Long-term outcomes of cardiac resynchronization therapy in adult congenital heart disease

Background and Aims: Randomized, controlled trials of cardiac resynchronization therapy (CRT) excluded patients with adult congenital heart disease (ACHD). We sought to explore long-term clinical outcomes. Methods and Results: In this single-center, observational study, events were collected from hospital records on patients with structural ACHD (sACHD) and adults with ischemic (ICM) or nonischemic (NICM) cardiomyopathy undergoing CRT. Patients with sACHD (n = 23, age: 41.6 ± 13.5 years [mean ± standard deviation]) and adults with ICM (n = 533) or NICM (n = 458) were followed-up for 4.1 years (median; interquartile range: 2.2-6.1). Total mortality was 5/23 (21.7%; 4.4 per 100 person-years) in sACHD, 221/533 (41.5%; 11.8 per 100 person-years) in ICM, and 154/458 (33.6%; 9.7 per 100 person-years) in NICM. In univariate analyses, total mortality in sACHD was lower than in ICM (hazard ratio [HR]: 0.38; 95% confidence interval [CI] 0.15-0.91), but similar to NICM (HR: 0.48, 95% CI 0.20-1.16). Cardiac mortality in sACHD was similar to ICM (HR: 0.78, 95% CI 0.32-1.92) and NICM (HR: 1.12, 95% CI 0.45-2.78). Heart failure (HF) hospitalization rates were similar to ICM (HR: 0.44, 95% CI 0.11-1.77) and NICM (HR: 0.75, 95% CI 0.18-3.08). In multivariate analyses, no differences emerged in total mortality, cardiac mortality, or HF hospitalization between sACHD and NICM or ICM, after adjustment for age, sex, New York Heart Association class, diabetes, atrial rhythm, QRS duration, QRS morphology, systemic ventricular ejection fraction, and medical therapy. Conclusion: Total mortality, cardiac mortality, and HF hospitalization after CRT in patients with sACHD was similar to adults with ICM or NICM

Survival after cardiac resynchronization therapy: results from 50 084 implantations

Aims Randomized controlled trials have shown that cardiac resynchronization therapy (CRT) prolongs survival in patients with heart failure. No studies have explored survival after CRT in relation to individuals in the general population (relative survival, RS). We sought to determine observed and RS after CRT in a nationwide cohort undergoing CRT. Methods and results A national administrative database was used to quantify observed mortality for patients undergoing CRT. Relative survival (RS) was quantified using life tables. In 50 084 patients [age 72.1 ± 11.6 years (mean ± standard deviation)] undergoing CRT with (CRT-D) (n = 25 273) or without (CRT-P) defibrillation (n = 24 811) over 8.8 years (median follow-up 2.7 years, interquartile range 1.3–4.8), expected survival decreased with age. Device type, male sex, ischaemic heart disease, diabetes, and chronic kidney disease predicted excess mortality. In multivariate analyses, excess mortality (analogue of RS) was lower after CRT-D than after CRT-P in all patients [adjusted hazard ratio (aHR) 0.80, 95% confidence interval (CI) 0.76–0.84] as well as in subgroups with (aHR 0.79, 95% CI 0.74–0.84) or without (aHR 0.82, 95% CI 0.74–0.91) ischaemic heart disease. A Charlson Comorbidity Index (CCI) ≥3 portended a higher excess mortality (aHR 3.04, 95% CI 2.76–3.34). Relative survival was higher in 2015–2017 than in 2009–2011 (aHR 0.64, 95% CI 0.59–0.69). Conclusion Reference RS data after CRT is presented. Sex, ischaemic heart disease, diabetes, chronic kidney disease, and CCI were major determinants of RS after CRT. CRT-D was associated with a higher RS than CRT-P in patients with or without ischaemic heart disease. Relative survival after CRT improved from 2009 to 2017

Systematic review of the incidence and clinical risk predictors of atrial fibrillation and permanent pacemaker implantation for bradycardia in Fabry disease

Introduction Fabry disease (FD) is an X-linked lysosomal storage disorder caused by enzyme deficiency, leading to glycosphingolipid accumulation. Cardiac accumulation triggers local tissue injury, electrical instability and arrhythmia. Bradyarrhythmia and atrial fibrillation (AF) incidence are reported in up to 16% and 13%, respectively.Objective We conducted a systematic review evaluating AF burden and bradycardia requiring permanent pacemaker (PPM) implantation and report any predictive risk factors identified.Methods We conducted a literature search on studies in adults with FD published from inception to July 2019. Study outcomes included AF or bradycardia requiring therapy. Databases included Embase, Medline, PubMed, Web of Science, CINAHL and Cochrane. The Risk of Bias Agreement tool for Non-Randomised Studies (RoBANS) was utilised to assess bias across key areas.Results 11 studies were included, eight providing data on AF incidence or PPM implantation. Weighted estimate of event rates for AF were 12.2% and 10% for PPM. Age was associated with AF (OR 1.05–1.20 per 1-year increase in age) and a risk factor for PPM implantation (composite OR 1.03). Left ventricular hypertrophy (LVH) was associated with AF and PPM implantation.Conclusion Evidence supporting AF and bradycardia requiring pacemaker implantation is limited to single-centre studies. Incidence is variable and choice of diagnostic modality plays a role in detection rate. Predictors for AF (age, LVH and atrial dilatation) and PPM (age, LVH and PR/QRS interval) were identified but strength of association was low. Incidence of AF and PPM implantation in FD are variably reported with arrhythmia burden likely much higher than previously thought.PROSPERO database CRD42019132045

The Functional Basis for Hemophagocytic Lymphohistiocytosis in a Patient with Co-inherited Missense Mutations in the Perforin (PFN1) Gene

About 30% of cases of the autosomal recessive immunodeficiency disorder hemophagocytic lymphohistiocytosis are believed to be caused by inactivating mutations of the perforin gene. We expressed perforin in rat basophil leukemia cells to define the basis of perforin dysfunction associated with two mutations, R225W and G429E, inherited by a compound heterozygote patient. Whereas RBL cells expressing wild-type perforin (67 kD) efficiently killed Jurkat target cells to which they were conjugated, the substitution to tryptophan at position 225 resulted in expression of a truncated (∼45 kD) form of the protein, complete loss of cytotoxicity, and failure to traffic to rat basophil leukemia secretory granules. By contrast, G429E perforin was correctly processed, stored, and released, but the rat basophil leukemia cells possessed reduced cytotoxicity. The defective function of G429E perforin mapped downstream of exocytosis and was due to its reduced ability to bind lipid membranes in a calcium-dependent manner. This study elucidates the cellular basis for perforin dysfunctions in hemophagocytic lymphohistiocytosis and provides the means for studying structure–function relationships for lymphocyte perforin

Improved prognosis after cardiac resynchronization therapy over a decade

Aims The past decade has seen an increased delivery of cardiac resynchronization therapy (CRT) for patients with heart failure (HF). We explored whether clinical outcomes after CRT have changed from the perspective of an entire public healthcare system. Methods and results A national database covering the population of England (56.3 million in 2019) was used to explore clinical outcomes after CRT from 2010 to 2019. A total of 64 698 consecutive patients (age 71.4 ± 11.7 years; 74.8% male) underwent CRT-defibrillation [n = 32 313 (49.7%)] or CRT-pacing [n = 32 655 (50.3%)] implantation. From 2010–2011 to 2018–2019, there was a 76% increase in CRT implantations. During the same period, the proportion of patients with hypertension (59.6–73.4%), diabetes (26.5–30.8%), and chronic kidney disease (8.62–22.5%) increased, as did the Charlson comorbidity index (CCI ≥ 3 from 20.0% to 25.1%) (all P < 0.001). Total mortality decreased at 30 days (1.43–1.09%) and 1 year (9.51–8.13%) after implantation (both P < 0.001). At 2 years, total mortality [hazard ratio (HR): 0.72; 95% confidence interval (CI) 0.69–0.76] and total mortality or HF hospitalization (HR: 0.59; 95% CI 0.57–0.62) decreased from 2010–2011 to 2018–2019, after correction for age, race, sex, device type (CRT-defibrillation or pacing), comorbidities (hypertension, diabetes, chronic kidney disease, and myocardial infarction), or the CCI (HR: 0.81; 95% CI 0.77–0.85). Conclusions From the perspective of an entire public health system, survival has improved and HF hospitalizations have decreased after CRT implantation over the past decade. This prognostic improvement has occurred despite an increasing comorbidity burden

Timing of cardiac resynchronization therapy implantation

AbstractAimsThe optimum timing of cardiac resynchronization therapy (CRT) implantation is unknown. We explored long-term outcomes after CRT in relation to the time interval from a first heart failure hospitalization (HFH) to device implantation.Methods and resultsA database covering the population of England (56.3 million in 2019) was used to quantify clinical outcomes after CRT implantation in relation to first HFHs. From 2010 to 2019, 64 968 patients [age: 71.4 ± 11.7 years; 48 606 (74.8%) male] underwent CRT implantation, 57% in the absence of a previous HFH, 12.9% during the first HFH, and 30.1% after ≥1 HFH. Over 4.54 (2.80–6.71) years [median (interquartile range); 272 989 person-years], the time in years from the first HFH to CRT implantation was associated with a higher risk of total mortality [hazard ratio (HR); 95% confidence intervals (95% CI)] (1.15; 95% CI 1.14–1.16, HFH (HR: 1.26; 95% CI 1.24–1.28), and the combined endpoint of total mortality or HFH (HR: 1.19; 95% CI 1.27–1.20) than CRT in patients with no previous HFHs, after co-variate adjustment. Total mortality (HR: 1.67), HFH (HR: 2.63), and total mortality or HFH (HR: 1.92) (all P &lt; 0.001) were highest in patients undergoing CRT ≥2 years after the first HFH.ConclusionIn this study of a healthcare system covering an entire nation, delays from a first HFH to CRT implantation were associated with progressively worse long-term clinical outcomes. The best clinical outcomes were observed in patients with no previous HFH and in those undergoing CRT implantation during the first HFH.Condensed abstractThe optimum timing of CRT implantation is unknown. In this study of 64 968 consecutive patients, delays from a first heart failure hospitalization (HFH) to CRT implantation were associated with progressively worse long-term clinical outcomes. Each year from a first HFH to CRT implantation was associated with a 21% higher risk of total mortality and a 34% higher risk of HFH. The best outcomes after CRT were observed in patients with no previous HFHs and in those undergoing implantation during their first HFH

Greyzone myocardial fibrosis and ventricular arrhythmias in patients with a left ventricular ejection fraction >35%

AIMS: To determine whether myocardial fibrosis and greyzone fibrosis (GZF) on cardiovascular magnetic resonance (CMR) is associated with ventricular arrhythmias in patients with coronary artery disease (CAD) and a left ventricular ejection fraction (LVEF) >35%. METHODS AND RESULTS: In this retrospective study of CAD patients, GZF mass using the 3SD method (GZF3SD) and total fibrosis mass using the 2SD method (TF2SD) on CMR were assessed in relation to the primary, combined endpoint of sudden cardiac death, ventricular tachycardia, ventricular fibrillation, or resuscitated cardiac arrest. Among 701 patients [age: 65.8 ± 12.3 years (mean ± SD)], 28 (3.99%) patients met the primary endpoint over 5.91 years (median; interquartile range 4.42-7.64). In competing risks analysis, a GZF3SD mass ≥5.0 g was strongly associated with the primary endpoint [subdistribution hazard ratio (sHR): 17.4 (95% confidence interval, CI 6.64-45.5); area under receiver operator characteristic curve (AUC): 0.85, P 35%, GZF3SD mass was strongly associated with the arrhythmic endpoint. These findings hold promise for its use in identifying patients with CAD and an LVEF >35% at risk of arrhythmic events

First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors.

PURPOSE: This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K). PATIENTS AND METHODS: Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated (18)F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue. RESULTS: Pictilisib was well tolerated. The most common toxicities were grade 1-2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC >20 h·μmol/L. Significant increase in plasma insulin and glucose levels, and >25% decrease in (18)F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF-mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. CONCLUSION: Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily.This study was supported by Genentech Inc. The Drug Development Unit, The Royal Marsden NHS Foundation Trust, and The Institute of Cancer Research (London) is supported in part by programme grants from Cancer Research UK. Support was also provided by Experimental Cancer Medicine Center grants (to The Institute of Cancer Research and the Cancer Research UK Center), the National Institute for Health Research Biomedical Research Center (jointly to The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research) and the Wellcome Trust (grant 090952/Z/09/Z to Dr. Ang). Paul Workman is a Cancer Research UK Life Fellow.Originally published by the American Association for Cancer Research in Clinical Cancer Research January 1, 2015 21; 77 http://dx.doi.org/10.1158/1078-0432.CCR-14-094

Hematologic Safety of Radium-223 Dichloride: Baseline Prognostic Factors Associated With Myelosuppression in the ALSYMPCA Trial.

BACKGROUND: Myelosuppression is common in patients with progressive castration-resistant prostate cancer and bone metastases. Radium-223 prolongs overall survival in these patients but may cause myelosuppression; understanding risk factors will improve clinical decision making. We describe hematologic safety of radium-223 in ALSYMPCA and post hoc analyses identifying patients at increased risk for hematologic toxicity. PATIENTS AND METHODS: Hematologic parameters and adverse events were analyzed. Multivariate analyses assessing baseline risk factors for hematologic toxicities were performed separately for radium-223 and placebo patients. RESULTS: Nine hundred one patients received radium-223 (n = 600) or placebo (n = 301); 65% of radium-223 and 48% of placebo patients had the full 6 cycles. Grade 3/4 thrombocytopenia was more common in radium-223 versus placebo patients (6% vs. 2%). Logistic regression analyses identified significant baseline predictors for grade 2-4 hematologic toxicities related to radium-223 treatment: extent of disease (6-20 vs. < 6 bone metastases; odds ratio [OR] = 2.76; P = .022) and elevated prostate-specific antigen (OR = 1.65; P = .006) for anemia; prior docetaxel (OR = 2.16; P = .035), decreased hemoglobin (OR = 1.35; P = .008), and decreased platelets (OR = 1.44; P = .030) for thrombocytopenia. Neutropenia events were too few in placebo patients for a comparative analysis. There were no significant associations between hematologic toxicities and number of radium-223 injections received (4-6 vs. 1-3). CONCLUSION: Radium-223 has a favorable safety profile with a low myelosuppression incidence. Understanding baseline factors associated with myelosuppression may assist clinicians in avoiding severe myelosuppression events with radium-223