Validation of Heart Failure Events in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Participants Assigned to Doxazosin and Chlorthalidone

BACKGROUND: The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized, double-blind, active-controlled trial designed to compare the rate of coronary heart disease events in high-risk hypertensive participants initially randomized to a diuretic (chlorthalidone) versus each of three alternative antihypertensive drugs: alpha-adrenergic blocker (doxazosin), ACE-inhibitor (lisinopril), and calcium-channel blocker (amlodipine). Combined cardiovascular disease risk was significantly increased in the doxazosin arm compared to the chlorthalidone arm (RR 1.25; 95% CI, 1.17-1.33; P <.001), with a doubling of heart failure (fatal, hospitalized, or non-hospitalized but treated) (RR 2.04; 95% CI, 1.79-2.32; P <.001). Questions about heart failure diagnostic criteria led to steps to validate these events further. METHODS AND RESULTS: Baseline characteristics (age, race, sex, blood pressure) did not differ significantly between treatment groups (P <.05) for participants with heart failure events. Post-event pharmacologic management was similar in both groups and generally conformed to accepted heart failure therapy. Central review of a small sample of cases showed high adherence to ALLHAT heart failure criteria. Of 105 participants with quantitative ejection fraction measurements provided, (67% by echocardiogram, 31% by catheterization), 29/46 (63%) from the chlorthalidone group and 41/59 (70%) from the doxazosin group were at or below 40%. Two-year heart failure case-fatalities (22% and 19% in the doxazosin and chlorthalidone groups, respectively) were as expected and did not differ significantly (RR 0.96; 95% CI, 0.67-1.38; P = 0.83). CONCLUSION: Results of the validation process supported findings of increased heart failure in the ALLHAT doxazosin treatment arm compared to the chlorthalidone treatment arm.     

Development of the Hearts of Lizards and Snakes and Perspectives to Cardiac Evolution

Birds and mammals both developed high performance hearts from a heart that must have been reptile-like and the hearts of extant reptiles have an unmatched variability in design. Yet, studies on cardiac development in reptiles are largely old and further studies are much needed as reptiles are starting to become used in molecular studies. We studied the growth of cardiac compartments and changes in morphology principally in the model organism corn snake (Pantherophis guttatus), but also in the genotyped anole (Anolis carolinenis and A. sagrei) and the Philippine sailfin lizard (Hydrosaurus pustulatus). Structures and chambers of the formed heart were traced back in development and annotated in interactive 3D pdfs. In the corn snake, we found that the ventricle and atria grow exponentially, whereas the myocardial volumes of the atrioventricular canal and the muscular outflow tract are stable. Ventricular development occurs, as in other amniotes, by an early growth at the outer curvature and later, and in parallel, by incorporation of the muscular outflow tract. With the exception of the late completion of the atrial septum, the adult design of the squamate heart is essentially reached halfway through development. This design strongly resembles the developing hearts of human, mouse and chicken around the time of initial ventricular septation. Subsequent to this stage, and in contrast to the squamates, hearts of endothermic vertebrates completely septate their ventricles, develop an insulating atrioventricular plane, shift and expand their atrioventricular canal toward the right and incorporate the systemic and pulmonary venous myocardium into the atria.     

Cognitive Function in Ambulatory Patients with Systolic Heart Failure: Insights from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial

We sought to determine whether cognitive function in stable outpatients with heart failure (HF) is affected by HF severity. A retrospective, cross-sectional analysis was performed using data from 2, 043 outpatients with systolic HF and without prior stroke enrolled in the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial. Multivariable regression analysis was used to assess the relationship between cognitive function measured using the Mini-Mental Status Exam (MMSE) and markers of HF severity (left ventricular ejection fraction [LVEF], New York Heart Association [NYHA] functional class, and 6-minute walk distance). The mean (SD) for the MMSE was 28.6 (2.0), with 64 (3.1%) of the 2,043 patients meeting the cut-off of MMSE <24 that indicates need for further evaluation of cognitive impairment. After adjustment for demographic and clinical covariates, 6-minute walk distance (β-coefficient 0.002, p<0.0001), but not LVEF or NYHA functional class, was independently associated with the MMSE as a continuous measure. Age, education, smoking status, body mass index, and hemoglobin level were also independently associated with the MMSE. In conclusion, six-minute walk distance, but not LVEF or NYHA functional class, was an important predictor of cognitive function in ambulatory patients with systolic heart failure.     

Outcomes of a Geriatric Liaison Intervention to Prevent the Development of Postoperative Delirium in Frail Elderly Cancer Patients: Report on a Multicentre,Randomized, Controlled Trial

Background

Delirium is a serious and common postoperative complication, especially in frail elderly patients. The aim of this study was to evaluate the effect of a geriatric liaison intervention in comparison with standard care on the incidence of postoperative delirium in frail elderly cancer patients treated with an elective surgical procedure for a solid tumour.

Methods

Patients over 65 years of age who were undergoing elective surgery for a solid tumour were recruited to a multicentre, prospective, randomized, controlled trial. The patients were randomized to standard treatment versus a geriatric liaison intervention. The intervention consisted of a preoperative geriatric consultation, an individual treatment plan targeted at risk factors for delirium, daily visits by a geriatric nurse during the hospital stay and advice on managing any problems encountered. The primary outcome was the incidence of postoperative delirium. The secondary outcome measures were the severity of delirium, length of hospital stay, complications, mortality, care dependency, quality of life, return to an independent preoperative living situation and additional care at home.

Results

In total, the data of 260 patients were analysed. Delirium occurred in 31 patients (11.9%), and there was no significant difference between the incidence of delirium in the intervention group and the usual-care group (9.4% vs. 14.3%, OR: 0.63, 95% CI: 0.29–1.35).

Conclusions

Within this study, a geriatric liaison intervention based on frailty for the prevention of postoperative delirium in frail elderly cancer patients undergoing elective surgery for a solid tumour has not proven to be effective.

Trial Registration

Nederlands Trial Register Trial ID NTR 823     

Secreted Frizzled-related Protein 5 Diminishes Cardiac Inflammation and Protects the Heart from Ischemia/Reperfusion Injury

Wnt signaling has diverse actions in cardiovascular development and disease processes. Secreted frizzled-related protein 5 (Sfrp5) has been shown to function as an extracellular inhibitor of non-canonical Wnt signaling that is expressed at relatively high levels in white adipose tissue. The aim of this study was to investigate the role of Sfrp5 in the heart under ischemic stress. Sfrp5 KO and WT mice were subjected to ischemia/reperfusion (I/R). Although Sfrp5-KO mice exhibited no detectable phenotype when compared with WT control at baseline, they displayed larger infarct sizes, enhanced cardiac myocyte apoptosis, and diminished cardiac function following I/R. The ischemic lesions of Sfrp5-KO mice had greater infiltration of Wnt5a-positive macrophages and greater inflammatory cytokine and chemokine gene expression when compared with WT mice. In bone marrow-derived macrophages, Wnt5a promoted JNK activation and increased inflammatory gene expression, whereas treatment with Sfrp5 blocked these effects. These results indicate that Sfrp5 functions to antagonize inflammatory responses after I/R in the heart, possibly through a mechanism involving non-canonical Wnt5a/JNK signaling.     

Healthy Dietary Interventions and Lipoprotein (a) Plasma Levels: Results from the Omni Heart Trial

Background

Increased lipoprotein(a) [Lp(a)] levels are associated with atherosclerotic cardiovascular disease. Studies of dietary interventions on changes in Lp(a) are sparse. We aimed to compare the effects of three healthy dietary interventions differing in macronutrient content on Lp(a) concentration.

Methods

Secondary analysis of a randomized, 3-period crossover feeding study including 155 (89 blacks; 66 whites) individuals. Participants were given DASH-type healthy diets rich in carbohydrates [Carb], in protein [Prot] or in unsaturated fat [Unsat Fat] for 6 weeks each. Plasma Lp(a) concentration was assessed at baseline and after each diet.

Results

Compared to baseline, all interventional diets increased mean Lp(a) by 2 to 5 mg/dl. Unsat Fat increased Lp(a) less than Prot with a difference of 1.0 mg/dl (95% CI, −0.5, 2.5; p = 0.196) in whites and 3.7 mg/dl (95% CI, 2.4, 5.0; p<0.001) in blacks (p-value between races = 0.008); Unsat Fat increased Lp(a) less than Carb with a difference of −0.6 mg/dl, 95% CI, −2.1, 0.9; p = 0.441) in whites and −1.5 mg/dl (95% CI, −0.2, −2.8; p = 0.021) in blacks (p-value between races = 0.354). Prot increased Lp(a) more than Carb with a difference of 0.4 mg/dl (95% CI, −1.1, 1.9; p = 0.597) in whites and 2.2 mg/dl (95%CI, 0.9, 3.5; p = 0.001) in blacks (p-value between races = 0.082).

Conclusion

Diets high in unsaturated fat increased Lp(a) levels less than diets rich in carbohydrate or protein with greater changes in blacks than whites. Our results suggest that substitutions with dietary mono- and polyunsaturated fatty acids in healthy diets may be preferable over protein or carbohydrates with regards to Lp(a).

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00051350","term_id":"NCT00051350"}}NCT00051350     

Engagement,Retention, and Progression to Type 2 Diabetes: A Retrospective Analysis of the Cluster-Randomised "Let's Prevent Diabetes" Trial

BackgroundPrevention of type 2 diabetes mellitus (T2DM) is a global priority. Let’s Prevent Diabetes is a group-based diabetes prevention programme; it was evaluated in a cluster-randomised trial, in which the primary analysis showed a reduction in T2DM (hazard ratio [HR] 0.74, 95% CI 0.48–1.14, p = 0.18). We examined the association of engagement and retention with the Let’s Prevent Diabetes prevention programme and T2DM incidence.ConclusionsThis study suggests that being retained/engaged in a relatively low-resource, pragmatic diabetes prevention programme for those at high risk is associated with reductions in the progression to T2DM in comparison to those who receive standard care. Nonengagers and nonretainers share similar high-risk traits. Service providers of programmes should focus on reaching these hard-to-reach groups.

Trial Registration

ClinicalTrials.gov ISRCTN80605705     

Time Interval from Symptom Onset to Hospital Care in Patients with Acute Heart Failure: A Report from the Tokyo Cardiac Care Unit Network Emergency Medical Service Database

Aims

There seems to be two distinct patterns in the presentation of acute heart failure (AHF) patients; early- vs. gradual-onset. However, whether time-dependent relationship exists in outcomes of patients with AHF remains unclear.

Methods

The Tokyo Cardiac Care Unit Network Database prospectively collects information of emergency admissions via EMS service to acute cardiac care facilities from 67 participating hospitals in the Tokyo metropolitan area. Between 2009 and 2011, a total of 3811 AHF patients were registered. The documentation of symptom onset time was mandated by the on-site ambulance team. We divided the patients into two groups according to the median onset-to-hospitalization (OH) time for those patients (2h); early- (presenting ≤2h after symptom onset) vs. gradual-onset (late) group (>2h). The primary outcome was in-hospital mortality.

Results

The early OH group had more urgent presentation, as demonstrated by a higher systolic blood pressure (SBP), respiratory rate, and higher incidence of pulmonary congestion (48.6% vs. 41.6%; P<0.001); whereas medical comorbidities such as stroke (10.8% vs. 7.9%; P<0.001) and atrial fibrillation (30.0% vs. 26.0%; P<0.001) were more frequently seen in the late OH group. Overall, 242 (6.5%) patients died during hospitalization. Notably, a shorter OH time was associated with a better in-hospital mortality rate (odds ratio, 0.71; 95% confidence interval, 0.51−0.99; P = 0.043).

Conclusions

Early-onset patients had rather typical AHF presentations (e.g., higher SBP or pulmonary congestion) but had a better in-hospital outcome compared to gradual-onset patients.     

Perspectives on the Behavior of Entomopathogenic Nematodes from Dispersal to Reproduction: Traits Contributing to Nematode Fitness and Biocontrol Efficacy

The entomopathogenic nematodes (EPN) Heterorhabditis and Steinernema are widely used for the biological control of insect pests and are gaining importance as model organisms for studying parasitism and symbiosis. In this paper recent advances in the understanding of EPN behavior are reviewed. The “foraging strategy” paradigm (distinction between species with ambush and cruise strategies) as applied to EPN is being challenged and alternative paradigms proposed. Infection decisions are based on condition of the potential host, and it is becoming clear that already-infected and even long-dead hosts may be invaded, as well as healthy live hosts. The state of the infective juvenile (IJ) also influences infection, and evidence for a phased increase in infectivity of EPN species is mounting. The possibility of social behavior - adaptive interactions between IJs outside the host - is discussed. EPNs’ symbiotic bacteria (Photorhabdus and Xenorhabdus) are important for killing the host and rendering it suitable for nematode reproduction, but may reduce survival of IJs, resulting in a trade-off between survival and reproduction. The symbiont also contributes to defence of the cadaver by affecting food-choice decisions of insect and avian scavengers. I review EPN reproductive behavior (including sperm competition, copulation and evidence for attractive and organizational effects of pheromones), and consider the role of endotokia matricida as parental behavior exploited by the symbiont for transmission.     

An Economic Evaluation of TENS in Addition to Usual Primary Care Management for the Treatment of Tennis Elbow: Results from the TATE Randomized Controlled Trial

Background

The TATE trial was a multicentre pragmatic randomized controlled trial of supplementing primary care management (PCM)–consisting of a GP consultation followed by information and advice on exercises–with transcutaneous electrical nerve stimulation (TENS), to reduce pain intensity in patients with tennis elbow. This paper reports the health economic evaluation.

Methods and Findings

Adults with new diagnosis of tennis elbow were recruited from 38 general practices in the UK, and randomly allocated to PCM (n = 120) or PCM plus TENS (n = 121). Outcomes included reduction in pain intensity and quality-adjusted-life-years (QALYs) based on the EQ5D and SF6D. Two economic perspectives were evaluated: (i) healthcare–inclusive of NHS and private health costs for the tennis elbow; (ii) societal–healthcare costs plus productivity losses through work absenteeism. Mean outcome and cost differences between the groups were evaluated using a multiple imputed dataset as the base case evaluation, with uncertainty represented in cost-effectiveness planes and through probabilistic cost-effectiveness acceptability curves). Incremental healthcare cost was £33 (95%CI -40, 106) and societal cost £65 (95%CI -307, 176) for PCM plus TENS. Mean differences in outcome were: 0.11 (95%CI -0.13, 0.35) for change in pain (0–10 pain scale); -0.015 (95%CI -0.058, 0.029) for QALY_EQ5D; 0.007 (95%CI -0.022, 0.035) for QALY_SF6D (higher score differences denote greater benefit for PCM plus TENS). The ICER (incremental cost effectiveness ratio) for the main evaluation of mean difference in societal cost (£) relative to mean difference in pain outcome was -582 (95%CI -8666, 8113). However, incremental ICERs show differences in cost–effectiveness of additional TENS, according to the outcome being evaluated.

Conclusion

Our findings do not provide evidence for or against the cost-effectiveness of TENS as an adjunct to primary care management of tennis elbow.     

Endobronchial Coils for Severe Emphysema Are Effective Up to 12 Months following Treatment: Medium Term and Cross-Over Results from a Randomised Controlled Trial

Background

There is a clinical need for therapeutic options to reduce hyperinflation associated with severe emphysema. Endobronchial Coils (coils) are nitinol devices implanted bronchoscopically under fluoroscopic guidance to re-tension the lung. We report the medium term effectiveness and safety of coils in a study of patients with emphysema.

Methods

Forty five subjects with severe airflow obstruction and hyperinflation received bilateral sequential treatment with coils (30 day interval between treatments) as part of a randomised controlled trial with a primary endpoint 90 days after the final treatment (Clinicaltrials.gov NCT01334307). Further assessments were made at 180 and 360 days and in this study the primary outcome was the effect of coil treatment on the St. George’s Respiratory Questionnaire (SGRQ) 360 days following treatment.

Results

At 360 days following treatment, there was an improvement in the SGRQ score of -6.1±14.0 points (p = 0.01) compared to baseline. Improvements in secondary outcomes were seen with increases in forced expiratory volume in the first second of 8.9 ±22.2% (p = 0.002) and 6-minute walking distance of 34.1±52.4m (p = 0.003). The safety profile was acceptable out to 360 days post-treatment.

Conclusions

Statistically and clinically meaningful benefits in quality of life, exercise capacity and pulmonary function in patients treated with coils are sustained twelve months after treatment.

Trial registration information

Clinicaltrials.gov NCT01334307.     

Review: Prospects for the Use of Extracts and Polysaccharides from Marine Algae to Prevent and Treat the Diseases Caused by Helicobacter pylori

Helicobacter pylori possesses a broad spectrum of pathogenic factors that allow it to survive and colonize the gastric mucosa, and thus, the pathogenetic targets, which have the same diversity, require search for and the development of alternative, effective, and innocuous means for the eradication of H. pylori. In recent years, fucoidans have been extensively studied due to the numerous interesting biological activities, including the anti‐adhesive, anti‐oxidative, antitoxic, immunomodulatory, anticoagulant, and anti‐infection effects. This review summarizes the data on the effects of extracts and sulfated polysaccharides of marine algae, mainly fucoidans, on pathogenic targets in Helicobacter infection. The pathogenetic targets for therapeutic agents after H. pylori infection, such as flagellas, urease, and other enzymes, including adhesins, cytotoxin A (VacA), phospholipase, and L‐8, are characterized here. The main target for the sulfated polysaccharides of seaweed is cell receptors of the gastric mucosa. This review presents the published data about the pleiotropic anti‐inflammatory effects of polysaccharides on the gastric mucosa. It is known that fucoidan and other sulfated polysaccharides from algae have anti‐ulcer effects, prevent the adhesion of H. pylori to, and reduce the formation of biofilm. The authors speculate that the effect of sulfated polysaccharides on the infectious process caused by H. pylori is related to their action on innate and adaptive immunity cells, and also anti‐oxidant and antitoxic potential. Presented in the review are materials indicated for the study of extracts and sulfated polysaccharides from seaweed during H. pylori infection, as these compounds are characterized by multimodality actions. Based on the analysis of literary materials in recent years, the authors concluded that fucoidan can be attributed to the generation of new candidates to create drugs intended for the inclusion in the scheme of eradication therapy of H. pylori infection.     

Distribution and Outcomes of a Phenotype-Based Approach to Guide COPD Management: Results from the CHAIN Cohort

RationaleThe Spanish guideline for COPD (GesEPOC) recommends COPD treatment according to four clinical phenotypes: non-exacerbator phenotype with either chronic bronchitis or emphysema (NE), asthma-COPD overlap syndrome (ACOS), frequent exacerbator phenotype with emphysema (FEE) or frequent exacerbator phenotype with chronic bronchitis (FECB). However, little is known on the distribution and outcomes of the four suggested phenotypes.ObjectiveWe aimed to determine the distribution of these COPD phenotypes, and their relation with one-year clinical outcomes.MethodsWe followed a cohort of well-characterized patients with COPD up to one-year. Baseline characteristics, health status (CAT), BODE index, rate of exacerbations and mortality up to one year of follow-up were compared between the four phenotypes.ResultsOverall, 831 stable COPD patients were evaluated. They were distributed as NE, 550 (66.2%); ACOS, 125 (15.0%); FEE, 38 (4.6%); and FECB, 99 (11.9%); additionally 19 (2.3%) COPD patients with frequent exacerbations did not fulfill the criteria for neither FEE nor FECB. At baseline, there were significant differences in symptoms, FEV₁ and BODE index (all p<0.05). The FECB phenotype had the highest CAT score (17.1±8.2, p<0.05 compared to the other phenotypes). Frequent exacerbator groups (FEE and FECB) were receiving more pharmacological treatment at baseline, and also experienced more exacerbations the year after (all p<0.05) with no differences in one-year mortality. Most of NE (93%) and half of exacerbators were stable after one year.ConclusionsThere is an uneven distribution of COPD phenotypes in stable COPD patients, with significant differences in demographics, patient-centered outcomes and health care resources use.