Ryanodine Receptor Calcium Leak in Circulating B-Lymphocytes as a Biomarker in Heart Failure.

BACKGROUND: Advances in congestive heart failure (CHF) management depend on biomarkers for monitoring disease progression and therapeutic response. During systole, intracellular Ca2+ is released from the sarcoplasmic reticulum into the cytoplasm through type-2 ryanodine receptor/Ca2+ release channels. In CHF, chronically elevated circulating catecholamine levels cause pathological remodeling of type-2 ryanodine receptor/Ca2+ release channels resulting in diastolic sarcoplasmic reticulum Ca2+ leak and decreased myocardial contractility. Similarly, skeletal muscle contraction requires sarcoplasmic reticulum Ca2+ release through type-1 ryanodine receptors (RyR1), and chronically elevated catecholamine levels in CHF cause RyR1-mediated sarcoplasmic reticulum Ca2+ leak, contributing to myopathy and weakness. Circulating B-lymphocytes express RyR1 and catecholamine-responsive signaling cascades, making them a potential surrogate for defects in intracellular Ca2+ handling because of leaky RyR channels in CHF. METHODS: Whole blood was collected from patients with CHF, CHF following left-ventricular assist device implant, and controls. Blood was also collected from mice with ischemic CHF, ischemic CHF+S107 (a drug that specifically reduces RyR channel Ca2+ leak), and wild-type controls. Channel macromolecular complex was assessed by immunostaining RyR1 immunoprecipitated from lymphocyte-enriched preparations. RyR1 Ca2+ leak was assessed using flow cytometry to measure Ca2+ fluorescence in B-lymphocytes in the absence and presence of RyR1 agonists that empty RyR1 Ca2+ stores within the endoplasmic reticulum. RESULTS: Circulating B-lymphocytes from humans and mice with CHF exhibited remodeled RyR1 and decreased endoplasmic reticulum Ca2+ stores, consistent with chronic intracellular Ca2+ leak. This Ca2+ leak correlated with circulating catecholamine levels. The intracellular Ca2+ leak was significantly reduced in mice treated with the Rycal S107. Patients with CHF treated with left-ventricular assist devices exhibited a heterogeneous response. CONCLUSIONS: In CHF, B-lymphocytes exhibit remodeled leaky RyR1 channels and decreased endoplasmic reticulum Ca2+ stores consistent with chronic intracellular Ca2+ leak. RyR1-mediated Ca2+ leak in B-lymphocytes assessed using flow cytometry provides a surrogate measure of intracellular Ca2+ handling and systemic sympathetic burden, presenting a novel biomarker for monitoring response to pharmacological and mechanical CHF therapy.

Comparison of Percutaneous and Surgical Right Ventricular Assist Device Support After Durable Left Ventricular Assist Device Insertion.

BACKGROUND: Early right ventricular (RV) failure after left ventricular assist device (LVAD) implantation increases morbidity and mortality. Percutaneous right ventricular assist device (pRVAD) support is an alternative to more invasive surgical RVAD (sRVAD). METHODS AND RESULTS: We retrospectively reviewed patients receiving isolated pRVAD or sRVAD after durable LVAD at our center in the years 2007-2018. Hemodynamic parameters before and after implantation and survival outcomes were compared among groups. Nineteen patients received pRVAD and 21 sRVAD. Hemodynamic parameters improved immediately with the use of pRVAD; central venous pressure decreased (from 15.9 ± 2.4 to 12.3 ± 3.2 mm Hg; P<.001) and cardiac index increased (from 2.4 ± 0.5 to 3.5 ± 0.8 L·min-1·m-2; P<.001). These were sustained after device removal and were similar to those with the use of sRVAD. Patients with pRVAD required fewer blood transfusions and mechanically ventilated days than those with sRVAD. Among survivors, intensive care unit and hospital days were fewer with the use of pRVAD: 21 (16-27) versus 34 (27-46) ICU days (P = .01); 43.5 (30-66) versus 91 (62-111) hospital days (P = .03). There was no significant difference in 30-day mortality with the use of pRVAD compared with sRVAD (21.1% vs 42.9%; P = .14), but there was a trend toward a higher rate of discharge free from hemodialysis (73.7% vs 47.6%; P = .09). CONCLUSIONS: Novel pRVAD systems for RV failure provide hemodynamic benefits similar to sRVAD, are associated with less morbidity, and should be considered as an alternative to sRVAD.

Cholesteryl Ester Transfer Protein Inhibition With Anacetrapib Decreases Fractional Clearance Rates of High-Density Lipoprotein Apolipoprotein A-I and Plasma Cholesteryl Ester Transfer Protein.

OBJECTIVE: Anacetrapib (ANA), an inhibitor of cholesteryl ester transfer protein (CETP) activity, increases plasma concentrations of high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I (apoA)-I, apoA-II, and CETP. The mechanisms responsible for these treatment-related increases in apolipoproteins and plasma CETP are unknown. We performed a randomized, placebo (PBO)-controlled, double-blind, fixed-sequence study to examine the effects of ANA on the metabolism of HDL apoA-I and apoA-II and plasma CETP. APPROACH AND RESULTS: Twenty-nine participants received atorvastatin (ATV) 20 mg/d plus PBO for 4 weeks, followed by ATV plus ANA 100 mg/d for 8 weeks (ATV-ANA). Ten participants received double PBO for 4 weeks followed by PBO plus ANA for 8 weeks (PBO-ANA). At the end of each treatment, we examined the kinetics of HDL apoA-I, HDL apoA-II, and plasma CETP after D3-leucine administration as well as 2D gel analysis of HDL subspecies. In the combined ATV-ANA and PBO-ANA groups, ANA treatment increased plasma HDL-C (63.0%; P<0.001) and apoA-I levels (29.5%; P<0.001). These increases were associated with reductions in HDL apoA-I fractional clearance rate (18.2%; P=0.002) without changes in production rate. Although the apoA-II levels increased by 12.6% (P<0.001), we could not discern significant changes in either apoA-II fractional clearance rate or production rate. CETP levels increased 102% (P<0.001) on ANA because of a significant reduction in the fractional clearance rate of CETP (57.6%, P<0.001) with no change in CETP production rate. CONCLUSIONS: ANA treatment increases HDL apoA-I and CETP levels by decreasing the fractional clearance rate of each protein.

Axillary evaluation and lymphedema in women with ductal carcinoma in situ.

Axillary evaluation in women with ductal carcinoma in situ (DCIS) is increasing; however, this may introduce additional morbidity with unclear benefit. Our objective was to examine the morbidity and mortality associated with axillary evaluation in DCIS. We conducted a retrospective cohort study of 10,504 women aged 65-90 years with DCIS who underwent breast conserving surgery between 2002 and 2012 using SEER-Medicare database. Patients were categorized by receipt of axillary evaluation with either sentinel lymph node biopsy (SLNB) or axillary node dissection (ALND). We determined the incidence of lymphedema treatment as defined by diagnostic and procedural codes, as well as 10-year breast cancer-specific and all-cause mortality. 18.3 % of those treated with BCS and 69.4 % of those treated with mastectomy had an axillary evaluation. One year after treatment, 8.2 % of women who had an axillary evaluation developed lymphedema, compared to 5.9 % of those who did not. In a multivariable Cox proportional hazard model, the incidence of lymphedema was higher among those who underwent axillary evaluation (HR 1.22, 95 % CI 1.04-1.45). Overall 10-year breast cancer-specific survival was similar between both groups (HR 0.83, 95 % CI 0.40-1.74). Only 44 (0.40 %) women died of breast cancer; receipt of axillary evaluation did not alter overall survival. Axillary evaluation is commonly performed in women with DCIS, especially those undergoing mastectomy. However, women who receive an axillary evaluation have higher rates of lymphedema, without breast cancer-specific or overall survival benefit. Efforts should be made to determine the population of women with DCIS who benefit from this procedure.

Psychosocial factors related to non-persistence with adjuvant endocrine therapy among women with breast cancer: the Breast Cancer Quality of Care Study (BQUAL).

Non-adherence to adjuvant endocrine therapy (ET) for breast cancer (BC) is common. Our goal was to determine the associations between psychosocial factors and ET non-persistence. We recruited women with BC receiving care in an integrated healthcare system between 2006 and 2010. Using a subset of patients treated with ET, we investigated factors related to ET non-persistence (discontinuation) based on pharmacy records (≥90 days gap). Serial interviews were conducted at baseline and every 6 months. The Functional Assessment of Cancer Therapy (FACT), Medical Outcomes Survey, Treatment Satisfaction Questionnaire (TSQM), Impact of Events Scale (IES), Interpersonal Processes of Care measure, and Decision-making beliefs and concerns were measured. Multivariate models assessed factors associated with non-persistence. Of the 523 women in our final cohort who initiated ET and had a subsequent evaluation, 94 (18 %) were non-persistent over a 2-year follow-up. The cohort was primarily white (74.4 %), stage 1 (60.6 %), and on an aromatase inhibitor (68.1 %). Women in the highest income category had a lower odds of being non-persistent (OR 0.43, 95 % CI 0.23-0.81). Quality of life and attitudes toward ET at baseline were associated with non-persistence. At follow-up, the FACT, TSQM, and IES were associated with non-persistence (p < 0.001). Most women continued ET. Women who reported a better attitude toward ET, better quality of life, and more treatment satisfaction, were less likely to be non-persistent and those who reported intrusive/avoidant thoughts were more likely to be non-persistent. Interventions to enhance the psychosocial well-being of patients should be evaluated to increase adherence.

Dynamics and prognostic role of galectin-3 in patients with advanced heart failure, during left ventricular assist device support and following heart transplantation.

BACKGROUND: Galectin-3 is a marker of myocardial inflammation and fibrosis shown to correlate with morbidity and mortality in heart failure (HF). We examined the utility of galectin-3 as a marker of the severity of HF, the response of galectin-3 levels to ventricular assist device (LVAD) implantation or heart transplantation (HTx), and its use as a prognostic indicator. METHODS: Plasma galectin-3 was measured using a commercially available ELISA assay in patients with stable HF (n = 55), severe HF (n = 63), at 3 (n = 17) and 6 (n = 14) months post-LVAD and at LVAD explantation (n = 23), patients following HTx (n = 85) and healthy controls (n = 30). RESULTS: Galectin-3 levels increase with the severity of HF (severe HF: 28.2 ± 14, stable HF: 19.7 ± 13, p = 0.001; controls: 13.2 ± 9 ng/ml, p = 0.02 versus stable HF). Following LVAD implantation, galectin-3 levels are initially lower (3 months: 23.7 ± 9, 6 months: 21.7 ± 9 versus 29.2 ± 14 ng/ml implantation; p = NS) but are higher at explantation (40.4 ± 19 ng/ml; p = 0.005 versus pre-LVAD). Galectin-3 levels >30 ng/ml are associated with lower survival post-LVAD placement (76.5 % versus 95.0 % at 2 years, p = 0.009). After HTx, galectin-3 levels are lower (17.8 ± 7.1 ng/ml post-HTx versus 28.2 ± 14 pre-HTx; p < 0.0001). Patients with coronary allograft vasculopathy (CAV) post-HTx showed higher galectin-3 levels (20.5 ± 8.8 ng/ml versus 16.8 ± 6.3, p = 0.1) and the degree of CAV correlated with levels of galectin-3 (r (2) = 0.17, p < 0.0001). CONCLUSIONS: Galectin-3 is associated with the severity of HF, exhibits dynamic changes during mechanical unloading and predicts survival post-LVAD. Further, galectin-3 is associated with the development on CAV post-HTx. Galectin-3 might serve as a novel biomarker in patients with HF, during LVAD support and following HTx.

Predictors of atrial fibrillation on implantable cardiac monitoring for cryptogenic stroke.

BACKGROUND: Since the CRYSTAL-AF trial, implantation and usage of implantable loop recorder (ICM) after cryptogenic stroke (CS) for detection of atrial fibrillation (AF) has increased. However, it is unclear which CS patients would most benefit from long term ICM monitoring. This study aims to determine the risk factors in patients that would confer maximum benefit from ICM placement following CS. METHODS: A Columbia University Institutional Review Board (IRB) approved retrospective analysis of medical records of 125 patients with CS followed by implantation of ICM was evaluated. Univariable and multivariable time-to-event analyses were performed on demographics, hours of activity and variability (HRV), stroke location, thrombosis etiology, and CHA2DS2 - VASc score. The primary outcome was presence of ICM-detected AF defined as AF lasting at least 2 min. RESULTS: One hundred twenty-five patients (mean 67.6 years ± 2.4 years, 60% male) were followed for at least 3 months. Twenty-two patients (18%) were found to have clinically verified detected AF; median of time to detection was 95 days. Upon univariable demographic analysis followed by multivariable Cox regression analysis, individuals with age 75 or older (HR: 3.987, p = 0.0046) or LVEF 40% and lower (HR: 3.056, p = 0.0213) had significantly higher risk of AF. Diabetics also had a lower AF detection in multivariable analysis (HR: 0.128, p = 0.0466). CONCLUSIONS: Age 75 or older and LVEF ≤40% were the factors on multivariable analysis that predicted AF detection. Diabetes is a possible significant factor which should be evaluated further. CHA2DS2 - VASc score was notably not predictive of AF detected on ICM.

Worldwide Survey of COVID-19-Associated Arrhythmias.

[Figure: see text].

Repeat Revascularization for Severe Recurrent Coronary Artery Disease in a Young Woman With Takayasu Arteritis.

A young woman with Takayasu arteritis presented with an acute coronary syndrome with ostial left main coronary artery stenosis. She underwent urgent coronary artery bypass surgery but developed recurrent symptoms 6 months later owing to graft failure. She was treated with percutaneous coronary intervention with resolution of her symptoms. (Level of Difficulty: Beginner.).

Preoperative Proteinuria and Reduced Glomerular Filtration Rate Predicts Renal Replacement Therapy in Patients Supported With Continuous-Flow Left Ventricular Assist Devices.

BACKGROUND: Renal failure requiring renal replacement therapy (RRT) has detrimental effects on quality of life and survival of patients with continuous-flow left ventricular assist devices (CF-LVADs). Current guidelines do not offer a decision-making algorithm for CF-LVAD candidates with poor baseline renal function. Objective of this study was to identify risk factors associated with RRT after CF-LVAD implantation. METHODS AND RESULTS: Three hundred and eighty-nine consecutive patients underwent contemporary CF-LVAD implantation at the Columbia University Medical Center between January 2004 and August 2015. Baseline demographics, comorbid conditions, clinical risk scores, and renal function were analyzed in patients with or without RRT after CF-LVAD implantation. Time-dependent receiver-operating characteristic curve analysis was performed to define optimal cutoffs for continuous risk factors. Forty-four patients (11.6%) required RRT during a median follow-up of 9.9 months. Patients requiring RRT had significantly worse renal function, lower hemoglobin, and increased proteinuria at baseline. Low estimated glomerular filtration rate (<40 mL/min/1.73 m2) and proteinuria (urine protein to creatinine ratio ≥0.55 mg/mg) were significant predictors of RRT after CF-LVAD support. Dipstick proteinuria was also a significant predictor of RRT after CF-LVAD implantation. Patients with both low estimated glomerular filtration rate and proteinuria had highest risk of RRT (63.6%) compared with those with either low estimated glomerular filtration rate or proteinuria (18.7%) and those with neither of these risk factors (2.7%) at 1-year follow-up (log-rank P<0.001). CONCLUSIONS: Estimated glomerular filtration rate and proteinuria are predictors RRT after CF-LVAD implantation and should be routinely assessed in CF-LVAD candidates to guide decision making.

The Influence of Hospital and Surgeon Factors on the Prevalence of Axillary Lymph Node Evaluation in Ductal Carcinoma In Situ.

IMPORTANCE: Although axillary lymph node evaluation is standard of care in the surgical management of invasive breast cancer, a benefit has not been demonstrated in ductal carcinoma in situ (DCIS). Despite uncertainty regarding the efficacy, axillary evaluation is often performed in women with DCIS. OBJECTIVE: To determine the incidence of axillary evaluation in women with DCIS and identify clinical, hospital, and surgeon-related factors associated with axillary evaluation. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analysis conducted from January 2006 through December 2012 of medical records contained in the Perspective database for women with DCIS who underwent breast-conserving surgery (BCS) or mastectomy. A total of 35,591 women aged 18 to 90 years were included in the analysis. MAIN OUTCOMES AND MEASURES: Receipt or nonreceipt of surgical axillary evaluation, categorized as sentinel lymph node biopsy (SLNB), axillary lymph node dissection (ALND), or none. Analyses were stratified by surgery type, and multivariable regression analysis was used to identify factors associated with axillary evaluation. RESULTS: Of women identified with DCIS, 26,580 (74.7%) underwent BCS while 9011 (25.3%) underwent mastectomy; 17.7% undergoing BCS and 63.0% undergoing mastectomy had an axillary evaluation. Rates of axillary evaluation increased over time with mastectomy (2006, 56.6%; 2012, 67.4%) and were relatively stable with BCS (2006, 18.5%; 2012, 16.2%). Rates of ALND decreased in women undergoing mastectomy (2006, 20.0%; 2012, 10.7%) and BCS (2006, 1.2%; 2012, 0.3%), with increasing use of SLNB. In a multivariable analysis, hospital factors including nonteaching hospital (risk ratio [RR], 1.17; 95% CI, 1.05-1.30) and urban location (RR, 1.15; 95% CI, 1.03-1.29) influenced axillary evaluation with mastectomy. Surgeon volume was the most significant predictor of axillary evaluation among women undergoing BCS (mid vs low volume: RR, 0.87; 95% CI, 0.70-0.94; high vs low volume: RR, 0.54; 95% CI, 0.44-0.65). CONCLUSIONS AND RELEVANCE: Despite guidelines recommending against axillary lymph node evaluation in women with DCIS undergoing BCS and uncertainty regarding its use with mastectomy, SLNB or ALND is performed frequently. Given the additional morbidity and cost of these procedures, alternative surgical approaches or prospective evaluation of the clinical benefit of axillary evaluation in women with DCIS is needed.

Household net worth, racial disparities, and hormonal therapy adherence among women with early-stage breast cancer.

PURPOSE: Nonadherence to adjuvant hormonal therapy is common and is associated with increased prescription copayment amount and black race. Studies suggest that household wealth may partly explain racial disparities. We investigated the impact of net worth on disparities in adherence and discontinuation. PATIENTS AND METHODS: We used the OptumInsight insurance claims database to identify women older than age 50 years diagnosed with early breast cancer, from January 1, 2007, to December 31, 2011, who were using hormonal therapy. Nonadherence was defined as a medication possession ratio of ≤ 80% of eligible days over a 2-year period. We evaluated the association of demographic and clinical characteristics, annual household income, household net worth (< $250,000, $250,000 to $750,000, or > $750,000), insurance type, and copayments (< $10, $10 to $20, or > $20) with adherence to hormonal therapy. Logistic regression analyses were conducted by sequentially adding sociodemographic and financial variables to race. RESULTS: We identified 10,302 patients; 2,473 (24%) were nonadherent. In the unadjusted analyses, adherence was negatively associated with black race (odds ratio [OR], 0.76; P < .001), advanced age, comorbidity, and Medicare insurance. Adherence was positively associated with medium (OR, 1.33; P < .001) and high (OR, 1.66; P < .001) compared with low net worth. The negative association of black race with adherence (OR, 0.76) was reduced by adding net worth to the model (OR, 0.84; P < .05). Correcting for other variables had a minimal impact on the association between race and adherence (OR, 0.87; P = .08). The interaction between net worth and race was significant (P < .01). CONCLUSION: We found that net worth partially explains racial disparities in hormonal therapy adherence. These results suggest that economic factors may contribute to disparities in the quality of care.