Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.
We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.
Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05–0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18–0·43), waist circumference (0·32 cm, 0·16–0·47), plasma insulin concentration (1·62%, 0·53–2·72), and plasma glucose concentration (0·23%, 0·02–0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00–1·05); the rs12916-T allele association was consistent (1·06, 1·03–1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18–1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10–0·38 in all trials; 0·33 kg, 95% CI 0·24–0·42 in placebo or standard care controlled trials and −0·15 kg, 95% CI −0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9–6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06–1·18 in all trials; 1·11, 95% CI 1·03–1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04–1·22 in intensive-dose vs moderate dose trials).
The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.
The funding sources are cited at the end of the paper.
Injury caused by trauma, burns, surgery, or disease often results in soft tissue loss leading to impaired function and permanent disfiguration. Tissue engineering aims to overcome the lack of viable donor tissue by fabricating synthetic scaffolds with the requisite properties and bioactive cues to regenerate these tissues. Biomaterial scaffolds designed to match soft tissue modulus and strength should also retain the elastomeric and fatigue-resistant properties of the tissue. Of particular design importance is the interconnected porous structure of the scaffold needed to support tissue growth by facilitating mass transport. Adequate mass transport is especially true for newly implanted scaffolds that lack vasculature to provide nutrient flux. Common scaffold fabrication strategies often utilize toxic solvents and high temperatures or pressures to achieve the desired porosity. In this study, a polymerized medium internal phase emulsion (polyMIPE) is used to generate an injectable graft that cures to a porous foam at body temperature without toxic solvents. These poly(ester urethane urea) scaffolds possess elastomeric properties with tunable compressive moduli (20–200 kPa) and strengths (4–60 kPa) as well as high recovery after the first conditioning cycle (97–99%). The resultant pore architecture was highly interconnected with large voids (0.5–2 mm) from carbon dioxide generation surrounded by water-templated pores (50–300 μm). The ability to modulate both scaffold pore architecture and mechanical properties by altering emulsion chemistry was demonstrated. Permeability and form factor were experimentally measured to determine the effects of polyMIPE composition on pore interconnectivity. Finally, initial human mesenchymal stem cell (hMSC) cytocompatibility testing supported the use of these candidate scaffolds in regenerative applications. Overall, these injectable polyMIPE foams show strong promise as a biomaterial scaffold for soft tissue repair.
Widespread sharing of data from electronic health records and patient-reported outcomes can strengthen the national capacity for conducting cost-effective clinical trials and allow research to be embedded within routine care delivery. While pragmatic clinical trials (PCTs) have been performed for decades, they now can draw on rich sources of clinical and operational data that are continuously fed back to inform research and practice. The Health Care Systems Collaboratory program, initiated by the NIH Common Fund in 2012, engages healthcare systems as partners in discussing and promoting activities, tools, and strategies for supporting active participation in PCTs. The NIH Collaboratory consists of seven demonstration projects, and seven problem-specific working group ‘Cores’, aimed at leveraging the data captured in heterogeneous ‘real-world’ environments for research, thereby improving the efficiency, relevance, and generalizability of trials. Here, we introduce the Collaboratory, focusing on its Phenotype, Data Standards, and Data Quality Core, and present early observations from researchers implementing PCTs within large healthcare systems. We also identify gaps in knowledge and present an informatics research agenda that includes identifying methods for the definition and appropriate application of phenotypes in diverse healthcare settings, and methods for validating both the definition and execution of electronic health records based phenotypes.
Clinical Research; Secondary Data Use; Phenotyping; Data quality
Summary: Although the 1000 Genomes haplotypes are the most commonly used reference panel for imputation, medical sequencing projects are generating large alternate sets of sequenced samples. Imputation in African Americans using 3384 haplotypes from the Exome Sequencing Project, compared with 2184 haplotypes from 1000 Genomes Project, increased effective sample size by 8.3–11.4% for coding variants with minor allele frequency <1%. No loss of imputation quality was observed using a panel built from phenotypic extremes. We recommend using haplotypes from Exome Sequencing Project alone or concatenation of the two panels over quality score-based post-imputation selection or IMPUTE2’s two-panel combination.
Supplementary data are available at Bioinformatics online.
To test the hypothesis that higher levels of red blood cell (RBC) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have a protective association with domain-specific cognitive function in women aged 65 years and older.
A total of 2,157 women with normal cognition enrolled in a clinical trial of postmenopausal hormone therapy were followed with annual cognitive testing for a median of 5.9 years. In this retrospective cohort study, we assessed the relationship between prerandomization RBC DHA + EPA levels and a) cognitive measures at baseline, and b) cognitive change over time. Endpoints were composite cognitive function and performance in 7 cognitive domains: fine motor speed, verbal memory, visual memory, spatial ability, verbal knowledge, verbal fluency, and working memory.
After adjustment for demographic, clinical, and behavioral characteristics, no significant (p < 0.01) cross-sectional cognitive differences were found between women in the high and low DHA + EPA tertiles at the time of the first annual cognitive battery. In addition, no significant (p < 0.01) differences were found between the high and low DHA + EPA tertiles in the rate of cognitive change over time.
We did not find an association between RBC DHA + EPA levels and age-associated cognitive decline in a cohort of older, dementia-free women.
The aim was to examine the relationship between baseline and on-study apolipoproteins (apo) A-1 and B and lipoprotein(a) [Lp(a)] levels and the development of subsequent cardiovascular (CV) events in the AIM-HIGH Trial.
Niacin has been reported to lower apoB and Lp(a) and to raise apoA-1.
Individuals with CV disease and low baseline levels of HDL-C were randomized to simvastatin plus placebo or simvastatin plus extended-release niacin (ERN, 1500–2000 mg/day), with ezetimibe added, as needed, in both groups to maintain an on-treatment LDL-C in the range of 40–80 mg/dL. Hazard ratios (HR) were used to evaluate the relationship between levels of apo A-1, apoB and Lp(a) and CV events in each treatment group.
Baseline apoB and the apoB/apoA-I ratio were significantly predictive of CV events only for the placebo group (HR=1.17, p=0.018 and HR=1.19, p=0.016). Baseline and on-study Lp(a) were predictive of CV events in both simvastatin+placebo (baseline HR= 1.24, p=0.002 and on-study HR=1.21, p=0.017) and the simvastatin+ERN group (baseline HR=1.25, p=0.001 and on-study HR=1.18 p=0.028). ERN modestly increased 1-year apoA-1 (7%), decreased apoB (13%), decreased the ApoB/ApoA-1 ratio (19%), and decreased Lp(a) 21%, but did not reduce CV events.
Lp(a) was associated with increased CV risk in both treatment groups indicating that it contributes to residual CV risk. However, there was no evidence that ERN reduced CV risk despite favorable lipoprotein changes.
LIPOPROTEIN(A); APOLIPOPROTEINS; CARDIOVASCULAR RISK; NIACIN; SIMVASTATIN
Bipolar disorder is associated with working memory (WM) impairments that persist during periods of symptomatic remission. However, the neural underpinnings of these deficits are not well understood.
Fifteen clinically remitted bipolar patients and 15 demographically matched healthy controls underwent functional magnetic resonance imaging while performing a novel delayed-non-match-to-sample (DNMS) task. This nonverbal DNMS task involves two conditions, one requiring the organization of existing memory traces (‘familiarity’), and one involving the formation of new memory traces (‘novelty’). These processes are thought to differentially engage the prefrontal cortex and medial temporal lobe, respectively.
Although behavioral performance did not differ between groups, bipolar patients and controls exhibited significantly different patterns of neural activity during task performance. Patients showed relative hyperactivation in the right prefrontal gyrus and relative hypoactivation in visual processing regions compared to healthy subjects across both task conditions. During the novelty condition, patients showed a pattern of hypoactivation relative to controls in medial temporal regions, with relative hyperactivation in the anterior cingulate.
These findings suggest that disruption in fronto-temporal neural circuitry may underlie memory difficulties frequently observed in patients with bipolar disorder.
bipolar disorder; cognition; euthymia; medial temporal lobe; prefrontal cortex; working memory
Alirocumab is a fully human monoclonal antibody to proprotein convertase subtilisin kexin type 9 (PCSK9) under investigation for treatment of hypercholesterolemia and reduction of cardiovascular events.
The COMBO studies, part of the Phase 3 ODYSSEY clinical trial program, are designed to evaluate the efficacy and safety of alirocumab as add-on therapy to stable, maximally tolerated daily statin, with or without other lipid-lowering therapy (LLT), in a planned 966 patients with hypercholesterolemia at high cardiovascular risk. COMBO I (
http://clinicaltrials.gov/show/NCT01644175) is placebo-controlled, with a double-blind treatment period of 52 weeks, and 306 planned patients who may receive other LLTs in addition to statin therapy. COMBO II (
http://clinicaltrials.gov/show/NCT01644188) has a double-blind treatment period of 104 weeks, comparing alirocumab with ezetimibe in 660 planned patients receiving statin therapy (but no other LLTs). The primary efficacy endpoint is the difference between treatment arms in percent change in low-density lipoprotein cholesterol (LDL-C) from baseline to week 24. Both studies utilized a starting dose of alirocumab 75 mg every 2 weeks (Q2W; administered as 1 mL solution via auto-injector). Patients with LDL-C levels ≥70 mg/dL after 8 weeks of treatment were up-titrated in a blinded manner at week 12 to alirocumab 150 mg Q2W (also 1 mL auto-injector).
In conclusion, the COMBO studies will provide information on the long-term efficacy and safety of alirocumab in high-risk patients when administered in addition to maximally tolerated statin therapy, with a flexible dosing strategy which allows for individualized therapy based on the degree of LDL-C lowering needed to achieve the desired treatment response.
COMBO I: NCT01644175 (
NCT01644175). COMBO II: NCT01644188 (
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2261-14-121) contains supplementary material, which is available to authorized users.
Alirocumab; Ezetimibe; Low-density lipoprotein cholesterol; Monoclonal antibody; Proprotein convertase subtilisin kexin type 9
Comparative effectiveness studies using Medicare claims data are vulnerable to treatment selection biases and supplemental data from a sample of patients has been recommended for examining the magnitude of this bias. Previous research using nationwide Medicare claims data has typically relied on the Medicare Current Beneficiary Survey (MCBS) for supplemental data. Because many important clinical variables for our specific research question are not available in the MCBS, we collected medical record data from a subsample of patients to assess the validity of assumptions and to aid in the interpretation of our estimates. This paper seeks to describe and document the process used to collect and validate this supplemental information.
Medicare claims data files for all patients with fee-for-service Medicare benefits who had an acute myocardial infarction (AMI) in 2007 or 2008 were obtained. Medical records were obtained and abstracted for a stratified subsample of 1,601 of these patients, using strata defined by claims-based measures of physician prescribing practices and drug treatment combinations. The abstraction tool was developed collaboratively by study clinicians and researchers, leveraging important elements from previously validated tools.
Records for 2,707 AMI patients were requested from the admitting hospitals and 1,751 were received for an overall response rate of 65%; 1,601 cases were abstracted by trained personnel at a contracted firm. Data were collected with overall 96% inter-abstractor agreement across all variables. Some non-response bias was detected at the patient and facility level.
Although Medicare claims data are a potentially powerful resource for conducting comparative effectiveness analyses, observational databases are vulnerable to treatment selection biases. This study demonstrates that it is feasible to abstract medical records for Medicare patients nationwide and collect high quality data, to design the sampling purposively to address specific research questions, and to more thoroughly evaluate the appropriateness of care delivered to AMI patients.
Acute myocardial infarction; Medical record abstraction; Medicare; Cardiovascular medications
Self-medication with alcohol is frequently hypothesized to explain anxiety and
alcohol dependence comorbidity. Yet, there is relatively little assessment of drinking
to self-medicate anxiety and its association with the occurrence or persistence of
alcohol dependence in population-based longitudinal samples, or associations within
demographic and clinical subgroups.
Hypothesizing that self-medication of anxiety with alcohol is associated with
the subsequent occurrence and persistence of alcohol dependence, we assessed these
associations using data from the National Epidemiologic Survey on Alcohol and Related
Conditions (NESARC), and examined these associations within population subgroups. This
nationally representative survey of the US population included 43,093 adults surveyed in
2001-2, and 34,653 re-interviewed in 2004-5. Logistic regression incorporating
propensity score methods was used.
Reports of drinking to self-medicate anxiety was associated with the subsequent
occurrence (adjusted odds ratio (AOR)=5.71, 95% confidence interval
(CI)=3.56-9.18, p<0.001) and persistence
(AOR=6.25, CI=3.24-12.05, p<0.001) of alcohol
dependence. The estimated proportion of the dependence cases attributable to
self-medication drinking were 12.7% and 33.4% for incident and
persistent dependence, respectively. Stratified analyses by age, sex, race-ethnicity,
anxiety disorders and sub-threshold anxiety symptoms, quantity of alcohol consumption,
history of treatment and family history of alcoholism showed few subgroup
Individuals who report drinking to self-medicate anxiety are more likely to
develop alcohol dependence, and the dependence is more likely to persist. There is
little evidence for interaction by the population subgroups assessed. Self-medication
drinking may be a useful target for prevention and intervention efforts aimed at
reducing the occurrence of alcohol dependence.
addiction; alcoholism; alcohol use disorder; anxiety disorder; epidemiology; generalized anxiety disorder; panic disorder; phobia
To examine whether self-medication with drugs confers risk of comorbid mood and drug use disorders.
A longitudinal, nationally representative survey was conducted by the National Institute on Alcohol Abuse and Alcoholism. The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) assessed DSM-IV psychiatric disorders, self-medication, and sociodemographic variables at two time points. A total of 34,653 adult, U.S. participants completed both waves of the survey. Wave 1 was conducted between 2001–2002 and Wave 2 interviews took place 3 years later (2004–2005). Logistic regression and population attributable fractions were calculated to obtain estimates of the association between self-medication and incident disorders.
Logistic regression analyses revealed that self-medication with drugs conferred a heightened risk of new-onset drug dependence among those with baseline mood disorders [adjusted odds ratio (AOR)=7.65; 95% confidence interval (CI) 3.70–15.82, p<.001], and accounted for over 25% of incident drug dependence disorders among people with mood disorders. Among those with comorbid mood and drug use disorders at baseline, self-medication with drugs was associated with the persistence of drug abuse (AOR=2.47; 95%CI=1.34–4.56, p<0.01), accounting for over one-fifth of the persistence of drug use disorders at three year follow-up.
Self-medication with drugs amongst individuals with mood disorders confers substantial risk of developing incident drug dependence, and is associated with the persistence of comorbid mood and drug use disorders. These results clarify a pathway that may lead to the development of mood and drug use disorder comorbidity, and indicate an at-risk population with potential points of intervention for prevention of comorbidity.
Self-medication; mood disorders; drug dependence; comorbidity; epidemiology
Mood disorders and alcohol dependence frequently co-occur. Etiologic theories concerning the comorbidity often focus on drinking to self-medicate or cope with affective symptoms. However, there has been little to no prospective studies in population-based samples of alcohol self-medication of mood symptoms with the occurrence of alcohol dependence. Furthermore, it’s not known whether these associations are effected by treatment, or symptom severity.
Alcohol self-medication of mood symptoms is hypothesized to increase the probability of subsequent onset, and the persistence or chronicity of alcohol dependence.
Prospective study, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).
Nationally representative survey of the US population.
Drinkers at risk for alcohol dependence among the 43,093 adults surveyed in 2001-2 (wave 1); 34,653 of which were re-interviewed in 2004-5 (wave 2).
Main outcome measure
Association of alcohol self-medication of mood symptoms with incident and persistent DSM-IV alcohol dependence using logistic regression and the propensity score method of inverse probability of treatment weighting.
The report of alcohol self-medication of mood symptoms was associated with an increased odds of incident alcohol dependence at follow-up (adjusted odds ratio [AOR]=3.10, 95% confidence interval [CI]=1.55-6.19, p=0.002), and persistence of dependence (AOR=3.45, CI=2.35-5.08, p<0.001). The population attributable fraction (PAF) was 11.9% (CI=6.7-16.9%) for incident dependence, and 30.6% (CI=24.8-36.0%) for persistent dependence. Stratified analyses were conducted by age, sex, raceethnicity, mood symptom severity, and treatment history for mood symptoms.
Individuals who drink to alleviate mood symptoms are more likely to develop alcohol dependence and to have persistent dependence once it develops. These associations occur among individuals with sub-threshold mood symptoms, with DSM-IV affective disorders, and for those who have received treatment. Drinking to self-medicate mood symptoms may be a potential target for prevention and early intervention efforts aimed at reducing the occurrence of alcohol dependence.
Postmenopausal hormone therapy with conjugated equine estrogens (CEE) may adversely affect older women’s cognitive function. It is not known whether this extends to younger women.
1,326 postmenopausal women, who had begun treatment in two randomized placebo-controlled clinical trials of hormone therapy when aged 50–55 years, were assessed with an annual telephone-administered cognitive battery that included measures of global (primary outcome) and domain-specific cognitive functions (verbal memory, attention, executive function, verbal fluency, and working memory). The clinical trials in which they participated had compared 0.625 mg CEE with or without 2.5 mg medroxyprogesterone acetate (MPA) over an average of 7.0 years. Cognitive testing was conducted an average of 7.2 years following the end of the trials, when women had mean age 67.2 years, and repeated one year later.
Global cognitive function scores from women who had been assigned to CEE-based therapies were similar to those from women assigned to placebo: mean [95% confidence interval] intervention effect of 0.02 [−0.08,0.12]standard deviation units (p=0.66). Similarly, no overall differences were found for any individual cognitive domain (all p>0.15). Pre-specified subgroup analyses found some evidence that CEE-based therapies may have adversely affected verbal fluency among women who had prior hysterectomy or prior use of hormone therapy: mean treatment effects of −0.17 [−0.33, −0.02] and −0.25 [−0.42, −0.08], respectively, however this may be a chance finding. We are not able to address whether initiating hormone therapy during the menopause and maintaining therapy until any symptoms are passed affects cognitive function, either in the short or longer term.
CEE-based therapies produced no overall sustained benefit or risk to cognitive function when administered to postmenopausal women aged 50–55 years.
Obesity is a major public health concern affecting an increasing proportion of reproductive-aged women. Avoiding unintended pregnancy is of major importance, given the increased risks associated with pregnancy, but obesity may affect the efficacy of hormonal contraceptives by altering how these drugs are absorbed, distributed, metabolized or eliminated. Limited data suggest that long-acting, reversible contraceptives maintain excellent efficacy in obese women. Some studies demonstrating altered pharmacokinetic parameters and increased failure rates with combined oral contraceptives, the contraceptive patch and emergency contraceptive pills suggest decreased efficacy of these methods. It is unclear whether bariatric surgery affects hormonal contraceptive efficacy. Obese women should be offered the full range of contraceptive options, with counseling that balances the risks and benefits of each method, including the risk of unintended pregnancy.
birth control; hormonal contraception; obesity; pharmacodynamics; pharmacokinetics
We tested variants in genes related to lutein and zeaxanthin status for association with age-related macular degeneration (AMD) in the Carotenoids in Age-Related Eye Disease Study (CAREDS).
Of 2005 CAREDS participants, 1663 were graded for AMD from fundus photography and genotyped for 424 single nucleotide polymorphisms (SNPs) from 24 candidate genes for carotenoid status. Of 337 AMD cases 91% had early or intermediate AMD. The SNPs were tested individually for association with AMD using logistic regression. A carotenoid-related genetic risk model was built using backward selection and compared to existing AMD risk factors using the area under the receiver operating characteristic curve (AUC).
A total of 24 variants from five genes (BCMO1, BCO2, NPCL1L1, ABCG8, and FADS2) not previously related to AMD and four genes related to AMD in previous studies (SCARB1, ABCA1, APOE, and ALDH3A2) were associated independently with AMD, after adjusting for age and ancestry. Variants in all genes (not always the identical SNPs) were associated with lutein and zeaxanthin in serum and/or macula, in this or other samples, except for BCO2 and FADS2. A genetic risk score including nine variants significantly (P = 0.002) discriminated between AMD cases and controls beyond age, smoking, CFH Y402H, and ARMS2 A69S. The odds ratio (95% confidence interval) for AMD among women in the highest versus lowest quintile for the risk score was 3.1 (2.0–4.9).
Variants in genes related to lutein and zeaxanthin status were associated with AMD in CAREDS, adding to the body of evidence supporting a protective role of lutein and zeaxanthin in risk of AMD.
In this study of over 1600 postmenopausal women of the CAREDS, we describe the first evidence that variation in multiple genes related to carotenoid status in the blood and macula are associated with age-related macular degeneration (AMD).
macular degeneration; carotenoids; genes
The Women’s Health Initiative Memory Study-Younger (WHIMS-Y) was designed to assess the effect of prior random assignment to hormone therapy (HT) (conjugated equine estrogen (CEE) alone or CEE plus medroxyprogesterone acetate (MPA)) on global cognitive function in younger middle-aged women relative to placebo. WHIMS-Y was an ancillary study to the Women’s Health Initiative (WHI) HT trial and enrolled 1361 women who were aged 50-54 years and postmenopausal at WHI enrollment. WHIMS-Y will examine whether an average of 5.4 years of HT during early menopause has longer term protective effects on global cognitive function and if these effects vary by regimen, time between menopause and study initiation, and prior use of HT. We present the study rationale and design. We describe enrollment, adherence to assigned WHI therapy, and compare risk factor characteristics of the WHIMS-Y cohort at the time of WHI enrollment to similar aged women in the WHI HT who did not enroll in WHIMS-Y. Challenges of WHIMS-Y include lower than expected and differential enrollment. Strengths of WHIMS-Y include balance in baseline risk factors between treatment groups, standardized and masked data collection, and high rates of retention and on-trial adherence and exposure. In addition, the telephone-administered cognitive battery showed adequate construct validity. WHIMS-Y provided an unprecedented chance to examine the hypothesis that HT may have protective effects on cognition in younger postmenopausal women aged 50-54 years. Integrated into the WHI, WHIMS-Y optimized the experience of WHI investigators to ensure high retention and excellent quality assurance across sites.
Postmenopausal hormone therapy; Cognitive function; Aging
Long and short sleep duration are associated with increased risk for coronary heart disease (CHD) and cardiovascular disease (CVD); however, evidence is inconsistent. We sought to identify whether self-reported sleep duration and insomnia, based on a validated questionnaire, are associated with increased incident CHD and CVD among postmenopausal women.
Women's Health Initiative Observational Study Participants (N=86,329; 50–79 years) who reported on sleep at baseline were followed for incident CVD events. Associations of sleep duration and insomnia with incident CHD and CVD were evaluated using Cox proportional hazards models over 10.3 years.
Women with high insomnia scores had elevated risk of CHD (38%) and CVD (27%) after adjustment for age and race, and in fully adjusted models (hazard ratio [HR]=1.19, 95% confidence interval [CI] 1.09–1.30; 1.11 95% CI 1.03–2.00). Shorter (≤5 hours) and longer (≥10 hours) sleep duration demonstrated significantly higher incident CHD (25%) and CVD (19%) in age- and race-adjusted models, but this was not significant in fully adjusted models. Formal tests for interaction indicated significant interactions between sleep duration and insomnia for risk of CHD (p<0.01) and CVD (p=0.02). Women with high insomnia scores and long sleep demonstrated the greatest risk of incident CHD compared to midrange sleep duration (HR=1.93, 95% CI 1.06—3.51) in fully adjusted models.
Sleep duration and insomnia are associated with CHD and CVD risk, and may interact to cause almost double the risk of CHD and CVD. Additional research is needed to understand how sleep quality modifies the association between prolonged sleep and cardiovascular outcomes.
We evaluated the risk factors and clinical course of Long QT syndrome (LQTS) in African-American patients.
The study involved 41 African-Americans and 3,456 Caucasians with a QTc ≥ 450 ms from the U.S. portion of the International LQTS Registry. Data included information about the medical history and clinical course of the LQTS patients with end points relating to the occurrence of syncope, aborted cardiac arrest, or LQTS- related sudden cardiac death from birth through age 40 years. The statistical analyses involved Kaplan-Meier time to event graphs and Cox regression models for multivariable risk factor evaluation.
The QTc was 29ms longer in African-Americans than Caucasians. Multivarite Cox analyses with adjustment for decade of birth revealed that the cardiac event rate was similar in African-Americans and Caucasians with LQTS and that β-blockers were equally effective in reducing cardiac events in the two racial groups.
The clinical course of LQTS in African-Americans is similar to that of Caucasians with comparable risk factors and benefit from β-blocker therapy in the two racial groups.
Men and women with type-2 long QT syndrome (LQT2) exhibit time-dependent differences in the risk for cardiac events. We hypothesized that data regarding the location of the disease-causing mutation in the KCNH2 channel may affect gender-specific risk in LQT2
To risk stratify LQT2 patients for life-threatening cardiac events based on clinical and genetic information.
The risk for life-threatening cardiac events from birth through age 40 (comprising aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) years was assessed among 1,166 LQT2 males (n=490) and females (n=676) by the location of the LQTS-causing mutation in the KCNH2 channel (pre-specified in the primary analysis as pore-loop vs. nonpore-loop).
During follow-up, the cumulative probability of life-threatening cardiac events years was significantly higher among LQT2 women (26%) as compared with men (14%; p<0.001). Multivariate analysis showed that the risk for life-threatening cardiac events was not significantly different between women with and without pore-loop mutations (HR=1.20; p=0.33). In contrast, men with pore-loop mutations displayed a significant >2-fold higher risk of a first ACA or SCD as compared with those with nonpore-loop mutations (HR=2.18; p=0.01). Consistently, women experienced a high rate of life-threatening events regardless of mutation-location (pore-loop: 35%, nonpore-loop: 23%), whereas in men the rate of ACA or SCD was high among those with pore-loop mutations (28%) and relatively low among those with nonpore-loop mutations (8%).
Combined assessment of clinical and mutation-specific data can be used for improved risk stratification for life-threatening cardiac events in type-2 long QT syndrome.
long-QT syndrome; pore-loop mutations; sudden cardiac death; gender
Individuals with heterozygous familial hypercholesterolemia (heFH) have higher levels of low-density lipoprotein cholesterol (LDL-C) and are predisposed to premature cardiovascular disease. Alirocumab is a fully-human, monoclonal antibody targeted to proprotein convertase subtilisin/kexin type 9 currently in Phase 3 development for the treatment of hypercholesterolemia. Described here are three ODYSSEY Phase 3 trials, FH I (NCT01623115), FH II (NCT01709500) and HIGH FH (patients with heFH and LDL-C levels ≥160 mg/dL) (NCT01617655), in which alirocumab is further evaluated in the heFH population.
Multicenter, multinational, randomized, double-blind, placebo-controlled studies have been designed to evaluate efficacy and safety of alirocumab in more than 800 patients with heFH who are not adequately controlled with a maximally-tolerated stable daily dose of statin for ≥4 weeks prior to the screening visit, with or without other lipid-lowering therapy. Patients are randomized (2:1) to receive alirocumab or placebo via a 1-mL subcutaneous auto-injection every 2 weeks (Q2W) for 78 weeks. In studies FH I and II, if their Week 8 LDL-C level is ≥70 mg/dL, patients will undergo a dose uptitration from 75 to 150 mg alirocumab Q2W at Week 12. In HIGH FH, patients will receive alirocumab 150 mg Q2W throughout the entire treatment period. The primary efficacy endpoint in all three studies is the percent change in calculated LDL-C from baseline to Week 24.
The ODYSSEY FH studies are three Phase 3 studies aiming to further evaluate the efficacy and long-term safety of alirocumab as an effective therapeutic option for patients with heFH.
Alirocumab; Heterozygous familial hypercholesterolemia; LDL-C; PCSK9
β-blockers are the mainstay therapy in patients with the congenital long-QT syndrome (LQTS) types 1 and 2. However, limited data exist regarding the efficacy and limitations of this form of medical management within high-risk subsets of these populations.
Methods and Results
Multivariate analysis was carried out to identify age-related gender- and genotype- specific risk factors for cardiac events (comprising syncope, aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) from birth through age 40 years among 971 LQT1 (n=549) and LQT2 (n=422) patients from the International LQTS Registry. Risk factors for cardiac events included the LQT1 genotype (HR=1.49, p=0.003) and male gender (HR=1.31, p=0.04) in the 0-14 years age-group; and the LQT2 genotype (HR=1.67, p<0.001) and female gender (HR=2.58, p<0.001) in the 15-40 years age-group. Gender-genotype subset analysis showed enhanced risk among LQT1 males (HR=1.93, p<0.001) and LQT2 females (HR=3.28, p<0.001) in the 2 respective age-groups. β-blocker therapy was associated with a significant risk-reduction in high-risk patients, including a 67% reduction (p=0.02) in LQT1 males and a 71% reduction (p<0.001) in LQT2 females. Life-threatening events (ACA/SCD) rarely occurred as a presenting symptom among β-blocker-treated patients. However, high-risk patients who experienced syncope during β-blocker therapy had a relatively high rate of subsequent ACA/SCD (>1 event per 100 patient-years).
The present findings suggest that β-blocker therapy should be routinely administered to all high-risk LQT1 and LQT2 patients without contraindications as a first line measure, whereas primary defibrillator therapy should be recommended for those who experience syncope during medical therapy.
long QT syndrome; β-blockers; cardiac events; sudden cardiac death
The clinical course and risk factors associated with β2-agonist therapy for asthma have not been investigated previously in patients with the Long QT Syndrome (LQTS). The risk of a first LQTS-related cardiac event due to β2-agonist therapy was examined in 3,287 patients enrolled in the International LQTS Registry with QTc≥450msec. The Cox proportional hazards model was used to assess the independent contribution of clinical factors for first cardiac events (syncope, aborted cardiac arrest, or sudden death) from birth through age 40. Time-dependent β2-agonist therapy for asthma was associated with an increased risk for cardiac events (hazard ratio (HR) = 2.00, 95% confidence interval 1.26–3.15, p = 0.003) after adjustment for relevant covariates including time-dependent β-blocker use, sex, QTc, and history of asthma. This risk was augmented within the first year after the initiation of β2-agonist therapy (HR = 3.53; p = 0.006). The combined use of β2-agonist and anti-inflammatory steroids was associated with an elevated risk for cardiac events (HR = 3.66; p < 0.01). β-blocker therapy was associated with a reduction in cardiac events in those using β2-agonists (HR = 0.14; P = 0.05). In conclusion, β2-agonist therapy was associated with an increased risk for cardiac events in asthmatic patients with LQTS, and this risk was diminished in patients receiving β-blockers.
The congenital long-QT syndrome (LQTS) is an important cause of sudden cardiac death (SCD) in children without structural heart disease. However, specific risk factors for life-threatening cardiac events in children with this genetic disorder have not been identified
Methods and Results
Cox proportional hazards regression modeling was used to identify risk factors for aborted cardiac arrest (ACA) or SCD in 3,015 LQTS children from the International LQTS Registry who were followed up from age 1 through 12 years. The cumulative probability of the combined end point was significantly higher in males (5%) than in females (1%; p<0.001). Risk factors for ACA or SCD during childhood included QTc duration >500 msec (HR=2.72 [95%CI 1.50 - 4.92]; p=0.001) and prior syncope (recent syncope [<2 years]: HR=6.16 [95%CI 3.41 - 11.15], p<0.001; remote syncope [≥2 years]: HR=2.67 [95% CI 1.22 - 5.85], p=0.01) in males, whereas prior syncope was the only significant risk factor among females (recent syncope: HR=27.82 [95%CI 9.72 - 79.60], p<0.001]; remote syncope: HR=12.04 [95%CI 3.79 - 38.26], p<0.001). β-blocker therapy was associated with a significant 53% reduction in the risk of ACA or SCD (p=0.01).
LQTS males experience a significantly higher rate of fatal or near-fatal cardiac events than females during childhood. A QTc duration >500 msec and a history of prior syncope identify risk in males, whereas prior syncope is the only significant risk factor among females. β-blocker therapy is associated with a significant reduction in the risk of life-threatening cardiac events during childhood.
long-QT syndrome; risk factors; sudden death
Patients with long QT syndrome (LQTS) who harbor multiple mutations (i.e. ≥ 2 mutations in ≥ 1 LQTS-susceptibility gene) may experience increased risk for life-threatening cardiac events.
The present study was designed to compare the clinical course of LQTS patients with multiple mutations to those with a single mutation.
The risk for life-threatening cardiac events (comprising aborted cardiac arrest, implantable defibrillator shock, or sudden cardiac death) from birth through age 40 years, by the presence of multiple vs. single mutations, was assessed among 403 patients from the LQTS Registry.
Patients with multiple mutations (n = 57) exhibited a longer QTc at enrollment compared with those with a single mutation (mean ± SD: 506 ± 72 vs. 480 ± 56 msec, respectively; p = 0.003) and had a higher rate of life threatening cardiac events during follow-up (23% vs. 11%, respectively; p < 0.001). Consistently, multivariate analysis demonstrated that patients with multiple mutations had a 2.3-fold (p = 0.015) increased risk for life threatening cardiac events as compared to patients with a single mutation. The presence of multiple mutations in a single LQTS gene was associated with a 3.2-fold increased risk for life threatening cardiac events (p = 0.010) whereas the risk associated with multiple mutation status involving > 1 LQTS gene was not significantly different from the risk associated with a single mutation (HR 1.7, p = 0.26).
LQTS patients with multiple mutations have a greater risk for life-threatening cardiac events as compared to patients with a single mutation.
Aborted cardiac arrest; Long QT syndrome; Mutation; Risk factor; Sudden cardiac death