Sex differences in heart failure patients assessed by combined echocardiographic and cardiopulmonary exercise testing

BackgroundWe aimed to test the differences in peak VO2 between males and females in patients diagnosed with heart failure (HF), using combined stress echocardiography (SE) and cardiopulmonary exercise testing (CPET).MethodsPatients who underwent CPET and SE for evaluation of dyspnea or exertional intolerance at our institution, between January 2013 and December 2017, were included and retrospectively assessed. Patients were divided into three groups: HF with preserved ejection fraction (HFpEF), HF with mildly reduced or reduced ejection fraction (HFmrEF/HFrEF), and patients without HF (control). These groups were further stratified by sex.ResultsOne hundred seventy-eight patients underwent CPET-SE testing, of which 40% were females. Females diagnosed with HFpEF showed attenuated increases in end diastolic volume index (P = 0.040 for sex × time interaction), significantly elevated E/e' (P < 0.001), significantly decreased left ventricle (LV) end diastolic volume:E/e ratio (P = 0.040 for sex × time interaction), and lesser increases in A-VO2 difference (P = 0.003 for sex × time interaction), comparing to males with HFpEF. Females diagnosed with HFmrEF/HFrEF showed diminished increases in end diastolic volume index (P = 0.050 for sex × time interaction), mostly after anaerobic threshold was met, comparing to males with HFmrEF/HFrEF. This resulted in reduced increases in peak stroke volume index (P = 0.010 for sex × time interaction) and cardiac output (P = 0.050 for sex × time interaction).ConclusionsCombined CPET-SE testing allows for individualized non-invasive evaluation of exercise physiology stratified by sex. Female patients with HF have lower exercise capacity compared to men with HF. For females diagnosed with HFpEF, this was due to poorer LV compliance and attenuated peripheral oxygen extraction, while for females diagnosed with HFmrEF/HFrEF, this was due to attenuated increase in peak stroke volume and cardiac output. As past studies have shown differences in clinical outcomes between females and males, this study provides an essential understanding of the differences in exercise physiology in HF patients, which may improve patient selection for targeted therapeutics

Lack of Significance of ISS Staging and Depth of Response in Predicting Overall Survival for Multiple Myeloma Patients

Abstract Introduction: Despite the advances for treating multiple myeloma (MM) patients (pts), it remains an incurable B-cell malignancy. Thus, the objective for treating these pts is to prolong overall survival (OS) and preserve quality of life. New classes of drugs in the past decade have improved OS for MM pts; however, most of the studies conducted to predict outcome and predict factors that determine OS have relied on older data sets derived from large institutions including pts not receiving treatment there and lacking accurate follow up of pts as well as information from centers in which therapeutic choices are limited. These studies have suggested that depth of response, specifically complete response (CR), and lower International Staging System (ISS) staging at diagnosis predict improved OS. We have now analyzed data on all MM pts who have received treatment in a single clinic specializing in MM. Methods: Data was obtained from all MM pts who received treatment in a single clinic specializing in MM that was established 10 years ago. Kaplan-Meier analysis was used to generate all survival curves and the log-rank test was used to measure difference between curves, with P&lt;0.05 representing statistical significance. Results: Two hundred sixty-three MM patients (161 male, 102 female) with a median follow-up of 52 months were analyzed in this study. The median age at diagnosis was 63 years (range, 31 to 88). Thirty-seven pts (14%) had smoldering MM (SMM) while the remainder (n=225 [86%]) were diagnosed with active MM. For pts with active disease, ISS staging at diagnosis (n=156) included 68 (44%), 46 (29%) and 42 (27%) pts with ISS Stages I, II and III. The median OS of all patients was 118 months with a 5-year survival of 77%. The 5-year OS of SMM pts was 88% compared to 76% for those with active disease. There were no significant differences in OS between pts with different ISS stages at the time of diagnosis. Specifically, the median 5-year survival of pts with ISS Stage I, II and III disease at diagnosis were 79, 91 and 84 months, respectively. We also analyzed OS of MM pts according to the depth of response from treatment. There were no significant differences in OS between pts who attained a CR during their first treatment regimen compared to those who achieved their first CR during subsequent regimens or those who never attained a CR. During their first treatment, pts with stable disease (SD; n=28) showed no difference in OS compared to those achieving &gt; minimal response (MR; n=135), &gt; partial response (PR; n=107), PR (n=72), or CR (n=35). The OS of pts who had achieved a CR with at least one regimen (n=83 [38% of pts]) was not different than among pts never achieving CR (n=135 [62% of pts]; P=0.1173). In order to further determine whether depth of response predicts OS during the patient’s course of disease, OS was determined based on the best response ever achieved to any anti-myeloma regimen. There was no significant difference in OS between patients who achieved a CR (n=84) with any treatment regimen compared to those who attained an MR or PR (n=108), PR (n=73), MR (n=35) or those who had achieved only an SD (n=11). However, OS among pts who achieved CR, &gt; PR, ≥ MR, or &gt; SD (SD+MR+PR+CR) was better than among those who had only demonstrated PD during their course of disease (P&lt;0.0001). In order to determine whether the initial treatment regimen predicted OS, we also analyzed survival of pts who received bortezomib-based therapy compared to those who received an IMiD or both drugs together as their initial treatment, and showed there was no significant differences in OS between these three upfront treatment approaches. Conclusion: Results from an analysis of a large cohort of MM pts from a single clinic specializing in MM show that the median survival has greatly improved to nearly 10 years due to the availability of many new treatment options. Although previous studies have suggested that ISS staging at diagnosis and depth of response to anti-MM regimens predict OS for MM pts, results from our study involving analysis of a large cohort of MM pts from a single clinic specializing in MM show that these prognostic factors do not predict OS for pts with this B-cell malignancy. Differences in our results compared to other previous studies may reflect the many treatment options available in the clinical setting used to obtain our results. Disclosures No relevant conflicts of interest to declare. </jats:sec

Serum B-Cell Maturation Antigen Is a Novel Prognostic Indicator for Multiple Myeloma Patients and Correlates with Clinical Status and Survival

Abstract Introduction:B-cell maturation antigen (BCMA) is a tumor necrosis factor receptor family member that is expressed on normal and malignant B-cells, including those from patients (pts) with multiple myeloma (MM). Our group has recently shown that this protein is present in the serum of MM pts, and preliminary findings from our group suggested that its levels may correlate with their clinical status and overall survival (OS; Sanchez et al. Brit J Haematol 2012). We now have analyzed the relationship between serum BCMA levels and monoclonal (M)-protein levels as well as the relationship of BCMA to response status, progression-free survival (PFS) and OS in a large cohort of MM pts including those with nonsecretory disease (NSD). Methods:Two hundred fifty-two MM pts were evaluated. Enzyme-linked immunosorbent assay (ELISA) was used to determine serum BCMA levels (R&amp;D Systems). The Kruskal-Wallis Test was used to assess the correlation between serum BCMA levels and clinical status, and Dunn’s posttest was used to assess differences between clinical status groups. Kaplan-Meier analysis and multivariate Cox regression models were also used. Kaplan-Meier survival of MM pts was determined from the time of initial serum BCMA measurement to death or the date of last follow-up. PFS of MM pts was evaluated from the time of initial serum BCMA measurement to date of first disease progression. Cox-proportional hazards regression was utilized to determine the predictive influence of serum BCMA and various other factors including age, creatinine, hemoglobin, ISS stage, and bone disease on OS and PFS. P-values less than .05 were considered statistically significant. Changes in serum BCMA levels were correlated with serum M-protein levels for 44 consecutive MM pts during their course of disease. Similarly, BCMA was correlated with bone marrow and PET scan findings for NSD pts. Results: Serum BCMA levels correlated with the patient’s clinical status at the time of its determination (p&lt;.0001). Specifically, pts with &gt; PR had significantly lower serum BCMA levels (median, 11.69 ng/mL) than those with stable and progressive disease (median, 64.17 ng/mL; p&lt;.001). Changes in serum BCMA levels highly correlated with changes in serum M-protein among 44 consecutive MM pts that had multiple determinations made during their course of disease. Notably, pts with NSD showed a direct correlation between changes in serum BCMA levels and their clinical status as reflected by PET scan and bone marrow findings during their course of disease. For the pts (n=64) for whom PFS was evaluable, it was markedly longer among pts with serum BCMA levels below the median (&lt;21.6 ng/mL) compared to those with levels above the median (p&lt;.0006). Among all 252 pts, OS of pts whose serum BCMA levels were above the median (≥ 38.5 ng/mL) was significantly shorter (5-year, 71%) than among those whose levels were below the median (5-year, 94%; &lt; 38.5 ng/mL; p&lt;.0001). We divided pts into three stages based on their serum BCMA levels: Stage 1 (n=118; &lt; 30 ng/ml), Stage 2 (n=79; &gt;30-140 ng/mL) and Stage 3 (n=55; &gt; 140 ng/mL). Pts in Stage 1 had a longer OS (5-year, 95%) compared to pts in Stage 2 (5-year, 72%; p &lt; 0.0002) while pts in Stage 2 had a longer OS than pts in Stage 3 (5-year, 60%; p &lt; 0.0109). We determined the relationship of OS to serum BCMA level, age, serum creatinine, hemoglobin, ISS stage, and bone disease through Cox proportional-hazards regression. In the multivariate regression analyses, serum BCMA levels significantly correlated with only OS (p&lt;.0003). In contrast, age, bone disease status, serum creatinine, hemoglobin, and ISS staging did not correlate with OS. Lastly, serum BCMA was independent of ISS staging and serum creatinine levels. Conclusion:The results of this study demonstrate that BCMA is a novel serum marker that can be used to follow the course of disease for MM pts. The level of this serum protein is also correlated with clinical status and predicts their PFS and OS. It also provides MM pts with NSD a new potential way to follow their disease course, which currently requires frequent PET scans and bone marrow exams. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare. </jats:sec

Sex differences in heart failure patients assessed by combined echocardiographic and cardiopulmonary exercise testing

BackgroundWe aimed to test the differences in peak VO2 between males and females in patients diagnosed with heart failure (HF), using combined stress echocardiography (SE) and cardiopulmonary exercise testing (CPET).MethodsPatients who underwent CPET and SE for evaluation of dyspnea or exertional intolerance at our institution, between January 2013 and December 2017, were included and retrospectively assessed. Patients were divided into three groups: HF with preserved ejection fraction (HFpEF), HF with mildly reduced or reduced ejection fraction (HFmrEF/HFrEF), and patients without HF (control). These groups were further stratified by sex.ResultsOne hundred seventy-eight patients underwent CPET-SE testing, of which 40% were females. Females diagnosed with HFpEF showed attenuated increases in end diastolic volume index (P = 0.040 for sex × time interaction), significantly elevated E/e' (P &amp;lt; 0.001), significantly decreased left ventricle (LV) end diastolic volume:E/e ratio (P = 0.040 for sex × time interaction), and lesser increases in A-VO2 difference (P = 0.003 for sex × time interaction), comparing to males with HFpEF. Females diagnosed with HFmrEF/HFrEF showed diminished increases in end diastolic volume index (P = 0.050 for sex × time interaction), mostly after anaerobic threshold was met, comparing to males with HFmrEF/HFrEF. This resulted in reduced increases in peak stroke volume index (P = 0.010 for sex × time interaction) and cardiac output (P = 0.050 for sex × time interaction).ConclusionsCombined CPET-SE testing allows for individualized non-invasive evaluation of exercise physiology stratified by sex. Female patients with HF have lower exercise capacity compared to men with HF. For females diagnosed with HFpEF, this was due to poorer LV compliance and attenuated peripheral oxygen extraction, while for females diagnosed with HFmrEF/HFrEF, this was due to attenuated increase in peak stroke volume and cardiac output. As past studies have shown differences in clinical outcomes between females and males, this study provides an essential understanding of the differences in exercise physiology in HF patients, which may improve patient selection for targeted therapeutics.</jats:sec

Soluble Bcma in Myeloma Serum Binds Its Ligands BAFF and Prevents Normal Antibody Production in Multiple Myeloma Patients

Abstract Introduction: A hallmark of multiple myeloma (MM) is the low levels of uninvolved immunoglobulin (Ig) levels. B-cell maturation antigen (BCMA) is a receptor expressed in mature non-malignant and malignant B lymphocytes, including plasma cells. Its ligands are B-cell activating factor (BAFF) and a proliferation inducing ligand (APRIL). We previously demonstrated that BCMA is present in the serum of MM patients (pts) and that its levels predict survival (Sanchez et al. Br J Haematol 2012). We hypothesized that circulating BCMA binds it ligands, preventing normal plasma cell development in MM patients which may explain their reduction in uninvolved Ig levels. Methods: BCMA-Fc and control Ig were obtained and reconstituted in PBS (R&amp;D Systems). Retro-orbital bleeds were performed on C57 Bl/6 and SCID mice implanted with the human MM xenografts LAGλ-1, LAGk-1A or LAGk-2. Human BCMA and mouse BAFF, IgM, IgA and IgG levels were measured with ELISA (R&amp;D Systems &amp; Bethyl Laboratories). The Raji B-cell line was obtained from the American Type Culture Collection (Rockville, MD, USA). Human IgA and IgG levels were determined in MM patients using nephelometry (Immage 800, Beckman Coulter). Hevylite® Assays (Binding Site) were used to quantify the levels of heavy-light chain isoform pairs in MM patients. Results: We determined if mBAFF formed complexes with human BCMA (hBCMA) in the plasma from SCID mice implanted with LAGλ-1, LAGκ-2 or LAGκ-1A, and were able to identify mBAFF-hBCMA complexes in plasma samples from these mice. To determine what effect human BCMA had on Ig levels in immune competent mice, rhBCMA-Fc or control Ig-Fc (100 mg) was injected into C57 Bl/6 mice, and plasma IgA, IgM and IgG levels were measured. Decreases in IgA levels were observed following BCMA treatment when compared to baseline plasma IgA on days 4 and 6 (P = 0.0031 and P = 0.0064, respectively), and the control group (P = 0.0087 and P = 0.0221). Samples were also analyzed for mouse IgM levels with similar marked reductions when compared to the untreated (P = 0.0001) and Ig-Fc (P = 0.0088) groups. For plasma IgG levels, a marked decrease was observed on day 6 following rhBCMA-Fc administration when compared to its baseline levels (P = 0.0023), and also when compared to the Ig-Fc control protein (P = 0.0014) and the untreated control (P = 0.0129) groups. We then set out to determine if sera from MM patients contained BCMA-BAFF complexes, using ELISA plates coated with an anti-human BAFF antibody followed by exposure to a polyclonal anti-human BCMA antibody. A strong absorbance indicating the presence of BCMA-BAFF complexes was detected in serum samples from MM patients, whereas no antibody cross reactivity was observed in control samples. We also determined whether human MM serum or rhBCMA-Fc blocked BAFF from binding to Raji B-cells. Raji cells (B-cell line) were incubated with serum from a MM patient containing hBCMA (0.75μg/ml) or rhBCMA-Fc (3 μg/ml) in the presence of rhBAFF (500 ng/ml). Myeloma serum and rhBCMA-Fc decreased rhBAFF binding to Raji cells by 71% (from 96.8 to 25.6 %) and 74% (from 96.8 to 22.9 %), respectively. Next, we determined whether serum BCMA levels inversely correlated with uninvolved Ig levels in MM pts. For pts with IgA (n = 134) or IgG (n = 313) MM, higher BCMA levels (&gt; 100 ng/ml) correlated with below normal levels of uninvolved IgG in IgA MM and uninvolved IgA in IgG MM, whereas lower BCMA levels (&lt; 100 ng/ml) correlated with normal uninvolved levels (P &lt; 0.0001). Using the Hevylite Assay, similar results were observed for the levels of BCMA compared to uninvolved IgG isoforms in both pts with involved IgG lambda (n = 62, P = 0.0006) and IgG kappa (n = 117, P &lt; 0.0001) MM. Conclusions: Our laboratory previously has reported that serum levels of BCMA are increased in the serum of MM patients, and correlates with response to treatment and predicts survival. We now demonstrate 1) the formation of complexes of BCMA with its B-cell ligand BAFF in the plasma of MM xenografts and sera of MM patients, 2) show that rhBCMA and MM patient serum blocks the binding of BAFF to human B-cells, 3) administration of rhBCMA to normal mice results in marked reductions in their antibody levels, and 4) show that BCMA levels inversely correlate with uninvolved Ig levels in MM pts. Thus, the lack of normal antibody production in MM pts results, in part, from circulating BCMA binding its ligands, preventing production of normal antibody-producing cells. Disclosures No relevant conflicts of interest to declare. </jats:sec