately 1 hour until the 6 hour infusion was stopped. Finally, in calves the intravenous infusion of DHC was able to maintain mild hypothermia with ΔT > -3°C for more than 12 hours.

Conclusions

Our data support the hypothesis that infusion of dihydrocapsaicin is a candidate for testing as a primary or adjunct method of inducing and maintaining therapeutic hypothermia.

Background

Survivors of a cardiac arrest often have persistent cardiovascular derangements following cardiopulmonary resuscitation including decreased cardiac output, arrhythmias and morphological myocardial damage. These cardiovascular derangements may lead to an increased susceptibility towards the external and internal environment of the cardiovascular system as compared to the healthy situation.

Methods

Here we tested the hypothesis that the cardiovascular system in healthy rats and rats resuscitated from a cardiac arrest may be differentially affected by a transient receptor potential vanilloid type 1 agonist, by continuous intravenous infusion of dihydrocapsaicin (DHC).

Results

Compared to baseline, infusion of DHC caused an initial increase in mean arterial blood pressure in both healthy and resuscitated rats of 25% and 10%, respectively. Also, we observed an initial response of tachycardia in both healthy and resuscitated rats of 30% and 20%, respectively. Then, at high levels of DHC infusion (> 2.0 mg/kg/hr) we observed two single episodes of transient bradycardia and hypotension in 33% of the healthy rats, which was consistent with a TRPV1 agonist induced Bezold-Jarisch reflex. In contrast, in resuscitated rats we observed multiple episodes of bradycardia/hypotension in 100% of the rats and at a dose of DHC of 0.65 mg/kg/hr. Notably, this DHC effect could be completely blocked in the resuscitated rats by pre-treatment with atropine, a muscarinic acetylcholine antagonist.

Conclusions

Our results indicate that the susceptibility of the rats towards TRPV1 agonist induced Bezold-Jarisch reflex is increased in those resuscitated from cardiac arrest compared to the healthy situation.

Ingestion of glucosinolates has previously been reported to improve endothelial function in spontaneously hypertensive rats, possibly because of an increase in NO availability in the endothelium due to an attenuation of oxidative stress; in our study we tried to see if this also would be the case in humans suffering from essential hypertension.

Methods

40 hypertensive individuals without diabetes and with normal levels of cholesterol were examined. The participants were randomized either to ingest 10 g dried broccoli sprouts, a natural donor of glucosinolates with high in vitro antioxidative potential, for a 4 week period or to continue their ordinary diet and act as controls. Blood pressure, endothelial function measured by flow mediated dilation (FMD) and blood samples were obtained from the participants every other week and the content of glucosinolates was measured before and after the study. Measurements were blinded to treatment allocation.

Results

In the interventional group overall FMD increased from 4% to 5.8% in the interventional group whereas in the control group FMD was stable (4% at baseline and 3.9% at the end of the study). The change in FMD in the interventional group was mainly due to a marked change in FMD in two participants while the other participants did not have marked changes in FMD. The observed differences were not statistically significant. Likewise significant changes in blood pressure or blood samples were not detected between or within groups. Diastolic blood pressure stayed essentially unchanged in both groups, while the systolic blood pressure showed a small non significant decrease (9 mm Hg) in the interventional group from a value of 153 mm Hg at start.

Conclusion

Daily ingestion of 10 g dried broccoli sprouts does not improve endothelial function in the presence of hypertension in humans.

Trial Registration

Clinicaltrials.gov NCT00252018

Background

Genetic testing identifies sarcomere mutation carriers (G+) before clinical diagnosis of hypertrophic cardiomyopathy (HCM), allowing characterization of initial disease manifestations. Prior studies demonstrated that impaired relaxation develops before left ventricular hypertrophy (LVH). The precise impact of sarcomere mutations on systolic function in early and late disease is unclear.

Methods and Results

Comprehensive echocardiography with strain imaging was performed on 146 genotyped individuals with mutations in 5 sarcomere genes. Contractile parameters were compared in 68 preclinical (G+/LVH−), 40 overt (G+/LVH+) HCM subjects, and 38 mutation (−) normal control relatives. All subjects had normal LV ejection fraction (EF). In preclinical HCM, global and regional peak systolic strain (εsys) and longitudinal systolic strain rate (SSR) were not significantly different from controls, but early diastolic mitral annular velocity (Ea) was reduced by 13%. In overt HCM, there was a significant 27% and 14% decrease in global longitudinal εsys and SSR respectively, compared with both preclinical HCM and controls (p<0.013 for all comparisons), and a 33% reduction in Ea.

Conclusions

Sarcomere mutations have disparate initial effects on diastolic and systolic function. Preclinical HCM is characterized by impaired relaxation but preserved systolic strain. In contrast, both diastolic and longitudinal systolic abnormalities are present in overt disease, despite normal EF. We propose that diastolic dysfunction is an early consequence of sarcomere mutations, whereas systolic dysfunction results from mutations combined with subsequent pathologic remodeling. Identifying mechanistic pathways triggered by these mutations may begin to reshape the clinical paradigm for treatment, based on early diagnosis and disease prevention.

Background

It is believed that hereditary hemochromatosis (HH) might play a role in cardiac disease (heart failure (HF) and ischemia). Mutations within several genes are HH-associated, the most common being the HFE gene. In a large cohort of HF patients, we sought to determine the etiological role and the prognostic significance of HFE genotypes.

Methods

We studied 667 HF patients (72.7% men) with depressed systolic function, enrolled in a multicentre trial with a follow-up period of up to 5 years. All were genotyped for the known HFE variants C282Y, H63D and S65C.

Results

The genotype and allele frequencies in the HF group were similar to the frequencies determined in the general Danish population. In multivariable analysis mortality was not predicted by C282Y-carrier status (HR 1.2, 95% CI: 0.8-1.7); H63D-carrier status (HR 1.0, 95% CI: 0.7-1.3); nor S65C-carrier status (HR 1.2, 95% CI: 0.7-2.0). We identified 27 (4.1%) homozygous or compound heterozygous carriers of HFE variants. None of these carriers had a clinical presentation suggesting hemochromatosis, but hemoglobin and ferritin levels were higher than in the rest of the cohort. Furthermore, a trend towards reduced mortality was seen in this group in univariate analyses (HR 0.4, 95% CI: 0.2-0.9, p = 0.03), but not in multivariate (HR 0.5, 95% CI: 0.2-1.2).

Conclusion

HFE genotypes do not seem to be a significant contributor to the etiology of heart failure in Denmark. HFE variants do not affect mortality in HF.

Background

The selection of patients for prophylactic implantable cardioverter‐defibrilator (ICD) treatment after myocardial infarction (MI) remains controversial.

Aim

To determine the optimum left ventricular ejection fraction (LVEF) dichotomy limit for ICD treatment in patients with a history of MI.

Methods and results

Data from the placebo arms of four randomised trials were pooled to create a cohort of 2828 patients (2206 men, mean (SD) age 65 (11) years) with reduced left ventricular function after MI. The median LVEF was 33% (range 6–40%). LVEF significantly predicted mortality. Each 10% reduction in LVEF <40% conferred a 42% increase in all‐cause mortality, a 39% increase in arrhythmic cardiac mortality and a 49% increase in non‐arrhythmic cardiac mortality over the 2‐year period of follow‐up (p<0.001 for all modes of mortality). As the LVEF progressively decreased from ⩽40% to ⩽10%, the data show a U‐shaped relationship between the dichotomy limit for LVEF used and the number of patients who must be treated to prevent one arrhythmic death in 2 years. At an LVEF of 16–20%, more patients are likely to die from arrhythmic than non‐arrhythmic cardiac deaths, whereas in those with LVEF ⩽10% all deaths were non‐arrhythmic. However, the total number of deaths substantially decreased with lower LVEF.

Conclusion

A trade‐off exists between the sensitivity and positive predictive accuracy across a range of LVEF, and no single dichotomy limit is completely satisfactory. In patients with LVEF ⩽10% ICD treatment was not beneficial as all patients in this subgroup died from non‐arrhythmic causes. The use of a single dichotomy limit for LVEF alone is not sufficient in selecting patients for ICD treatment in the primary prevention of cardiac arrest.

Background

In patients hospitalized for myocardial infarction, there are limited data examining the long-term prognostic effect of diabetes.

The aim of this study was to systematically evaluate the development of diabetes as an independent long-term prognostic factor after myocardial infarction.

Methods

Prospective follow-up of 6676 consecutive MI patients screened for entry in the Trandolapril Cardiac Evaluation (TRACE) study. The patients were analysed by Kaplan-Meier survival analysis, landmark analysis and Cox proportional hazard models and outcome measure was all-cause mortality.

Results

The mortality in patients with diabetes was 82,7% at 10 years of follow-up and 91,1% at 15 years of follow-up, while patients without diabetes had a mortality of 60,2% at 10 years of follow-up and 72,9% at 15 years of follow-up (p < 0.0001). Landmark analysis continued to show prognostic significance of diabetes throughout the duration of follow-up. Multivariable Cox proportional-hazards model showed that the hazard ratio for death in patients with diabetes overall was 1.47 (95% confidence intervals (CI) 1.35-1.61) and varied between 1.19 (CI 1.04-1.37) and 2.13 (CI 1.33-3.42) in the 2-year periods of follow-up.

Conclusions

Diabetes is an important independent long-term prognostic factor after MI and continues to predict mortality even 17 years after index MI.

This underscores the importance of aggressive diagnostic and therapeutic approach in diabetes patients with MI.

Aim

Studies of beta blockade in patients with type 2 diabetes have shown inferiority of metoprolol treatment compared to carvedilol on indices of insulin resistance. The aim of this study was to examine the effect of metoprolol versus carvedilol on endothelial function and insulin-stimulated endothelial function in patients with type 2 diabetes.

Method

24 patients with type 2 diabetes were randomized to receive either 200 mg metoprolol succinate or 50 mg carvedilol daily. Endothelium-dependent vasodilation was assessed by using venous occlusion plethysmography with increasing doses of intra-arterial infusions of the agonist serotonin. Insulin-stimulated endothelial function was assessed after co-infusion of insulin for sixty minutes. Vaso-reactivity studies were done before and after the two-month treatment period.

Results

Insulin-stimulated endothelial function was deteriorated after treatment with metoprolol, the percentage change in forearm blood-flow was 60.19% ± 17.89 (at the highest serotonin dosages) before treatment and -33.80% ± 23.38 after treatment (p = 0.007). Treatment with carvedilol did not change insulin-stimulated endothelial function. Endothelium-dependent vasodilation without insulin was not changed in either of the two treatment groups.

Conclusion

This study shows that vascular insulin sensitivity was preserved during treatment with carvedilol while blunted during treatment with metoprolol in patients with type 2 diabetes.

Trial registration

Current Controlled Trials NCT00497003

Background:

Dronedarone has been developed for treatment of atrial fibrillation (AF) or atrial flutter (AFL). It is an amiodarone analogue but noniodinized and without the same adverse effects as amiodarone.

Objective and methods:

This is a review of 7 studies (DAFNE, ADONIS, EURIDIS, ATHENA, ANDROMEDA, ERATO and DIONYSOS) on dronedarone focusing on efficacy, safety and prevention of stroke. There was a dose-finding study (DAFNE), 3 studies focusing on maintenance of sinus rhythm (ADONIS, EURIDIS and DIONYSOS), 1 study focusing on rate control (ERATO) and 2 studies investigating mortality and morbidity (ANDROMEDA and ATHENA).

Results:

The target dose for dronedarone was established in the DAFNE study to be 400 mg twice daily. Both EURIDIS and ADONIS studies demonstrated that dronedarone was superior to placebo for maintaining sinus rhythm. However, DIONYSOS found that dronedarone is less efficient at maintaining sinus rhythm than amiodarone. ERATO concluded that dronedarone reduces ventricular rate in patients with chronic AF. The ANDROMEDA study in patients with severe heart failure was discontinued because of increased mortality in dronedarone group. Dronedarone reduced cardiovascular hospitalizations and mortality in patients with AF or AFL in the ATHENA trial. Secondly, according to a post hoc analysis a significant reduction in stroke was observed (annual rate 1.2% on dronedarone vs 1.8% on placebo, respectively [hazard ratio 0.66, confidence interval 0.46 to 0.96, P = 0.027]). In total, 54 cases of stroke occurred in 3439 patients (crude rate 1.6%) receiving dronedarone compared to 76 strokes in 3048 patients on placebo (crude rate 2.5%), respectively.

Conclusion:

Dronedarone can be used for maintenance of sinus rhythm and can reduce stroke in patients with AF who receive usual care, which includes antithrombotic therapy and heart rate control.

Background

Obesity, type 2 diabetes mellitus (T2D) and unhealthy blood lipid profile are strongly associated with the risk of developing cardiovascular disease (CVD). We examined whether blood lipid changes with short term administration of the weight lowering drug, sibutramine and lifestyle modification in obese and overweight high-risk patients was associated with T2D status at screening.

Methods

The Sibutramine Cardiovascular OUTcomes (SCOUT) trial included obese and overweight patients at increased risk of cardiovascular events. All patients received guidance on diet and exercise plus once-daily 10 mg sibutramine during the 6-week, single blind lead-in period. Multivariable regression models were used to investigate factors associated with changes in lipid levels during the first four weeks of treatment.

Results

A total of 10 742 patients received at least one dose of sibutramine during the 6-week lead-in period of SCOUT. After four weeks, patients experienced mean reductions in low density lipoprotein (LDL-C) 0.19 mmol/L, high density lipoprotein (HDL-C) 0.019 mmol/L, very low density lipoprotein (VLDL-C) 0.08 mmol/L, total cholesterol (TC) 0.31 mmol/L and triglycerides 0.24 mmol/L (p < 0.0001 for each). Four week changes in LDL-C, HDL-C and total cholesterol for patients without vs. with T2D were: LDL-C:-0.25 mmol/L vs. -0.18 mmol/L, P = 0.0004; HDL-C: -0.03 mmol/L vs. -0.02 mmol/L, P = 0.0014; total cholesterol: -0.37 mmol/l vs. -0.29 mmol/l, P = 0.0009. Multivariable regression analysis showed that similar decreases in body mass index (BMI) affected lipid changes differently according to diabetes status. A 1 kg/m2 decrease in BMI in patients with T2D was associated with -0.09 mmol/L in LDL-C (P < 0.0001) and -0.01 mmol/L in HDL-C (P = 0.0001) but larger changes of -0.16 mmol/L LDL-C and -0.03 mmol/L in HDL-C (P < 0.0001 for both) in patients without T2D.

Conclusion

Short term weight management with sibutramine therapy in obese or overweight high-risk patients induced significant mean reductions for all lipids. Those without T2D benefited most. Patients with hyperlipidaemia and the less obese patients also had greater falls in LDL-C and TC during weight loss. The trial is registered at ClinicalTrial.gov number: NCT00234832.

Background

The optimal duration of clopidogrel treatment after percutaneous coronary intervention (PCI) is unclear. We studied the risk of death or recurrent myocardial infarction (MI) in relation to 6- and 12-months clopidogrel treatment among MI patients treated with PCI.

Methods

Using nationwide registers of hospitalizations and drug dispensing from pharmacies we identified 11 680 patients admitted with MI, treated with PCI and clopidogrel. Clopidogrel treatment was categorized in a 6-months and a 12-months regimen. Rates of death, recurrent MI or a combination of both were analyzed by the Kaplan Meier method and Cox proportional hazards models. Bleedings were compared between treatment regimens.

Results

The Kaplan Meier analysis indicated no benefit of the 12-months regimen compared with the 6-months in all endpoints. The Cox proportional hazards analysis confirmed these findings with hazard ratios for the 12-months regimen (the 6-months regimen used as reference) for the composite endpoint of 1.01 (confidence intervals 0.81-1.26) and 1.24 (confidence intervals 0.95-1.62) for Day 0-179 and Day 180-540 after discharge. Bleedings occurred in 3.5% and 4.1% of the patients in the 6-months and 12-months regimen (p = 0.06).

Conclusions

We found comparable rates of death and recurrent MI in patients treated with 6- and 12-months' clopidogrel. The potential benefit of prolonged clopidogrel treatment in a real-life setting remains uncertain.