Does any therapy really work for neurocardiogenic syncope?

Effectiveness of a treatment for neurocardiogenic syncope can be defined in terms of symptom response, quality-of-life, healthcare utilization, treatment side effects and cost-effectiveness. Most trials have focused on syncope recurrence or burden, without assessing quality-of-life formally. Drug and device interventions are characterized by a dearth of randomized controlled trials, with those few of robust design demonstrating little impact on recurrence of syncope. General advice includes hydration, trigger recognition and counter pressure maneuvers to attenuate episodes. Lifestyle recommendations have limited comparative effectiveness evidence, but are favored due to lack of side effects and low cost. The frequency of syncope improves in many patients regardless of the intervention, although ultimate recurrence of syncope remains high. In the minority of patients seeking treatment due to recurrence, midodrine has reasonable supporting evidence for effectiveness with some evidence for beta-blockers in older age patients. Emerging evidence favors pacing in patients with asystole during spontaneous (as opposed to provoked) syncope. Combining long-term implantable cardiac monitoring, tilt and adenosine triphosphate testing may yet accurately define the optimal minority who benefit from pacing. In the remaining majority, pharmacologic and device interventions should be used sparingly until clear benefits are established. Better understanding of patient fears, beliefs and behaviors may help develop cognitive therapies and improve quality-of-life alongside the focus on physical symptoms

Eligibility for cardiac resynchronization therapy in patients hospitalized with heart failure

Aims: Recent guidelines recommend cardiac resynchronization therapy (CRT) in mildly symptomatic heart failure (HF) but favour left bundle branch block (LBBB) morphology in patients with moderate QRS prolongation (120–150 ms). We defined how many patients hospitalized with HF fulfil these criteria. Methods and results: A single-centre retrospective cohort study of 363 consecutive patients hospitalized with HF (438 admissions) was performed. Electronic imaging, electrocardiograms, and records were reviewed. Overall, 153 patients (42%) had left ventricular ejection fraction (LVEF) ≤ 35%, and 34% of patients had QRS prolongation. Eighty patients (22%) were potentially eligible with LVEF ≤ 35% and QRS ≥ 120 ms or existing CRT. The majority (68 of 80) had a Class I or IIa recommendation according to international guidelines (LBBB or non-LBBB QRS ≥ 150 ms or right ventricular pacing). Only a minority (12 of 80) had moderate QRS prolongation of non-LBBB morphology. One-quarter (n = 22) of patients fulfilling criteria were ineligible for reasons including dementia, co-morbidities, or palliative care. A further eight patients required optimization of medical therapy. CRT was therefore immediately indicated in 50 patients. Of these, 29 were implanted or had existing CRT systems. Twenty-one of the 80 patients eligible for CRT were not identified or treated (6% of the total hospitalized cohort). Conclusions: Twenty-two per cent of elderly real-life patients hospitalized with HF fulfil LVEF and QRS criteria for CRT, most having a Class I or IIa indication. However, a large proportion is ineligible owing to co-morbidities or requires medical optimization. Although uptake of CRT was reasonable, there remain opportunities for improvement

Reporting of lost to follow-up and treatment discontinuation in device and pharmacotherapy trials in chronic heart failure: a systematic review

Background—Premature treatment discontinuation and loss to follow-up (LTFU) with unknown outcomes leave uncertainty about the true efficacy and safety of a treatment and a lack of confidence in the results of any trial. We reviewed the extent of (and trends over time in) reporting LTFU and treatment discontinuation in large studies in chronic heart failure published since 1990. Methods and Results—Online databases were systematically reviewed to identify randomized controlled clinical trials (RCTs) in chronic heart failure with >400 participants and utilizing all-cause mortality as a component of the primary or secondary end point. Assessments were made of documentation of treatment discontinuation, LTFU, inclusion of and completeness of a Consolidated Standards Of Reporting Trials (CONSORT) diagram, and whether LTFU was differentiated from withdrawal of consent. Sixty-eight trials were identified, with >154 000 participants. Reasons for treatment discontinuation in pharmacotherapy trials were infrequently reported (35%), particularly in a CONSORT diagram (20%). Eighty-three percent of trials reported LTFU, although only 34% of these differentiated LTFU for vital status from withdrawal of consent. Use of a CONSORT diagram increased over time, although reporting of LTFU in the CONSORT diagram remained low overall at 35%. Conclusions—Participant flow through RCTs in chronic heart failure has not been uniformly reported, and the use of a complete CONSORT diagram has been low, although it seems to be improving. All study participants should be accounted for within a CONSORT diagram in any RCT to enable the practicing cardiologist to interpret how the results should influence his/her clinical practice

Heart failure in young adults is associated with high mortality: a contemporary population-level analysis

Background: Data on young patients with heart failure (HF) are sparse. We examined the characteristics, healthcare utilization and survival of younger versus older patients with HF. Methods: Analysis of linked administrative databases in Alberta, Canada. 34,548 patients with first hospitalization for HF as principal diagnosis were identified from 2002 to 2014. Patients were stratified into four age groups: 20-44, 45-54, 55-64, and ≥65 years. Results: Of the 34548 patients, 496 (1.4%), 1319 (3.8%), 3359 (9.7%) and 29374 (85%) patients were aged 20-44, 45-54, 55-64 and ≥65 years, respectively. Incidence of HF hospitalization decreased over time among patients ≥65 years, and increased among men aged 20 – 64 years. In the year following the index HF hospitalization, younger compared to older patients were less likely to present to the emergency department (ED) (e.g. 67.2% of those aged 20-44 years vs. 74.8% of those aged ≥65 years) or be hospitalized: for any reason (48.5% vs. 61.2%), cardiovascular causes (28.6% vs. 34.4%), or HF (14.8% vs. 23.6%). Mortality rates were lower in younger patients aged 20-44 years, but still substantial: 3.9%, 12.4%, and 27.7% at 30 days, 1 year, and 5 years respectively. Conclusions: Although young patients, especially those <45 years of age, accounted for a small proportion of the total population, adverse events were frequent, with half of the younger patients being readmitted, two thirds presenting to an ED, and over 10% dying within a year

Heart failure and atrial flutter: a systematic review of current knowledge and practices

While the interplay between heart failure (HF) and atrial fibrillation (AF) has been extensively studied, little is known regarding HF and atrial flutter (AFL), which may be managed differently. We reviewed the incidence, prevalence, and predictors of HF in AFL and vice versa, and the outcomes of treatment of AFL in HF. A systematic literature review of PubMed/Medline and EMBASE yielded 65 studies for inclusion and qualitative synthesis. No study described the incidence or prevalence of AFL in unselected patients with HF. Most cohorts enrolled patients with AF/AFL as interchangeable diagnoses, or highly selected patients with tachycardia‐induced cardiomyopathy. The prevalence of HF in AFL ranged from 6% to 56%. However, the phenotype of HF was never defined by left ventricular ejection fraction (LVEF). No studies reported the predictors, phenotype, and prognostic implications of AFL in HF. There was significant variation in treatments studied, including the proportion that underwent ablation. When systolic dysfunction was tachycardia‐mediated, catheter ablation demonstrated LVEF normalization in up to 88%, as well as reduced cardiovascular mortality. In summary, AFL and HF often coexist but are understudied, with no randomized trial data to inform care. Further research is warranted to define the epidemiology and establish optimal management

Clinical characteristics and outcomes of patients with heart failure with reduced ejection fraction and chronic obstructive pulmonary disease: insights from PARADIGM-HF

Background: Chronic obstructive pulmonary disease (COPD) is a common comorbidity in heart failure with reduced ejection fraction, associated with undertreatment and worse outcomes. New treatments for heart failure with reduced ejection fraction may be particularly important in patients with concomitant COPD. Methods and Results: We examined outcomes in 8399 patients with heart failure with reduced ejection fraction, according to COPD status, in the PARADIGM‐HF (Prospective Comparison of Angiotensin Receptor Blocker–Neprilysin Inhibitor With Angiotensin‐Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. Cox regression models were used to compare COPD versus non‐COPD subgroups and the effects of sacubitril/valsartan versus enalapril. Patients with COPD (n=1080, 12.9%) were older than patients without COPD (mean 67 versus 63 years; P<0.001), with similar left ventricular ejection fraction (29.9% versus 29.4%), but higher NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide; median, 1741 pg/mL versus 1591 pg/mL; P=0.01), worse functional class (New York Heart Association III/IV 37% versus 23%; P<0.001) and Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score (73 versus 81; P<0.001), and more congestion and comorbidity. Medical therapy was similar in patients with and without COPD except for beta‐blockade (87% versus 94%; P<0.001) and diuretics (85% versus 80%; P<0.001). After multivariable adjustment, COPD was associated with higher risks of heart failure hospitalization (hazard ratio [HR], 1.32; 95% CI, 1.13–1.54), and the composite of cardiovascular death or heart failure hospitalization (HR, 1.18; 95% CI, 1.05–1.34), but not cardiovascular death (HR, 1.10; 95% CI, 0.94–1.30), or all‐cause mortality (HR, 1.14; 95% CI, 0.99–1.31). COPD was also associated with higher risk of all cardiovascular hospitalization (HR, 1.17; 95% CI, 1.05–1.31) and noncardiovascular hospitalization (HR, 1.45; 95% CI, 1.29–1.64). The benefit of sacubitril/valsartan over enalapril was consistent in patients with and without COPD for all end points. Conclusions: In PARADIGM‐HF, COPD was associated with lower use of beta‐blockers and worse health status and was an independent predictor of cardiovascular and noncardiovascular hospitalization. Sacubitril/valsartan was beneficial in this high‐risk subgroup. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01035255

Impact of chronic obstructive pulmonary disease in patients with heart failure with preserved ejection fraction: insights from PARAGON‐HF

Background: Little is known about the impact of chronic obstructive pulmonary disease (COPD) in patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results: We examined outcomes in patients with heart failure with preserved ejection fraction, according to COPD status, in the PARAGON‐HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction) trial. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and cardiovascular death. Of 4791 patients, 670 (14%) had COPD. Patients with COPD were more likely to be men (58% versus 47%; P<0.001) and had worse New York Heart Association functional class (class III/IV 24% versus 19%), worse Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores (69 versus 76; P<0.001) and more frequent history of heart failure hospitalization (54% versus 47%; P<0.001). The decrement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores with COPD was greater than for other common comorbidities. Patients with COPD had echocardiographic right ventricular enlargement, higher serum creatinine (100 μmol/L versus 96 μmol/L) and neutrophil‐to‐lymphocyte ratio (2.7 versus 2.5), than those without COPD. After multivariable adjustment, COPD was associated with worse outcomes: adjusted rate ratio for the primary outcome 1.51 (95% CI, 1.25–1.83), total heart failure hospitalization 1.54 (95% CI, 1.24–1.90), cardiovascular death (adjusted hazard ratio [HR], 1.42; 95% CI, 1.10–1.82), and all‐cause death (adjusted HR, 1.52; 95% CI, 1.25–1.84). COPD was associated with worse outcomes than other comorbidities and Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores declined more in patients with COPD than in those without. Conclusions: Approximately 1 in 7 patients with heart failure with preserved ejection fraction had concomitant COPD, which was associated with greater functional limitation and a higher risk of heart failure hospitalization and death

Genome modeling system: A knowledge management platform for genomics

In this work, we present the Genome Modeling System (GMS), an analysis information management system capable of executing automated genome analysis pipelines at a massive scale. The GMS framework provides detailed tracking of samples and data coupled with reliable and repeatable analysis pipelines. The GMS also serves as a platform for bioinformatics development, allowing a large team to collaborate on data analysis, or an individual researcher to leverage the work of others effectively within its data management system. Rather than separating ad-hoc analysis from rigorous, reproducible pipelines, the GMS promotes systematic integration between the two. As a demonstration of the GMS, we performed an integrated analysis of whole genome, exome and transcriptome sequencing data from a breast cancer cell line (HCC1395) and matched lymphoblastoid line (HCC1395BL). These data are available for users to test the software, complete tutorials and develop novel GMS pipeline configurations. The GMS is available at https://github.com/genome/gms

13C Metabolic Flux Analysis Identifies an Unusual Route for Pyruvate Dissimilation in Mycobacteria which Requires Isocitrate Lyase and Carbon Dioxide Fixation

Mycobacterium tuberculosis requires the enzyme isocitrate lyase (ICL) for growth and virulence in vivo. The demonstration that M. tuberculosis also requires ICL for survival during nutrient starvation and has a role during steady state growth in a glycerol limited chemostat indicates a function for this enzyme which extends beyond fat metabolism. As isocitrate lyase is a potential drug target elucidating the role of this enzyme is of importance; however, the role of isocitrate lyase has never been investigated at the level of in vivo fluxes. Here we show that deletion of one of the two icl genes impairs the replication of Mycobacterium bovis BCG at slow growth rate in a carbon limited chemostat. In order to further understand the role of isocitrate lyase in the central metabolism of mycobacteria the effect of growth rate on the in vivo fluxes was studied for the first time using 13C-metabolic flux analysis (MFA). Tracer experiments were performed with steady state chemostat cultures of BCG or M. tuberculosis supplied with 13C labeled glycerol or sodium bicarbonate. Through measurements of the 13C isotopomer labeling patterns in protein-derived amino acids and enzymatic activity assays we have identified the activity of a novel pathway for pyruvate dissimilation. We named this the GAS pathway because it utilizes the Glyoxylate shunt and Anapleurotic reactions for oxidation of pyruvate, and Succinyl CoA synthetase for the generation of succinyl CoA combined with a very low flux through the succinate – oxaloacetate segment of the tricarboxylic acid cycle. We confirm that M. tuberculosis can fix carbon from CO2 into biomass. As the human host is abundant in CO2 this finding requires further investigation in vivo as CO2 fixation may provide a point of vulnerability that could be targeted with novel drugs. This study also provides a platform for further studies into the metabolism of M. tuberculosis using 13C-MFA

Effects of dapagliflozin in heart failure with reduced ejection fraction, and chronic obstructive pulmonary disease: an analysis of DAPA-HF

Aims: Chronic obstructive pulmonary disease (COPD) is an important comorbidity in HFrEF, associated with worse outcomes and often suboptimal treatment because of under‐prescription of beta‐blockers. Consequently, additional effective therapies are especially relevant in patients with COPD. To examine outcomes related to COPD in a post hoc analysis of the Dapagliflozin And Prevention of Adverse‐outcomes in Heart Failure trial (DAPA‐HF). Methods and Results: We examined whether the effects of dapagliflozin in DAPA‐HF were modified by COPD status. The primary outcome was the composite of an episode of worsening heart failure (HF) event or cardiovascular (CV) death. 585 (12.3%) of the 4744 patients randomized had a history of COPD. Patients with COPD were more likely to be older men with a history of smoking, worse renal function, and higher baseline NT‐proBNP, and less likely to be treated with a beta‐blocker or mineralocorticoid receptor antagonist. The incidence of the primary outcome was higher in patients with COPD than in those without 18.9 (95% CI 16.0–22.2) versus 13.0 (12.1–14.0) per 100 person‐years; hazard ratio (HR) for COPD versus no COPD 1.44 (1.21–1.72), P<0.001. The effect of dapagliflozin, compared with placebo, on the primary outcome, was consistent in patients with (HR 0.67 [95%CI 0.48–0.93]) and without COPD (0.76 [0.65–0.87]); interaction p‐value 0.47. Conclusions: In DAPA‐HF, one‐in‐eight patients with HFrEF had concomitant COPD. Participants with COPD had a higher risk of the primary outcome. The benefit of dapagliflozin on all prespecified outcomes was consistent in patients with and without COPD