Heart valve diseases are common with an estimated prevalence of 2.5% in the Western world. The number is rising because of an ageing population. Once symptomatic, heart valve diseases are potentially lethal, and heavily influence daily living and quality of life. Surgical treatment, either valve replacement or repair, remains the treatment of choice. However, post-surgery, the transition to daily living may become a physical, mental and social challenge. We hypothesize that a comprehensive cardiac rehabilitation program can improve physical capacity and self-assessed mental health and reduce hospitalization and healthcare costs after heart valve surgery.
This randomized clinical trial, CopenHeartVR, aims to investigate whether cardiac rehabilitation in addition to usual care is superior to treatment as usual after heart valve surgery. The trial will randomly allocate 210 patients 1:1 to an intervention or a control group, using central randomization, and blinded outcome assessment and statistical analyses. The intervention consists of 12 weeks of physical exercise and a psycho-educational intervention comprising five consultations. The primary outcome is peak oxygen uptake (VO2 peak) measured by cardiopulmonary exercise testing with ventilatory gas analysis. The secondary outcome is self-assessed mental health measured by the standardized questionnaire Short Form-36. Long-term healthcare utilization and mortality as well as biochemistry, echocardiography and cost-benefit will be assessed. A mixed-method design will be used to evaluate qualitative and quantitative findings, encompassing a survey-based study before the trial and a qualitative pre- and post-intervention study.
This randomized clinical trial will contribute with evidence of whether cardiac rehabilitation should be provided after heart valve surgery. The study is approved by the local regional Research Ethics Committee (H-1-2011-157), and the Danish Data Protection Agency (j.nr. 2007-58-0015).
Trial registered 16 March 2012; ClinicalTrials.gov (NCT01558765).
Heart valve surgery; Rehabilitation; Physical exercise; Psycho-education
To assess the association of hypoglycemic treatment regimens with cardiovascular adverse events and mortality in a large population of type 2 diabetic patients at increased cardiovascular risk.
RESEARCH DESIGN AND METHODS
This analysis included 8,192 overweight patients with type 2 diabetes from the Sibutramine Cardiovascular Outcomes (SCOUT) trial randomized to lifestyle intervention with or without sibutramine for up to 6 years. Patients were grouped according to hypoglycemic treatment at baseline. The primary end point was the time from randomization to the first occurrence of a primary outcome event (POE), nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death. Multivariable Cox proportional hazards regression models were used to assess the impact of antiglycemic treatment on POE and all-cause mortality.
Treatments for type 2 diabetes were as follows: diet alone (n = 1,394 subjects), metformin monotherapy (n = 1,631), insulin monotherapy (n = 1,116), sulfonylurea monotherapy (n = 1,083), metformin plus sulfonylurea (n = 1,565), and metformin plus insulin (n = 1,000); 905 subjects experienced a POE and 708 died. Metformin monotherapy was associated with lower risk of POE than insulin (hazard ratio [HR], 0.74; 95% CI, 0.57–0.95; P = 0.02). Diet alone also was associated with lower risk of POE (HR, 0.65; 95% CI, 0.48–0.87; P = 0.004). Metformin monotherapy also was associated with lower mortality (HR, 0.73; 95% CI, 0.54–0.99; P < 0.05), whereas no other monotherapies or combination therapies were significantly associated with POE or all-cause mortality compared with insulin as monotherapy.
In obese patients with type 2 diabetes and high risk of cardiovascular disease, monotherapy with metformin or diet-only treatment was associated with lower risk of cardiovascular events than treatment with insulin.
Cardiac autonomic neuropathy (CAN) and elevated nocturnal blood pressure are independent risk factors for cardiovascular disease in patients with diabetes. Previously, associations between CAN, non-dipping of nocturnal blood pressure and coronary artery calcification have been demonstrated. The present protocol describes a trial to test the efficacy of bedtime dosing of the ACE inhibitor enalapril on night time blood pressure and left ventricular mass in patients with type 1 diabetes.
Materials and methods
In a randomised, double-blind, two-way cross-over study, 24 normoalbuminuric patients with type 1 diabetes with CAN will be treated for 12 weeks with either morning or bedtime dosing of 20 mg enalapril, followed by 12 weeks of switched treatment regimen. During each treatment period, two 24 h ambulatory blood pressure measurements will be performed and after each treatment period left ventricular mass will be determined by multisliced CT. Primary end points will be reduction in blood pressure and reduction in left ventricular mass.
Ethics and dissemination
The study has been approved by the Danish Medicines Agency, the Scientific-Ethical Committee of the Capital Region of Denmark and the Danish Data Protection Agency. An external monitoring committee (the Good Clinical Practice Unit at Copenhagen University Hospital) will oversee the study. The results of the study will be presented at national and international scientific meetings and publications will be submitted to peer-reviewed journals.
Trial registration number
Background and purpose
Obesity is a risk factor for osteoarthritis in the lower limb, yet the cardiovascular risks associated with obesity in hip or knee replacement surgery are unknown. We examined associations between body mass index (BMI) and the risk of a major adverse cardiovascular event (MACE: ischemic stroke, acute myocardial infarction, or cardiovascular death) or the risk of all-cause mortality in a nationwide Danish cohort of patients who underwent primary hip or knee replacement surgery.
Using Danish nationwide registries, we identified 34,744 patients aged ≥ 20 years who underwent elective primary hip or knee replacement surgery between 2005 and 2011. We used multivariable Cox regression models to calculate the 30-day risks of MACE and mortality associated with 5 BMI groups (underweight (BMI < 18.5 kg/m2), normal weight (18.5–24 kg/m2), overweight (25–29 kg/m2), obese 1 (30–34 kg/m2), and obese 2 (≥ 35 kg/m2)).
In total, 232 patients (0.7%) had a MACE and 111 (0.3%) died. Compared with overweight, adjusted hazard ratios (HRs) were 1.2 (95% CI: 0.4–3.3), 1.3 (0.95–1.8), 1.6 (1.1–2.2), and 1.0 (0.6–1.9) for underweight, normal weight, obese 1, and obese 2 regarding MACE. Regarding mortality, the corresponding HRs were 7.0 (2.8–15), 2.0 (1.2–3.2), 1.5 (0.9–2.7), and 1.9 (0.9–4.2). Cubic splines suggested a significant U-shaped relationship between BMI and risks with nadir around 27–28.
In an unselected cohort of patients undergoing elective primary hip or knee replacement surgery, U-shaped risks of perioperative MACE and mortality were found in relation to BMI. Patients within the extreme ranges of BMI may warrant further attention.
We sought to perform a study assessing the association between electrocardiographic
ST‐segment deviations and cardiovascular death (CVD), in relation to sex and age (≥
and <65 years), in a large primary care population without overt ischemic heart disease.
Methods and Results
Using computerized analysis of ECGs from 285 194 persons, we evaluated the association between
precordial ST‐segment deviations and the risk of CVD. All data on medication, comorbidity,
and outcomes were retrieved from Danish registries. After a median follow‐up period of 5.8
years, there were 6679 cardiovascular deaths. Increasing ST‐depression was associated with an
increased risk of CVD in almost all of the precordial leads, with the most robust association seen
in lead V5 to V6. ST‐elevations in lead V2 to V6 were associated with increased risk of CVD
in young women, but not in men. However, ST‐elevations in V1 increased the risk for both
genders and age groups, exemplified by a HR of 1.80 (95% CI [1.19 to 2.74],
P=0.005) for men <65 years with ST‐elevations ≥150
μV versus a nondeviating ST‐segment (−50 μV to +50 μV). In
contrast, for men <65 years, ST‐elevations in lead V2 to V3 conferred a decreased risk
of CVD with a HR of 0.77 (95% CI [0.62 to 0.96], P<0.001) for
ST‐elevations ≥150 μV in V2.
We found that ST‐depressions were associated with a dose‐responsive increased risk
of CVD in nearly all the precordial leads. ST‐elevations conferred an increased risk of CVD
in women and with regard to lead V1 also in men. However, ST‐elevations in V2 to V3 were
associated with a decreased risk of CVD in young men.
Brugada; ECG; gender differences; general population; Marquette 12SL validation; ST‐segment
Rapid risk stratification is a core task in emergency medicine. Identifying patients at high and low risk shortly after admission could help clinical decision-making regarding treatment, level of observation, allocation of resources and post discharge follow-up. The purpose of the present study was to determine short-, mid- and long-term mortality by plasma measurement of copeptin in unselected admitted patients.
Consecutive patients >40-years-old admitted to an inner-city hospital were included. Within the first 24 hours after admission, a structured medical interview was conducted and self-reported medical history was recorded. All patients underwent a clinical examination, an echocardiographic evaluation and collection of blood for later measurement of risk markers.
Plasma for copeptin measurement was available from 1,320 patients (average age 70.5 years, 59.4% women). Median follow-up time was 11.5 years (range 11.0 to 12.0 years). Copeptin was elevated (that is, above the 97.5 percentile in healthy individuals).
Mortality within the first week was 2.7% (17/627) for patients with elevated copeptin (above the 97.5 percentile, that is, >11.3 pmol/L) compared to 0.1% (1/693) for patients with normal copeptin concentrations (that is, ≤11.3 pmol/L) (P <0.01). Three-month mortality was 14.5% (91/627) for patients with elevated copeptin compared to 3.2% (22/693) for patients with normal copeptin. Similar figures for one-year mortality and for the entire observation period were 27.6% (173/627) versus 8.7% (60/693) and 82.9% (520/527) versus 57.5% (398/693) (P <0.01 for both), respectively.
Using multivariable Cox regression analyses shows that elevated copeptin was significantly and independently related to short-, mid- and long-term mortality. Adjusted hazard ratios were 2.4 for three-month mortality, 1.9 for one-year mortality and 1.4 for mortality in the entire observation period.
In patients admitted to an inner-city hospital, copeptin was strongly associated with short-, mid- and long-term mortality. The results suggest that rapid copeptin measurement could be a useful tool for both disposition in an emergency department and for mid- and long-term risk assessment.
Biomarker; Mortality; Inflammation
Metabolic disorders are relatively uncommon in young women, but may increase with obesity. The associations between body mass index (BMI) and risks of diabetes, hypertension, and dyslipidemia in apparently healthy, young women have been insufficiently investigated, and are the aims of this study.
Methods and Results
Women giving birth during the years 2004–2009, with no history of cardiovascular disease, renal insufficiency, pregnancy‐associated metabolic disorders, diabetes, hypertension, or dyslipidemia were identified in nationwide registers. Women were categorized as underweight (BMI<18.5 kg/m2), normal weight (BMI=18.5 to <25 kg/m2), overweight (BMI=25 to <30 kg/m2), obese‐I (BMI=30 to <35 kg/m2), obese‐II (BMI=35 to <40 kg/m2), and obese‐III (BMI≥40 kg/m2). We assessed risks by Poisson regression models (adjusted for age, calendar year; reference=normal weight). The cohort comprised 252 472 women with a median age of 30.4 years (IQR=27.2;33.7) and a median follow‐up of 5.5 years (IQR=3.9;6.8). In total, 2029 women developed diabetes, 3133 women developed hypertension, and 1549 women developed dyslipidemia. Rate ratios (RRs) of diabetes were: 0.84 (95% confidence interval [CI]=0.62 to 1.14) for underweight, 2.63 (CI=2.36 to 2.93) for overweight, 4.83 (CI=4.27 to 5.47) for obese grade‐I, 7.17 (CI=6.10 to 8.48) for obese grade‐II, and 6.93 (CI=5.47 to 8.79) for obese grade‐III women. For hypertension, corresponding RRs were 0.86 (CI=0.69 to 1.09), 1.82 (CI=1.67 to 1.98), 2.81 (CI=2.52 to 3.13), 3.92 (CI=3.36 to 4.56), and 5.69 (CI=4.71 to 6.89), and for dyslipidemia, RRs were 1.18 (CI=0.85 to 1.65), 2.01 (CI=1.75 to 2.31), 3.11 (CI=2.61 to 3.70), 4.64 (CI=3.66 to 5.87), and 3.72 (CI=2.53 to 5.48).
In this nationwide study of fertile, apparently healthy women, pre‐pregnancy BMI was strongly associated with an increased risk of diabetes, hypertension, and dyslipidemia within 5.5 years following childbirth.
body mass index; diabetes; hypercholesterolemia; hypertension; women
Using a large, contemporary primary care population we aimed to provide absolute long-term risks of cardiovascular death (CVD) based on the QTc interval and to test whether the QTc interval is of value in risk prediction of CVD on an individual level.
Methods and results
Digital electrocardiograms from 173 529 primary care patients aged 50–90 years were collected during 2001–11. The Framingham formula was used for heart rate-correction of the QT interval. Data on medication, comorbidity, and outcomes were retrieved from administrative registries. During a median follow-up period of 6.1 years, 6647 persons died from cardiovascular causes. Long-term risks of CVD were estimated for subgroups defined by age, gender, cardiovascular disease, and QTc interval categories. In general, we observed an increased risk of CVD for both very short and long QTc intervals. Prolongation of the QTc interval resulted in the worst prognosis for men whereas in women, a very short QTc interval was equivalent in risk to a borderline prolonged QTc interval. The effect of the QTc interval on the absolute risk of CVD was most pronounced in the elderly and in those with cardiovascular disease whereas the effect was negligible for middle-aged women without cardiovascular disease. The most important improvement in prediction accuracy was noted for women aged 70–90 years. In this subgroup, a total of 9.5% were reclassified (7.2% more accurately vs. 2.3% more inaccurately) within clinically relevant 5-year risk groups when the QTc interval was added to a conventional risk model for CVD.
Important differences were observed across subgroups when the absolute long-term risk of CVD was estimated based on QTc interval duration. The accuracy of the personalized CVD prognosis can be improved when the QTc interval is introduced to a conventional risk model for CVD.
QTc interval; Gender; Marquette 12SL validation; Cardiovascular death; Risk prediction
New‐onset atrial fibrillation (AF) is reported to increase the risk of death in myocardial infarction (MI) patients. However, previous studies have reported conflicting results and no data exist to explain the underlying cause of higher death rates in these patients.
Methods and Results
All patients with first acute MI between 1997 and 2009 in Denmark, without prior AF, were identified from Danish nationwide administrative registers. The impact of new‐onset AF on all‐cause mortality, cardiovascular death, fatal/nonfatal stroke, fatal/nonfatal re‐infarction and noncardiovascular death, were analyzed by multiple time‐dependent Cox models and additionally in propensity score matched analysis. In 89 703 patients with an average follow‐up of 5.0±3.5 years event rates were higher in patients developing AF (n=10 708) versus those staying in sinus‐rhythm (n=78 992): all‐cause mortality 173.9 versus 69.4 per 1000 person‐years, cardiovascular death 137.2 versus 50.0 per 1000 person‐years, fatal/nonfatal stroke 19.6/19.9 versus 6.2/5.6 per 1000 person‐years, fatal/nonfatal re‐infarction 29.0/60.7 versus 14.2/37.9 per 1000 person‐years. In time‐dependent multiple Cox analyses, new‐onset AF remained predictive of increased all‐cause mortality (HR: 1.9 [95% CI: 1.8 to 2.0]), cardiovascular death (HR: 2.1 [2.0 to 2.2]), fatal/nonfatal stroke (HR: 2.3 [2.1 to 2.6]/HR: 2.5 [2.2 to 2.7]), fatal/nonfatal re‐infarction (HR: 1.7 [1.6 to 1.8]/HR: 1.8 [1.7 to 1.9]), and non‐ cardiovascular death (HR: 1.4 [1.3 to 1.5]) all P<0.001). Propensity‐score matched analyses yielded nearly identical results (all P<0.001).
New‐onset AF after first‐time MI is associated with increased mortality, which is largely explained by more cardiovascular deaths. Focus on the prognostic impact of post‐infarct AF is warranted.
cardiovascular mortality; mortality; myocardial infarction; new‐onset atrial fibrillation; re‐myocardial infarction; stroke
The association of natriuretic peptide measurement with all-cause mortality in a broad selection of acutely admitted patients has not yet been examined.
To test the risk association between pro-atrial natriuretic peptide (ANP) and short-term and long-term mortality and its predictive value in acutely hospitalised patients and compare this to N-terminal B-type natriuretic peptide (NT-proBNP).
Design, setting and patients
Participants were selected from the Copenhagen Hospital Heart Failure Study (n=3644). Medical history, satisfactory echocardiography and blood samples were available on 2193 participants in 1998–1999 where NT-proBNP was measured. Vital status after discharge was obtained from national central data registers. A total of 1337 participants with eligible blood samples were selected in 2010–2011 for proANP measurement. Among these, 1255 (94%) were acutely hospitalised in 1998–1999.
Main outcome measure(s)
1-year and long-term mortality.
Median follow-up period was 11.5 years. At the end of follow-up, 926 patients had died, 239 during the first year. ProANP quartiles to 2–4 (median proANP levels 594 pmol/L, 990 pmol/L and 2052 pmol/L, respectively) associated with a stepwise increase in risk of 1-year and long-term mortality compared to the first quartile (336 pmol/L) in multivariable adjusted Cox proportional regression models (HR 1.53 95% CI 1.30 to 1.81 and HR 1.26 95% CI 1.17 to 1.36, respectively). An addition of NT-proBNP attenuated proANP's association with mortality in the models (HR 1.24 95% CI 1.01 to 1.53 and 1.14 95% CI 1.03 to 1.26, respectively). The increased risk was observed in participants with the highest proANP levels (fourth quartile). Similar results were observed in subgroups of participants with no evidence of cardiovascular disease (CVD). ProANP in quartiles improved discrimination when added to traditional risk factors in prediction models for 1-year (integrated discrimination improvement (IDI) 0.141 95% CI 0.085 to 0.197; C-index 0.753 95% CI 0.724 to 0.783, P for improvement 0.003) and long-term mortality (IDI 0.053 95% CI 0.032 to 0.074; C-index 0.736 95% CI 0.720 to 0.752, P for improvement <0.001) with similar results in subgroups. Discrimination was best in a combined model with proANP as well as NT-proBNP included.
Conclusions and relevance
High plasma proANP concentrations are associated with and predict short-term and long-term all-cause mortality in acutely hospitalised patients irrespective of CVD status at admission.
Accident & Emergency Medicine; Chemical Pathology
Cardiovascular autonomic neuropathy (CAN) is associated with increased mortality in diabetes. Since CAN often develops in parallel with diabetic nephropathy as a confounder, we aimed to investigate the isolated impact of CAN on cardiovascular disease in normoalbuminuric patients. Fifty-six normoalbuminuric, type 1 diabetic patients were divided into 26 with (+) and 30 without (−) CAN according to tests of their autonomic nerve function. Coronary artery plaque burden and coronary artery calcium score (CACS) were evaluated using computed tomography. Left ventricular function was evaluated using echocardiography. Blood pressure and electrocardiography were recorded through 24 h to evaluate nocturnal drop in blood pressure (dipping) and pulse pressure. In patients +CAN compared with −CAN, the CACS was higher, and only patients +CAN had a CACS >400. A trend toward a higher prevalence of coronary plaques and flow-limiting stenosis in patients +CAN was nonsignificant. In patients +CAN, left ventricular function was decreased in both diastole and systole, nondipping was more prevalent, and pulse pressure was increased compared with −CAN. In multivariable analysis, CAN was independently associated with increased CACS, subclinical left ventricular dysfunction, and increased pulse pressure. In conclusion, CAN in normoalbuminuric type 1 diabetic patients is associated with distinct signs of subclinical cardiovascular disease.
Mitral regurgitation (MR) has been associated with adverse outcomes after myocardial infarction (MI). Without structural valve disease, functional MR has been related to left ventricular (LV) remodeling and geometric deformation of the mitral apparatus. The aims of this study were to elucidate the mechanistic components of MR after high-risk MI and to identify predictors of MR progression during follow-up.
The Valsartan in Acute Myocardial Infarction Echo substudy prospectively enrolled 610 patients with LV dysfunction, heart failure, or both after MI. MR at baseline, 1 month, and 20 months was quantified by mapping jet expansion in the left atrium in 341 patients with good-quality echocardiograms. Indices of LV remodeling, left atrial size, and diastolic function and parameters of mitral valve deformation, including tenting area, coaptation depth, anterior leaflet concavity, annular diameters, and contractility, were assessed and related to baseline MR. The progression of MR was further analyzed, and predictors of worsening among the baseline characteristics were identified.
Tenting area, coaptation depth, annular dilatation, and left atrial size were all associated with the degree of baseline MR. Tenting area was the only significant and independent predictor of worsening MR; a tenting area of 4 cm2 was a useful cutoff to identify worsening of MR after MI and moderate to severe MR after 20 months.
Increased mitral tenting and larger mitral annular area are determinants of MR degree at baseline, and tenting area is an independent predictor of progression of MR after MI. Although LV remodeling itself contributes to ischemic MR, this influence is directly dependent on alterations in mitral geometry.
Mitral regurgitation; Myocardial infarction; Mitral geometry; Tenting area; Left ventricular remodeling
Heart valve diseases are common with an estimated prevalence of 2.5% in the Western world. The number is rising due to an ageing population. Once symptomatic, heart valve diseases are potentially lethal, and heavily influence daily living and quality of life. Surgical treatment, either valve replacement or repair, remains the treatment of choice. However, post surgery, the transition to daily living may become a physical, mental and social challenge. We hypothesise that a comprehensive cardiac rehabilitation programme can improve physical capacity and self-assessed mental health and reduce hospitalisation and healthcare costs after heart valve surgery.
A randomised clinical trial, CopenHeartVR, aims to investigate whether cardiac rehabilitation in addition to usual care is superior to treatment as usual after heart valve surgery. The trial will randomly allocate 210 patients, 1:1 intervention to control group, using central randomisation, and blinded outcome assessment and statistical analyses. The intervention consists of 12 weeks of physical exercise, and a psycho-educational intervention comprising five consultations. Primary outcome is peak oxygen uptake (VO2 peak) measured by cardiopulmonary exercise testing with ventilatory gas analysis. Secondary outcome is self-assessed mental health measured by the standardised questionnaire Short Form 36. Also, long-term healthcare utilisation and mortality as well as biochemistry, echocardiography and cost-benefit will be assessed. A mixed-method design is used to evaluate qualitative and quantitative findings encompassing a survey-based study before the trial and a qualitative pre- and post-intervention study.
The study is approved by the local regional Research Ethics Committee (H-1-2011-157), and the Danish Data Protection Agency (j.nr. 2007-58-0015).
Heart valve surgery; Rehabilitation; Physical exercise; Psycho-education
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.
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].
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.
Hypertrophic Cardiomyopathy; Electrocardiography; Genetics; Sarcomere
To describe the use of emergency coronary angiography (CAG) and primary percutaneous coronary intervention (PCI) and the association with short- and long-term survival in consecutive comatose survivors after out-of-hospital cardiac arrest (OHCA).
In the period 2004–10, a total of 479 consecutive patients with OHCA of suspected cardiac cause were referred to a tertiary cardiac centre, 360 patients were comatose and admitted to the ICU for post-resuscitative care. The population was stratified in two groups according to the pattern of the first ECG obtained after re-established circulation; ST-segment elevation (STEMI, n=116) and ECG without STEMI pattern (No-STEMI, n=244). Emergency CAG (≤12 hours after OHCA) was performed at the discretion of the attending cardiologist. Primary outcome was 30-day and 1-year survival.
Emergency CAG was performed in all patients in the STEMI group compared to 82 (34%) in the group without STEMI pattern (p<0.0001) with significant coronary lesions found in 108 (93%) compared to 43 (52%) patients, respectively (p<0.0001). Survival at 30 day according to emergency CAG vs. no emergency CAG was 65% in the STEMI group compared to 66% and 54% in the group without STEMI pattern (p
log-rank=0.11). The use of emergency CAG in the group without STEMI pattern was not associated with reduced mortality (HRadjusted=0.69, 95% CI 0.4–1.2, p=0.18).
In comatose survivors of OHCA presenting with STEMI, a high prevalence of coronary disease and culprit lesions suitable for emergency PCI was found, whereas in patients without STEMI pattern, significant coronary stenosis was less frequent. Clinical benefits of emergency CAG/PCI in comatose survivors of OHCA presenting without STEMI could not be identified.
Cardiac arrest; coronary angiography; coronary intervention; hypothermia; outcome; survival
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.
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).
Patients within the higher LVEF categories have a greater mortality risk attributable to diabetes than patients within the lower LVEF categories.
To study the association between exposures to glucose-lowering therapy and risk of cancer using the nationwide administrative registers in Denmark.
Nationwide cohort study.
All hospitals in Denmark.
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.
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.
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.
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.
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.
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.
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.
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.
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.
AMPK; metabolic remodeling; mitochondria; oxidative phosphorylation
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.
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.
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).
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.
insulin resistance; diabetes; heart failure; endothelial function
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.
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.
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.
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.
Current Controlled Trials NCT00497003
Heart failure; Endothelial function; Beta blocker
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.
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.
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).
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).