by
Peter Jandus;
Kayluz Frias Boligan;
David F. Smith;
Elisabeth de Graauw;
Bodo Grimbacher;
Camilla Jandus;
Mai M. Abdelhafez;
Alain Despont;
Nicolai Bovin;
Dagmar Simon;
Robert Rieben;
Hans-Uwe Simon;
Richard D. Cummings;
Stephan von Gunten
Immune system failure in primary antibody deficiencies (PADs) has been linked to recurrent infections, autoimmunity, and cancer, yet clinical judgment is often based on the reactivity to a restricted panel of antigens. Previously, we demonstrated that the human repertoire of carbohydrate-specific immunoglobulin G (IgG) exhibits modular organization related to glycan epitope structure. The current study compares the glycan-specific IgG repertoires between different PAD entities. Distinct repertoire profiles with extensive qualitative glycan-recognition defects were observed, which are characterized by the common loss of Galα and GalNAc reactivity and disease-specific recognition of microbial antigens, self-antigens, and tumor-associated carbohydrate antigens. Antibody repertoire analysis may provide a useful tool to elucidate the degree and the clinical implications of immune system failure in individual patients.
Statins are powerful agents for the reduction of low-density lipoprotein cholesterol (LDL-C) and reduction of cardiovascular risk. Newly developed statins with increased potency, such as rosuvastatin (Crestor™) and NK-104 (in earlier clinical development), are capable of achieving marked LDL-C reductions. Cholesterol-lowering agents with mechanisms of action distinct from those of the statins are in active development. These include bile transport inhibitors, such as improved bile acid-absorbing resins and specific inhibitors of the ileal Na+/bile acid cotransporter. There are also specific inhibitors of cholesterol absorption, such as ezetimibe, which may provide cholesterol lowering that is additive to that achieved with statin treatment. Another approach is to reduce cardiovascular risk by modifying atherosclerotic processes within the arterial wall, as represented by the acyl CoA:cholesterol acyltransferase (ACAT) inhibitor avasimibe; ibe; ACAT inhibitors may reduce atherosclerotic lesions by inhibiting macrophage cholesterol storage.
Background-The American Heart Association has defined metrics of ideal cardiovascular health known as Life's Simple 7 (LS7) to prevent cardiovascular disease. We examined the association between LS7 and incident atrial fibrillation (AF) in a biracial cohort of middle- and older-aged adults without known cardiovascular disease. Methods and Results-This analysis included 13 182 ARIC (Atherosclerosis Risk in Communities) study participants (mean baseline age=54±5.7 years; 56% women; 25% black) free of AF and cardiovascular disease. An overall LS7 score was calculated as the sum of the LS7 component scores and classified as inadequate (0-4), average (5-9), or optimal (10-14) cardiovascular health. The primary outcome was incident AF, identified primarily by ECG and hospital discharge coding of AF through December 31, 2014. A total of 2266 (17%) incident AF cases were detected over a median follow-up of 25.1 years. Compared with the inadequate category (n=1057), participants in the average (n=8629) and optimal (n=3496) categories each had a lower risk of developing AF in a multivariable Cox proportional hazards model (hazard ratio 0.59, 95% confidence interval 0.51, 0.67 for average; and hazard ratio 0.38, 95% confidence interval 0.32, 0.44 for optimal). In a similar model, a 1-point-higher LS7 score was associated with a 12% lower risk of incident AF (hazard ratio 0.88, 95% confidence interval 0.86, 0.89). Conclusions-A higher LS7 score is strongly associated with a lower risk of AF in individuals without baseline cardiovascular disease. Determining whether interventions that improve the population's cardiovascular health also reduce AF incidence is needed.
BACKGROUND: Although peripheral artery disease as defined by ankle-brachial index (ABI) is associated with incident atrial fibrillation (AF), questions remain about the risk of AF in borderline ABI (>0.90 to <1.0) or noncompressible arteries (>1.4). We evaluated the association of borderline ABI and ABI >1.4 in the ARIC (Atherosclerosis Risk in Communities) study, a population-based prospective cohort study. METHODS AND RESULTS: We included 14 794 participants (age, 54.2±5.8 years, 55% women, 26% blacks) with ABI measured at the baseline (1987-1989) and without AF. AF was identified from hospital records, death certificates, and ECGs. Using Cox proportional hazards, we evaluated the association between ABI and AF. During a median follow-up of 23.3 years, there were 2288 AF cases. After adjustment for cardiovascular risk factors, hazard ratio (HR) (95% confidence interval) for AF among individuals with ABI <1.0 compared with ABI 1.0 to 1.4, was 1.13 (1.01-1.27). ABI >1.4 was not associated with increased AF risk. ABI ≤0.9 and borderline ABI were associated with a higher risk of AF compared with ABI 1.0 to 1.4. Demographics-adjusted HRs (95% confidence interval) were 1.43 (1.17-1.75) and 1.32 (1.16-1.50), respectively. However, the associations of ABI ≤0.9 and borderline ABI with AF were attenuated after adjusting for cardiovascular risk factors (HR [95% confidence interval], 1.10 [0.90-1.34] and 1.14 [1.00-1.30]), respectively. CONCLUSIONS: Peripheral artery disease indicated by low ABI, including borderline ABI, is a weak risk factor for AF. ABI >1.4 is not associated with an increased AF risk. The relationship between peripheral artery disease and AF appears to be mostly explained by traditional atherosclerotic risk factors.
Background: Advanced heart failure treated with a left ventricular assist device is associated with a higher risk of right heart failure. Many advanced heart failures patients are treated with an ICD, a relative contraindication to MRI, prior to assist device placement. Given this limitation, left and right ventricular function for patients with an ICD is calculated using radionuclide angiography utilizing planar multigated acquisition (MUGA) and first pass radionuclide angiography (FPRNA), respectively. Given the availability of MRI protocols that can accommodate patients with ICDs, we have correlated the findings of ventricular functional analysis using radionuclide angiography to cardiac MRI, the reference standard for ventricle function calculation, to directly correlate calculated ejection fractions between these modalities, and to also assess agreement between available echocardiographic and hemodynamic parameters of right ventricular function. Methods: A retrospective review from January 2012 through May 2014 was performed to identify advanced heart failure patients who underwen t both cardiac MRI and radionuclide angiography for ventricular functional analysis. Nine heart failure patients (8 men, 1 woman; mean age of 57.0 years) were identified. The average time between the cardiac MRI and radionuclide angiography exams was 38.9 days (range: 1 - 119 days). All patients undergoing cardiac MRI were scanned using an institutionally approved protocol for ICD with no device-related complications identified. A retrospective chart review of each patient for cardiomyopathy diagnosis, clinical follow-up, and echocardiogram and right heart catheterization performed during evaluation was also performed. Results: The 9 patients demonstrated a mean left ventricular ejection fraction (LVEF) using cardiac MRI of 20.7% (12 - 40%). Mean LVEF using MUGA was 22.6% (12 - 49%). The mean right ventricular ejection fraction (RVEF) utilizing cardiac MRI was 28.3% (16 - 43%), and the mean RVEF calculated by FPRNA was 32.6% (9 - 56%). The mean discrepancy for LVEF between cardiac MRI and MUGA was 4.1% (0 - 9%), and correlation of calculated LVEF using cardiac MRI and MUGA demonstrated an R of 0.9. The mean discrepancy for RVEF between cardiac MRI and FPRNA was 12.0% (range: 2 - 24%) with a moderate correlation (R = 0.5). The increased discrepancies for RV analysis were statistically significant using an unpaired t-test (t = 3.19, p = 0.0061). Echocardiogram parameters of RV function, including TAPSE and FAC, were for available for all 9 patients and agreement with cardiac MRI demonstrated a kappa statistic for TAPSE of 0.39 (95% CI of 0.06 - 0.72) and for FAC of 0.64 (95% of 0.21 - 1.00). Conclusion: Heart failure patients are increasingly requiring left ventricular assist device placement; however, definitive evaluation of biventricular function is required due to the increased mortality rate associated with right heart failure after assist device placement. Our results suggest that FPRNA only has a moderate correlation with reference standard RVEFs calculated using cardiac MRI, which was similar to calculated agreements between cardiac MRI and echocardiographic parameters of right ventricular function. Given the need for identification of patients at risk for right heart failure, further studies are warranted to determine a more accurate estimate of RVEF for heart failure patients during pre-operative ventricular assist device planning.
by
C. Noel Bairey Merz;
Eileen M. Handberg;
Chrisandra Shufelt;
Puja Mehta;
Margo B. Minissian;
Janet Wei;
Louise E.J. Thomson;
Daniel S. Berman;
Leslee Shaw;
John W. Petersen;
Garrett H. Brown;
R. David Anderson;
Jonathan J. Shuster;
Galen Cook-Wiens;
André Rogatko;
Carl J. Pepine
Aims: The mechanistic basis of the symptoms and signs of myocardial ischaemia in patients without obstructive coronary artery disease (CAD) and evidence of coronary microvascular dysfunction (CMD) is unclear. The aim of this study was to mechanistically test short-term late sodium current inhibition (ranolazine) in such subjects on angina, myocardial perfusion reserve index, and diastolic filling.
Materials and results: Randomized, double-blind, placebo-controlled, crossover, mechanistic trial in subjects with evidence of CMD [invasive coronary reactivity testing or non-invasive cardiac magnetic resonance imaging myocardial perfusion reserve index (MPRI)]. Short-term oral ranolazine 500–1000 mg twice daily for 2 weeks vs. placebo. Angina measured by Seattle Angina Questionnaire (SAQ) and SAQ-7 (co-primaries), diary angina (secondary), stress MPRI, diastolic filling, quality of life (QoL). Of 128 (96% women) subjects, no treatment differences in the outcomes were observed. Peak heart rate was lower during pharmacological stress during ranolazine (−3.55 b.p.m., P < 0.001). The change in SAQ-7 directly correlated with the change in MPRI (correlation 0.25, P = 0.005). The change in MPRI predicted the change in SAQ QoL, adjusted for body mass index (BMI), prior myocardial infarction, and site (P = 0.0032). Low coronary flow reserve (CFR <2.5) subjects improved MPRI (P < 0.0137), SAQ angina frequency (P = 0.027), and SAQ-7 (P = 0.041).
Conclusions: In this mechanistic trial among symptomatic subjects, no obstructive CAD, short-term late sodium current inhibition was not generally effective for SAQ angina. Angina and myocardial perfusion reserve changes were related, supporting the notion that strategies to improve ischaemia should be tested in these subjects.
by
Daniel E. Forman;
Michael W. Rich;
Karen P. Alexander;
Susan Zieman;
Mathew S. Maurer;
Samer S. Najjar;
Joseph C. Cleveland;
Harlan M. Krumholz;
Nanette Wenger
by
Jacob P. Laubach;
Javid J. Moslehi;
Sanjeev A. Francis;
Jesús F. San Miguel;
Pieter Sonneveld;
Robert Z. Orlowski;
Philippe Moreau;
Laura Rosinol;
Edward A. Faber;
Peter Voorhees;
Maria-Victoria Mateos;
Loreta Marquez;
Huaibao Feng;
Avinash Desai;
Helgi van de Velde;
Jennifer Elliott;
Hongliang Shi;
Edward Dow;
Nishith Jobanputra;
Sagar Lonial
This retrospective analysis aimed to establish the overall cardiac safety profile of bortezomib using patient-level data from one phase 2 and seven phase 3 studies in previously untreated and relapsed/refractory multiple myeloma (MM). Seven clinically relevant primary [congestive heart failure (CHF), arrhythmias, ischaemic heart disease (IHD), cardiac death] and secondary (hypertension, dyspnoea, oedema) cardiac endpoints were defined based on MedDRA v16.0 preferred terms. 2509 bortezomib-treated patients and 1445 patients in non-bortezomib-based control arms were included. The incidence of grade ≥3 CHF was 1·3–4·0% in studies in relapsed/refractory MM and 1·2–4·7% in previously untreated MM (2·0–7·6% all grades), with no significant differences between bortezomib- and non-bortezomib-based arms in comparative studies. Incidences of arrhythmias (1·3–5·9% grade ≥2; 0·6–4·1% grade ≥3), IHD (1·2–2·9% all grades; 0·4–2·7% grade ≥3) and cardiac death (0–1·4%) were low, with no differences between bortezomib-based and non-bortezomib-based arms. Higher rates of oedema (mostly grade 1/2) were seen in bortezomib-based versus non-bortezomib-based arms in one study and a pooled transplant study analysis. Logistic regression analyses of comparative studies showed no impact on cardiac risk with bortezomib-based versus non-bortezomib-based treatment. Bortezomib-based treatment was associated with low incidences of cardiac events.