Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial.

BACKGROUND: Patients with dilated cardiomyopathy whose symptoms and cardiac function have recovered often ask whether their medications can be stopped. The safety of withdrawing treatment in this situation is unknown. METHODS: We did an open-label, pilot, randomised trial to examine the effect of phased withdrawal of heart failure medications in patients with previous dilated cardiomyopathy who were now asymptomatic, whose left ventricular ejection fraction (LVEF) had improved from less than 40% to 50% or greater, whose left ventricular end-diastolic volume (LVEDV) had normalised, and who had an N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) concentration less than 250 ng/L. Patients were recruited from a network of hospitals in the UK, assessed at one centre (Royal Brompton and Harefield NHS Foundation Trust, London, UK), and randomly assigned (1:1) to phased withdrawal or continuation of treatment. After 6 months, patients in the continued treatment group had treatment withdrawn by the same method. The primary endpoint was a relapse of dilated cardiomyopathy within 6 months, defined by a reduction in LVEF of more than 10% and to less than 50%, an increase in LVEDV by more than 10% and to higher than the normal range, a two-fold rise in NT-pro-BNP concentration and to more than 400 ng/L, or clinical evidence of heart failure, at which point treatments were re-established. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02859311. FINDINGS: Between April 21, 2016, and Aug 22, 2017, 51 patients were enrolled. 25 were randomly assigned to the treatment withdrawal group and 26 to continue treatment. Over the first 6 months, 11 (44%) patients randomly assigned to treatment withdrawal met the primary endpoint of relapse compared with none of those assigned to continue treatment (Kaplan-Meier estimate of event rate 45·7% [95% CI 28·5-67·2]; p=0·0001). After 6 months, 25 (96%) of 26 patients assigned initially to continue treatment attempted its withdrawal. During the following 6 months, nine patients met the primary endpoint of relapse (Kaplan-Meier estimate of event rate 36·0% [95% CI 20·6-57·8]). No deaths were reported in either group and three serious adverse events were reported in the treatment withdrawal group: hospital admissions for non-cardiac chest pain, sepsis, and an elective procedure. INTERPRETATION: Many patients deemed to have recovered from dilated cardiomyopathy will relapse following treatment withdrawal. Until robust predictors of relapse are defined, treatment should continue indefinitely. FUNDING: British Heart Foundation, Alexander Jansons Foundation, Royal Brompton Hospital and Imperial College London, Imperial College Biomedical Research Centre, Wellcome Trust, and Rosetrees Trust.

Association Between Midwall Late Gadolinium Enhancement and Sudden Cardiac Death in Patients With Dilated Cardiomyopathy and Mild and Moderate Left Ventricular Systolic Dysfunction.

BACKGROUND: Current guidelines only recommend the use of an implantable cardioverter defibrillator in patients with dilated cardiomyopathy for the primary prevention of sudden cardiac death (SCD) in those with a left ventricular ejection fraction (LVEF) <35%. However, registries of out-of-hospital cardiac arrests demonstrate that 70% to 80% of such patients have an LVEF >35%. Patients with an LVEF >35% also have low competing risks of death from nonsudden causes. Therefore, those at high risk of SCD may gain longevity from successful implantable cardioverter defibrillator therapy. We investigated whether late gadolinium enhancement (LGE) cardiovascular magnetic resonance identified patients with dilated cardiomyopathy without severe LV systolic dysfunction at high risk of SCD. METHODS: We prospectively investigated the association between midwall LGE and the prespecified primary composite outcome of SCD or aborted SCD among consecutive referrals with dilated cardiomyopathy and an LVEF ≥40% to our center between January 2000 and December 2011 who did not have a preexisting indication for implantable cardioverter defibrillator implantation. RESULTS: Of 399 patients (145 women, median age 50 years, median LVEF 50%, 25.3% with LGE) followed for a median of 4.6 years, 18 of 101 (17.8%) patients with LGE reached the prespecified end point, compared with 7 of 298 (2.3%) without (hazard ratio [HR], 9.2; 95% confidence interval [CI], 3.9-21.8; P<0.0001). Nine patients (8.9%) with LGE compared with 6 (2.0%) without (HR, 4.9; 95% CI, 1.8-13.5; P=0.002) died suddenly, whereas 10 patients (9.9%) with LGE compared with 1 patient (0.3%) without (HR, 34.8; 95% CI, 4.6-266.6; P<0.001) had aborted SCD. After adjustment, LGE predicted the composite end point (HR, 9.3; 95% CI, 3.9-22.3; P<0.0001), SCD (HR, 4.8; 95% CI, 1.7-13.8; P=0.003), and aborted SCD (HR, 35.9; 95% CI, 4.8-271.4; P<0.001). Estimated HRs for the primary end point for patients with an LGE extent of 0% to 2.5%, 2.5% to 5%, and >5% compared with those without LGE were 10.6 (95% CI, 3.9-29.4), 4.9 (95% CI, 1.3-18.9), and 11.8 (95% CI, 4.3-32.3), respectively. CONCLUSIONS: Midwall LGE identifies a group of patients with dilated cardiomyopathy and an LVEF ≥40% at increased risk of SCD and low risk of nonsudden death who may benefit from implantable cardioverter defibrillator implantation. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00930735.

Comparison of 3 T and 1.5 T for T2* magnetic resonance of tissue iron.

BACKGROUND: T2* magnetic resonance of tissue iron concentration has improved the outcome of transfusion dependant anaemia patients. Clinical evaluation is performed at 1.5 T but scanners operating at 3 T are increasing in numbers. There is a paucity of data on the relative merits of iron quantification at 3 T vs 1.5 T. METHODS: A total of 104 transfusion dependent anaemia patients and 20 normal volunteers were prospectively recruited to undergo cardiac and liver T2* assessment at both 1.5 T and 3 T. Intra-observer, inter-observer and inter-study reproducibility analysis were performed on 20 randomly selected patients for cardiac and liver T2*. RESULTS: Association between heart and liver T2* at 1.5 T and 3 T was non-linear with good fit (R (2) = 0.954, p < 0.001 for heart white-blood (WB) imaging; R (2) = 0.931, p < 0.001 for heart black-blood (BB) imaging; R (2) = 0.993, p < 0.001 for liver imaging). R2* approximately doubled between 1.5 T and 3 T with linear fits for both heart and liver (94, 94 and 105 % respectively). Coefficients of variation for intra- and inter-observer reproducibility, as well as inter-study reproducibility trended to be less good at 3 T (3.5 to 6.5 %) than at 1.5 T (1.4 to 5.7 %) for both heart and liver T2*. Artefact scores for the heart were significantly worse with the 3 T BB sequence (median 4, IQR 2-5) compared with the 1.5 T BB sequence (4 [3-5], p = 0.007). CONCLUSION: Heart and liver T2* and R2* at 3 T show close association with 1.5 T values, but there were more artefacts at 3 T and trends to lower reproducibility causing difficulty in quantifying low T2* values with high tissue iron. Therefore T2* imaging at 1.5 T remains the gold standard for clinical practice. However, in centres where only 3 T is available, equivalent values at 1.5 T may be approximated by halving the 3 T tissue R2* with subsequent conversion to T2*.

Validation of T2* in-line analysis for tissue iron quantification at 1.5 T.

BACKGROUND: There is a need for improved worldwide access to tissue iron quantification using T2* cardiovascular magnetic resonance (CMR). One route to facilitate this would be simple in-line T2* analysis widely available on MR scanners. We therefore compared our clinically validated and established T2* method at Royal Brompton Hospital (RBH T2*) against a novel work-in-progress (WIP) sequence with in-line T2* measurement from Siemens (WIP T2*). METHODS: Healthy volunteers (n = 22) and patients with iron overload (n = 78) were recruited (53 males, median age 34 years). A 1.5 T study (Magnetom Avanto, Siemens) was performed on all subjects. The same mid-ventricular short axis cardiac slice and transaxial slice through the liver were used to acquire both RBH T2* images and WIP T2* maps for each participant. Cardiac white blood (WB) and black blood (BB) sequences were acquired. Intraobserver, interobserver and interstudy reproducibility were measured on the same data from a subset of 20 participants. RESULTS: Liver T2* values ranged from 0.8 to 35.7 ms (median 5.1 ms) and cardiac T2* values from 6.0 to 52.3 ms (median 31 ms). The coefficient of variance (CoV) values for direct comparison of T2* values by RBH and WIP were 6.1-7.8 % across techniques. Accurate delineation of the septum was difficult on some WIP T2* maps due to artefacts. The inability to manually correct for noise by truncation of erroneous later echo times led to some overestimation of T2* using WIP T2* compared with the RBH T2*. Reproducibility CoV results for RBH T2* ranged from 1.5 to 5.7 % which were better than the reproducibility of WIP T2* values of 4.1-16.6 %. CONCLUSIONS: Iron estimation using the T2* CMR sequence in combination with Siemens' in-line data processing is generally satisfactory and may help facilitate global access to tissue iron assessment. The current automated T2* map technique is less good for tissue iron assessment with noisy data at low T2* values.

T1 at 1.5T and 3T compared with conventional T2* at 1.5T for cardiac siderosis.

BACKGROUND: Myocardial black blood (BB) T2* relaxometry at 1.5T provides robust, reproducible and calibrated non-invasive assessment of cardiac iron burden. In vitro data has shown that like T2*, novel native Modified Look-Locker Inversion recovery (MOLLI) T1 shortens with increasing tissue iron. The relative merits of T1 and T2* are largely unexplored. We compared the established 1.5T BB T2* technique against native T1 values at 1.5T and 3T in iron overload patients and in normal volunteers. METHODS: A total of 73 subjects (42 male) were recruited, comprising 20 healthy volunteers (controls) and 53 patients (thalassemia major 22, sickle cell disease 9, hereditary hemochromatosis 9, other iron overload conditions 13). Single mid-ventricular short axis slices were acquired for BB T2* at 1.5T and MOLLI T1 quantification at 1.5T and 3T. RESULTS: In healthy volunteers, median T1 was 1014 ms (full range 939-1059 ms) at 1.5T and modestly increased to 1165ms (full range 1056-1224 ms) at 3T. All patients with significant cardiac iron overload (1.5T T2* values <20 ms) had T1 values <939 ms at 1.5T, and <1056 ms at 3T. Associations between T2* and T1 were found to be moderate with y =377 · x(0.282) at 1.5T (R(2) = 0.717), and y =406 · x(0.294) at 3T (R(2) = 0.715). Measures of reproducibility of T1 appeared superior to T2*. CONCLUSIONS: T1 mapping at 1.5T and at 3T can identify individuals with significant iron loading as defined by the current gold standard T2* at 1.5T. However, there is significant scatter between results which may reflect measurement error, but it is also possible that T1 interacts with T2*, or is differentially sensitive to aspects of iron chemistry or other biology. Hurdles to clinical implementation of T1 include the lack of calibration against human myocardial iron concentration, no demonstrated relation to cardiac outcomes, and variation in absolute T1 values between scanners, which makes inter-centre comparisons difficult. The relative merits of T1 at 3T versus T2* at 3T require further consideration.

Effect of induced LV dyssynchrony by right ventricular apical pacing on all-cause mortality and heart failure hospitalization rates at long-term follow-up.

BACKGROUND: Right ventricular apical (RVA) pacing may induce left ventricular (LV) dyssynchrony. The long-term prognostic implications of induction of LV dyssynchrony were retrospectively evaluated in a cohort of patients who underwent RVA pacing. METHODS: A total of 169 patients (62 ± 13 years, 69% male) with high RVA pacing burden were included. Echocardiographic evaluation of LV volumes, ejection fraction, and dyssynchrony were performed before and after device implantation. LV dyssynchrony was assessed by 2-dimensional radial strain speckle tracking echocardiography. Based on the median LV dyssynchrony value after RVA pacing, the patient population was dichotomized (induced and noninduced LV dyssynchrony groups) and was followed up for the occurrence of all-cause mortality and heart failure (HF) hospitalization. RESULTS: Baseline mean LV ejection fraction was 51 ± 11%. Median LV dyssynchrony value was 40 ms (12-85 ms) before RVA pacing and increased to 91 ms (81-138 ms) after a median of 13 months (3-26 months) after RVA pacing. Median follow-up duration was 70 months (interquartile range 42-96 months). Patients with induced LV dyssynchrony, defined as LV dyssynchrony value superior to the median at follow-up (≥91 ms), showed higher mortality rates (5% and 27% vs. 1% and 3% at 3 and 5 years follow-up; log-rank P = 0.003) and HF hospitalization rates (18% and 24% vs. 3% and 4% at 3 and 5 years follow-up; log-rank P < 0.001) than patients with LV dyssynchrony <91 ms after RVA pacing. A multivariate model was developed to identify independent associates of a combined endpoint of all-cause mortality or HF hospitalization. Induction of LV dyssynchrony was independently associated with increased risk of combined endpoint (HR [95% CI]: 3.369 [1.732-6.553], P < 0.001). CONCLUSION: Induction of LV dyssynchrony by RVA pacing is associated with worse long-term mortality and increased HF hospitalization rates.

Effect of atrioventricular and ventriculoventricular delay optimization on clinical and echocardiographic outcomes of patients treated with cardiac resynchronization therapy: a meta-analysis.

BACKGROUND: Optimization of atrioventricular (AV) and ventriculoventricular (VV) delays of cardiac resynchronization therapy (CRT) devices maximizes left ventricular filling and stroke volume. However, the incremental value of these optimizations over empiric device programming remains unclear. The objective of this analysis was to perform a systematic review and meta-analysis of the effects of AV and VV delay optimization on clinical and echocardiographic end points of patients with heart failure treated with CRT. METHODS: A standardized search strategy was performed and identified 12 trials comparing AV and/or VV delay optimization and conventional CRT device programming and their effects on various clinical and echocardiographic outcomes. Pooled odds ratios were analyzed using random-effect meta-analysis with Mantel-Haenszel method. RESULTS: Combined data from a total of 4,356 patients with heart failure treated with CRT showed no differences in clinical or echocardiographic outcomes between patients who underwent AV and/or VV delay optimization and patients who underwent empiric device programming (Mantel-Haenszel odds ratio 0.86 [95% CI 0.68-1.09], P value for overall effect = .21 by intention-to-treat analysis). CONCLUSION: The current literature suggests that routine AV and/or VV delay optimization has a neutral effect on clinical and echocardiographic outcomes based on pooled data from randomized and nonrandomized studies. Standardization of patient selection and optimization timing and method may help to further define the role of CRT device optimization.

Clinical, echocardiographic, and neurohormonal response to cardiac resynchronization therapy: are they interchangeable?

BACKGROUND: The relationship between changes in N-terminal pro-brain natriuretic peptide (NT-proBNP) and echocardiographic or clinical definitions of response to cardiac resynchronization therapy (CRT) has not been evaluated. The aims of the present evaluation were to assess: (1) the relationship between changes in NT-proBNP after 6 months of CRT and clinical and echocardiographic responses; (2) the association between NT-proBNP changes and long-term outcome. METHODS: In 170 patients treated with CRT (age 61 ± 11 years, 75% male), clinical and echocardiographic parameters and circulating NT-proBNP levels were assessed at baseline and 6 months after CRT. At 6 months follow-up, improvement in New York Heart Association class ≥ 1 point, decrease in left ventricular end-systolic volume ≥ 15%, and decrease in NT-proBNP ≥ 15% defined clinical, echocardiographic, and neurohormonal CRT response, respectively. All-cause mortality data were collected and related to neurohormonal response. RESULTS: Neurohormonal, echocardiographic, and clinical response rates were 54%, 58%, and 66%, respectively. The majority of patients (71%) showing echocardiographic response had NT-proBNP reduction ≥ 15%. In contrast, only 58% of patients who showed clinical response also had NT-proBNP reduction ≥ 15%. During a median follow-up of 32 months, 40 patients died. Patients with neurohormonal response demonstrated a superior long-term outcome compared to patients without neurohormonal response (log-rank P = 0.02). CONCLUSIONS: NT-proBNP reduction ≥ 15% showed better agreement with echocardiographic response compared to clinical response. Neurohormonal response was associated with superior long-term outcome compared to insufficient reduction in NT-proBNP levels.

Predictors of long-term benefit of cardiac resynchronization therapy in patients with right bundle branch block.

AIMS: The aims of this study were: (i) to characterize consecutive cardiac resynchronization therapy (CRT) recipients with right bundle branch block (RBBB) in comparison with left bundle branch block (LBBB) and (ii) to identify independent predictors of long-term outcome among CRT recipients with RBBB. The presence of RBBB has been associated with poorer prognosis after CRT compared with LBBB; however, little is known about the differences in cardiac mechanics between RBBB and LBBB patients. Furthermore, predictors of favourable outcome after CRT in patients with RBBB have not been identified. METHODS AND RESULTS: Five hundred and sixty-one consecutive CRT recipients (89 with RBBB and 472 with LBBB) underwent echocardiography before and 6 months after CRT to determine left ventricular (LV) size and function, and interventricular and LV dyssynchrony (as measured by tissue Doppler imaging). Long-term follow-up to identify a composite endpoint of all-cause mortality or heart failure hospitalization was available. Right bundle branch block patients exhibited a higher prevalence of male gender, ischaemic heart disease, atrial fibrillation, and lower exercise capacity when compared with LBBB patients, despite smaller LV volumes. In addition, the extent of both interventricular and LV dyssynchrony was less in RBBB patients. Six months after CRT, RBBB patients also showed limited LV reverse remodelling. At long-term follow-up, LV dyssynchrony and mitral regurgitation were identified as independent predictors of all-cause mortality or heart failure hospitalization among RBBB patients. CONCLUSION: Left ventricular dyssynchrony may be an important determinant of outcome following CRT in patients with RBBB and may help in the selection of CRT candidates.

Effect of cardiac resynchronization therapy in patients without left intraventricular dyssynchrony.

AIMS: To evaluate the effects of cardiac resynchronization therapy (CRT) on long-term survival of patients without baseline left ventricular (LV) mechanical dyssynchrony. METHODS AND RESULTS: A total of 290 heart failure patients (age 67 ± 10 years, 77% males) without significant baseline LV dyssynchrony (<60 ms as assessed with tissue Doppler imaging) were treated with CRT. Patients were divided according to the median LV dyssynchrony measured after 48 h of CRT into two groups. All-cause mortality was compared between the subgroups. In addition, the all-cause mortality rates of these subgroups were compared with the all-cause mortality of 290 heart failure patients treated with CRT who showed significant LV dyssynchrony (≥60 ms) at baseline. In the group of patients without significant LV dyssynchrony, median LV dyssynchrony increased from 22 ms (inter-quartile range 16-34 ms) at baseline to 40 ms (24-56 ms) 48 h after CRT. The cumulative mortality rates at 1-, 2-, and 3-year follow-up of patients with LV dyssynchrony ≥40 ms 48 h after CRT implantation were significantly higher when compared with patients with LV dyssynchrony <40 ms (10, 17, and 23 vs. 3, 8, and 10%, respectively; log-rank P< 0.001). Finally, the cumulative mortality rates at 1-, 2-, and 3-year follow-up of patients with baseline LV dyssynchrony were 3, 8, and 11%, respectively (log-rank P= 0.375 vs. patients with LV dyssynchrony <40 ms). Induction of LV dyssynchrony after CRT was an independent predictor of mortality (hazard ratio: 1.247; P= 0.009). CONCLUSION: In patients without significant LV dyssynchrony, the induction of LV dyssynchrony after CRT may be related to a less favourable long-term outcome.

Alterations in multidirectional myocardial functions in patients with aortic stenosis and preserved ejection fraction: a two-dimensional speckle tracking analysis.

AIMS: To identify changes in multidirectional strain and strain rate (SR) in patients with aortic stenosis (AS). METHODS AND RESULTS: A total of 420 patients (age 66.1 ± 14.5 years, 60.7% men) with aortic sclerosis, mild, moderate, and severe AS with preserved left ventricular (LV) ejection fraction [(EF), ≥50%] were included. Multidirectional strain and SR imaging were performed by two-dimensional speckle tracking. Patients were more likely to be older (P < 0.001) and at a worse New York Heart Association functional class (P < 0.001) with increasing AS severity. There was a progressive stepwise impairment in longitudinal, circumferential, and radial strain and SR with increasing AS severity (all P < 0.001). The myocardial dysfunction appeared to start in the subendocardium with mild AS, to mid-wall dysfunction with moderate AS, and eventually transmural dysfunction with severe AS. Aortic valve area, as a measure of AS severity, was an independent determinant of multidirectional strain and SR on multiple linear regressions. CONCLUSIONS: Patients with AS have evidence of subclinical myocardial dysfunction early in the disease process despite normal LVEF. The myocardial dysfunction appeared to start in the subendocardium and progressed to transmural dysfunction with increasing AS severity. Symptomatic moderate and severe AS patients had more impaired multidirectional myocardial functions compared with asymptomatic patients.

Clinical and echocardiographic predictors of nonresponse to cardiac resynchronization therapy.

BACKGROUND: Lack of response to cardiac resynchronization therapy (CRT) ranges between 30% to 40% of heart failure (HF) patients. The present study aimed to evaluate the clinical and echocardiographic determinants of nonresponse to CRT. METHODS: A total of 581 patients (66.4 ± 10.0 years, 77.9% male) with advanced HF scheduled for CRT implantation were included. Clinical and echocardiographic evaluations were performed at baseline and 6 months of follow-up. Nonresponse was defined as no improvement in the New York Heart Association functional class, death from worsening HF or heart transplantation, and <15% reduction in left ventricular (LV) end-systolic volume. RESULTS: At 6 months of follow-up, 254 patients (44%) did not respond to CRT. The nonresponders were more frequently male (81.9% vs 74.3%, P = .030) and had ischemic cardiomyopathy (69.7% vs 53.2%, P < .001), shorter QRS duration (150.6 ± 29.9 milliseconds vs 156.0 ± 32.5 milliseconds, P = .041), worse New York Heart Association functional class (2.8 ± 0.6 vs 2.7 ± 0.6, P = .008) and shorter 6-minute walk distance (297.9 ± 110.7 m vs 331.8 ± 112.6 m, P = .001), larger left atrial volumes (44.9 ± 16.9 mL/m(2) vs 40.9 ± 17.6 mL/m(2), P = .006), less baseline LV dyssynchrony (56.2 ± 41.3 milliseconds vs 69.1 ± 39.9 milliseconds, P < .001), and, more frequently, anterior LV lead position (12.4% vs 4.0%, P = .007). At multivariate analysis, only the ischemic etiology of HF (odds ratio [OR] 2.264, P = .005), shorter 6-minute walk distance at baseline (OR 0.998, P = .030), less baseline LV dyssynchrony (OR 0.989, P < .001), and anterior LV lead position (OR 3.713, P < .010) remained independent predictors of nonresponse to CRT. CONCLUSIONS: Ischemic etiology of HF, shorter baseline 6-minute walk distance, less baseline LV dyssynchrony, and anterior LV lead position are independent determinants of nonresponse to CRT.

Effects of Low-Load/High-Repetition Resistance Training on Exercise Capacity, Health Status, and Limb Muscle Adaptation in Patients With Severe COPD: A Randomized Controlled Trial.

BACKGROUND: Training volume is paramount in the magnitude of physiological adaptations following resistance training. However, patients with severe COPD are limited by dyspnea during traditional two-limb low-load/high-repetition resistance training (LLHR-RT), resulting in suboptimal training volumes. During a single exercise session, single-limb LLHR-RT decreases the ventilatory load and enables higher localized training volumes compared with two-limb LLHR-RT. RESEARCH QUESTION: Does single-limb LLHR-RT lead to more profound effects compared with two-limb LLHR-RT on exercise capacity (6-min walk distance [6MWD]), health status, muscle function, and limb adaptations in patients with severe COPD? STUDY DESIGN AND METHODS: Thirty-three patients (mean age 66 ± 7 years; FEV1 39 ± 10% predicted) were randomized to 8 weeks of single- or two-limb LLHR-RT. Exercise capacity (6MWD), health status, and muscle function were compared between groups. Quadriceps muscle biopsy specimens were collected to examine physiological responses. RESULTS: Single-limb LLHR-RT did not further enhance 6MWD compared with two-limb LLHR-RT (difference, 14 [-12 to 39 m]. However, 73% in the single-limb group exceeded the known minimal clinically important difference of 30 m compared with 25% in the two-limb group (P = .02). Health status and muscle function improved to a similar extent in both groups. During training, single-limb LLHR-RT resulted in a clinically relevant reduction in dyspnea during training compared with two-limb LLHR-RT (-1.75; P = .01), but training volume was not significantly increased (23%; P = .179). Quadriceps muscle citrate synthase activity (19%; P = .03), hydroxyacyl-coenzyme A dehydrogenase protein levels (32%; P < .01), and capillary-to-fiber ratio (41%; P < .01) were increased compared with baseline after pooling muscle biopsy data from all participants. INTERPRETATION: Single-limb LLHR-RT did not further increase mean 6MWD compared with two-limb LLHR-RT, but it reduced exertional dyspnea and enabled more people to reach clinically relevant improvements in 6MWD. Independent of execution strategy, LLHR-RT improved exercise capacity, health status, muscle endurance, and enabled several physiological muscle adaptations, reducing the negative consequences of limb muscle dysfunction in COPD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02283580; URL: www.clinicaltrials.gov.

A novel cardiovascular magnetic resonance risk score for predicting mortality following surgical aortic valve replacement.

The increasing prevalence of patients with aortic stenosis worldwide highlights a clinical need for improved and accurate prediction of clinical outcomes following surgery. We investigated patient demographic and cardiovascular magnetic resonance (CMR) characteristics to formulate a dedicated risk score estimating long-term survival following surgery. We recruited consecutive patients undergoing CMR with gadolinium administration prior to surgical aortic valve replacement from 2003 to 2016 in two UK centres. The outcome was overall mortality. A total of 250 patients were included (68 ± 12 years, male 185 (60%), with pre-operative mean aortic valve area 0.93 ± 0.32cm2, LVEF 62 ± 17%) and followed for 6.0 ± 3.3 years. Sixty-one deaths occurred, with 10-year mortality of 23.6%. Multivariable analysis showed that increasing age (HR 1.04, P = 0.005), use of antiplatelet therapy (HR 0.54, P = 0.027), presence of infarction or midwall late gadolinium enhancement (HR 1.52 and HR 2.14 respectively, combined P = 0.12), higher indexed left ventricular stroke volume (HR 0.98, P = 0.043) and higher left atrial ejection fraction (HR 0.98, P = 0.083) associated with mortality and developed a risk score with good discrimination. This is the first dedicated risk prediction score for patients with aortic stenosis undergoing surgical aortic valve replacement providing an individualised estimate for overall mortality. This model can help clinicians individualising medical and surgical care.Trial Registration ClinicalTrials.gov Identifier: NCT00930735 and ClinicalTrials.gov Identifier: NCT01755936.

Prognostic Significance of Nonischemic Myocardial Fibrosis in Patients With Normal LV Volumes and Ejection-Fraction.

OBJECTIVES: This study aims to investigate the prognostic significance of late gadolinium enhancement (LGE) in patients without coronary artery disease and with normal range left ventricular (LV) volumes and ejection fraction. BACKGROUND: Nonischemic patterns of LGE with normal LV volumes and ejection fraction are increasingly detected on cardiovascular magnetic resonance, but their prognostic significance, and consequently management, is uncertain. METHODS: Patients with midwall/subepicardial LGE and normal LV volumes, wall thickness, and ejection fraction on cardiovascular magnetic resonance were enrolled and compared to a control group without LGE. The primary outcome was actual or aborted sudden cardiac death (SCD). RESULTS: Of 748 patients enrolled, 401 had LGE and 347 did not. The median age was 50 years (interquartile range: 38-61 years), LV ejection fraction 66% (interquartile range: 62%-70%), and 287 (38%) were women. Scan indications included chest pain (40%), palpitation (33%) and breathlessness (13%). No patient experienced SCD and only 1 LGE+ patient (0.13%) had an aborted SCD in the 11th follow-up year. Over a median of 4.3 years, 30 patients (4.0%) died. All-cause mortality was similar for LGE+/- patients (3.7% vs 4.3%; P = 0.71) and was associated with age (HR: 2.04 per 10 years; 95% CI: 1.46-2.79; P < 0.001). Twenty-one LGE+ and 4 LGE- patients had an unplanned cardiovascular hospital admission (HR: 7.22; 95% CI: 4.26-21.17; P < 0.0001). CONCLUSIONS: There was a low SCD risk during long-term follow-up in patients with LGE but otherwise normal LV volumes and ejection fraction. Mortality was driven by age and not LGE presence, location, or extent, although the latter was associated with greater cardiovascular hospitalization for suspected myocarditis and symptomatic ventricular tachycardia.

Prevalence and characteristics of patients with clinical improvement but not significant left ventricular reverse remodeling after cardiac resynchronization therapy.

BACKGROUND: Although most patients who improve in clinical status after cardiac resynchronization therapy (CRT) also show a significant left ventricular (LV) reverse remodeling, some patients do not show echocardiographic improvement. The aim of the present study was to evaluate the degree of agreement between clinical and echocardiographic response to CRT in a large cohort of heart failure patients, and to evaluate the characteristics of patients with clinical response but without echocardiographic response. METHODS: In 440 consecutive heart failure patients (mean age 66 ± 11 years, 81% men) treated with CRT, agreement between clinical and echocardiographic responses at 6 months of follow-up were evaluated. The combined clinical response was defined as: ≥1-point New York Heart Association functional class improvement or ≥15% increase in 6-minute walk test. Echocardiographic response was defined by a reduction in LV end-systolic volume (LVESV) ≥15%. RESULTS: At 6 months of follow-up, clinical response was observed in 84% (n = 370) of the patients. Significant reduction in LVESV was noted in 63% (n = 276). The majority of patients who improved clinically did show LV reverse remodeling (72%, n = 268). Importantly, 28% (n = 102) of patients who improved clinically did not show significant LV reverse remodeling. The patients with clinical response but without echocardiographic response had more often ischemic heart failure as compared to patients with positive clinical and echocardiographic response (69.6% vs 57.5%; P = .021). Moreover, patients with such discordant responses had more narrow QRS complex (148 ± 31 vs 159 ± 31 milliseconds; P = .004), and showed less LV dyssynchrony than patients with concordant positive responses (90 ± 77 vs 171 ± 105 milliseconds; P < .001). CONCLUSIONS: Although there is a good concordance between echocardiographic and clinical response to CRT, up to 28% of the population experienced clinical response without significant LV reverse remodeling. Subjects with such discrepant responses have more frequently ischemic heart failure and show more narrow QRS complex and less LV dyssynchrony than patients with both clinical and echocardiographic response.

Evolution of high-sensitivity troponin-T and echocardiography parameters in patients undergoing high efficiency on-line hemodiafiltration versus conventional low-flux hemodialysis.

BACKGROUND AND OBJECTIVES: On-line hemodiafiltration (HDF) has been associated with better inflammatory markers profile and survival than low-flux hemodialysis (HD). This study aimed at determining the effect of HDF vs HD on hs-TnT and echocardiography parameters evolution at one year follow-up. METHOD: Patients were randomized from 2007 to 2013 to HD or HDF in accordance with the CONvective TRAnsport STudy protocol initially as part of the Montreal cohort and subsequently as part of a local cohort. Pre-dialysis hs-TnT were analyzed at baseline and 1-year follow-up. RESULTS: A total of 54 HDF patients and 59 HD patients were included. At baseline, median hs-TnT value was 49 ng/L (IQR 31-89) in the HDF group vs. 60 ng/L (36-96) in the HD group (p = 0.370). At one year follow-up, median hs-TnT remained stable in the HDF group (p = 0.707 vs. baseline), but significantly increased to 62 ng/L (40-104) in the HD group (p = 0.021 vs. baseline). The median variation (delta) in hs-TnT values was -3 ng/L (IQR -7-+8) in the HDF group vs. +8 ng/L (-5 -+25) in the HD group (p = 0.042). In the HDF group, LVEF increased from 60.0% (IQR 55.0-65.0) at baseline to 65.0% (60.0-65.5) at 1-year follow-up (p = 0.040) whereas it remained stable in the HD group (LVEF of 60.0% [IQR 55.0-65.0] at baseline and 65.0% [55.0-65.0] at 1-year follow-up [p = 0.312]). CONCLUSIONS: High-efficiency HDF is associated with stability in hs-TnT values, whereas low-flux HD is associated with significant increase in hs-TnT levels.

Early-onset emphysema in a large French-Canadian family: a genetic investigation.

BACKGROUND: Inherited mutations in SERPINA1 coding for the alpha-1 antitrypsin (A1AT) protein is the only well established cause of hereditary emphysema. We aimed to identify the genetic ecause of early-onset emphysema in a five-generation French-Canadian family free of A1AT deficiency. METHODS: Between Dec 1, 2014, and April 1, 2017, we investigated 63 individuals from a single pedigree, including 55 with DNA available. Whole-exome sequencing was done in a convenience sample of 14 individuals (nine with unambiguous expression of the typical form of emphysema observed in this family). We filtered rare non-synonymous variants that were predicted to be damaging to identify a single mutation in a biologically relevant gene shared among all affected individuals. We assessed segregation with the disease in additional family members who were not evaluated by whole-exome sequencing. The effect of the candidate variant on protein function was evaluated in vitro. mRNA and protein expression of the candidate gene was assessed in lung samples from unrelated individuals (n=80) with and without emphysema who underwent surgery for lung cancer at our institution. FINDINGS: A rare in-silico-predicted damaging variant (Ala455Thr) was identified in the protein tyrosine phosphatase non-receptor type 6 (PTPN6) gene, also known as SHP-1, an important negative regulator of immune processes. 20 (95%) of 21 family members with computed tomography-confirmed emphysema were heterozygotes for the Ala455Thr mutation. No Thr455 homozygotes were identified. Emphysema or reduced diffusion capacity was observed in all heterozygotes with a history of smoking. Incomplete penetrance of the mutation and variable degrees of emphysema were observed in never smokers. The Ala455Thr mutation in SHP-1 caused a reduction in phosphatase activity in vitro, confirming the loss-of-function effect of the mutation. mRNA and protein expression of PTPN6 were upregulated in smokers, but were not associated with emphysema or severity of airflow limitation. INTERPRETATION: An inherited variant in the gene PTPN6 is responsible for early-onset emphysema in this family. To our knowledge, this is the second form of hereditary emphysema since the discovery of A1AT deficiency in the 1960s, representing a breakthrough in understanding the genetics and pathogenesis of emphysema. FUNDING: Fonds sur les maladies respiratoires J.-D. Bégin-P.-H. Lavoie de l'Université Laval, Fondation de l'Institut universitaire de cardiologie et de pneumologie de Québec, CIHR/GSK research Chair on COPD at Université Laval, and the Canadian Institutes of Health Research.

Intracardiac Vortex Dynamics by High-Frame-Rate Doppler Vortography-In Vivo Comparison With Vector Flow Mapping and 4-D Flow MRI.

Recent studies have suggested that intracardiac vortex flow imaging could be of clinical interest to early diagnose the diastolic heart function. Doppler vortography has been introduced as a simple color Doppler method to detect and quantify intraventricular vortices. This method is able to locate a vortex core based on the recognition of an antisymmetric pattern in the Doppler velocity field. Because the heart is a fast-moving organ, high frame rates are needed to decipher the whole blood vortex dynamics during diastole. In this paper, we adapted the vortography method to high-frame-rate echocardiography using circular waves. Time-resolved Doppler vortography was first validated in vitro in an ideal forced vortex. We observed a strong correlation between the core vorticity determined by high-frame-rate vortography and the ground-truth vorticity. Vortography was also tested in vivo in ten healthy volunteers using high-frame-rate duplex ultrasonography. The main vortex that forms during left ventricular filling was tracked during two-three successive cardiac cycles, and its core vorticity was determined at a sampling rate up to 80 duplex images per heartbeat. Three echocardiographic apical views were evaluated. Vortography-derived vorticities were compared with those returned by the 2-D vector flow mapping approach. Comparison with 4-D flow magnetic resonance imaging was also performed in four of the ten volunteers. Strong intermethod agreements were observed when determining the peak vorticity during early filling. It is concluded that high-frame-rate Doppler vortography can accurately investigate the diastolic vortex dynamics.

Chemical contaminants (trace metals, persistent organic pollutants) in albacore tuna from western Indian and south-eastern Atlantic Oceans: Trophic influence and potential as tracers of populations.

Albacore tuna (Thunnus alalunga) is a highly commercial fish species harvested in the world's Oceans. Identifying the potential links between populations is one of the key tools that can improve the current management across fisheries areas. In addition to characterising populations' contamination state, chemical compounds can help refine foraging areas, individual flows and populations' structure, especially when combined with other intrinsic biogeochemical (trophic) markers such as carbon and nitrogen stable isotopes. This study investigated the bioaccumulation of seven selected trace metals - chromium, nickel, copper (Cu), zinc (Zn), cadmium (Cd), mercury (Hg) and lead - in the muscle of 443 albacore tunas, collected over two seasons and/or years in the western Indian Ocean (WIO: Reunion Island and Seychelles) and in the south-eastern Atlantic Ocean (SEAO: South Africa). The main factor that explained metal concentration variability was the geographic origin of fish, rather than the size and the sex of individuals, or the season/year of sampling. The elements Cu, Zn, Cd and Hg indicated a segregation of the geographic groups most clearly. For similar sized-individuals, tunas from SEAO had significantly higher concentrations in Cu, Zn and Cd, but lower Hg concentrations than those from WIO. Information inferred from the analysis of trophic markers (δ13C, δ15N) and selected persistent organic pollutants, as well as information on stomach contents, corroborated the geographical differences obtained by trace metals. It also highlighted the influence of trophic ecology on metal bioaccumulation. Finally, this study evidenced the potential of metals and chemical contaminants in general as tracers, by segregating groups of individuals using different food webs or habitats, to better understand spatial connectivity at the population scale. Limited flows of individuals between the SEAO and the WIO are suggested. Albacore as predatory fish also provided some information on environmental and food web chemical contamination in the different study areas.