Autoantibodies Specifically Against ß1 Adrenergic Receptors and Adverse Clinical Outcome in Patients With Chronic Systolic Heart Failure in the ß-Blocker Era: The Importance of Immunoglobulin G3 Subclass.

OBJECTIVE: To elucidate the prevalence and role of ß1 adrenergic receptor autoantibodies (ß1AR-AAb) belonging to the immunoglobulin (Ig)G3 subclass in patients with heart failure (HF) treated with ß-adrenergic blockers. BACKGROUND: Several cardiac AAbs have been reported to be present in sera from patients with dilated cardiomyopathy and other etiologies. Among AAbs, those recognizing ß1AR-AAbs show agonist-like effects, have detrimental effects on cardiomyocytes, and may induce persistent myocardial damage. METHODS: We quantify total IgG and IgG3 subclass ß1AR-AAb in subjects with chronic stable HF with long-term follow-up. RESULTS: In our study cohort of 121 subjects, non-IgG3-ß1AR-AAb and IgG3-ß1AR-AAb were found to be positive in 20 (17%) and 26 patients (21%), respectively. The positive rate of IgG3-ß1AR-AAb was significantly higher for those with nonischemic compared with ischemic HF etiology (27% vs 8%, P = .01), but the positive rate for non-IgG3-ß1AR-AAb was similar between the 2 groups (18% vs 16%, respectively, P = NS). There were no significant differences in clinical and echocardiographic measures among total ß1AR-AAb negative, non-IgG3-ß1AR-AAb positive, and IgG3-ß1AR-AAb positive groups at baseline. During 2.2 ± 1.2 years of follow-up, we observed similar rates of the composite endpoint of all-cause mortality, cardiac transplantation, or hospitalization resulting from HF between total IgG-ß1AR-AAb negative and positive patients. However, the composite endpoint events were significantly more common in the patients without than in those with IgG3-ß1AR-AAb (P = .048, log-rank test). CONCLUSIONS: Presence of IgG3-ß1AR-AAb, not total IgG, was associated with paradoxically more favorable outcomes in our cohort of patients with chronic systolic HF largely treated by ß-blockers.

Utilizing cardiac biomarkers to detect and prevent chemotherapy-induced cardiomyopathy.

The success achieved in advances in cancer therapy has been marred by development of cardiotoxicity, which causes significant morbidity and mortality. This has led to the development of surveillance protocols for cardiotoxicity utilizing multimodality imaging techniques and investigation of various drugs to treat and prevent cardiotoxicity in this subset of patients. Cardiac biomarkers hold important diagnostic and prognostic value in various cardiac diseases. In this review, we discuss the use of biomarkers in patients receiving chemotherapy, highlighting data behind the use of troponin, B-type natriuretic peptide, and myeloperoxidase. We also discuss the use of dexrazoxane, angiotensin-converting enzyme inhibitors, and beta blockers in the treatment and prevention of chemotherapy-induced cardiotoxicity. Cardiac biomarkers may serve an important role in selecting patients that are at high risk of cardiotoxicity and can potentially be used to guide the administration of drugs to treat and prevent cardiotoxicity.

Cancer therapy-induced left ventricular dysfunction: interventions and prognosis.

BACKGROUND: For multiple chemotherapeutics, cardiotoxicity is dose limiting and can lead to substantial morbidity and mortality. Early cardiac intervention has the potential to positively affect clinical course. METHODS AND RESULTS: We reviewed 247 consecutive patients referred to the Stanford cardiology clinic for cancer therapy-associated cardiac abnormalities from 2004 to 2012. A comprehensive review of records was performed, with documentation of baseline characteristics, cardiac imaging, medications, and clinical course. Seventy-nine patients who had left ventricular ejection fraction (LVEF) declines temporally associated with cancer therapy were included. The most common malignancies were breast (46%) and hematologic (35%); 71% of the patients were female, and overall mean age was 52 years. The primary cancer therapeutics associated with LVEF decline included anthracyclines, trastuzumab, and tyrosine kinase inhibitors. The mean LVEF was 60% before cancer therapy and 40% after cancer therapy. The most common cardiac interventions included beta-blockers (84%) and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (83%). Mean LVEF after cardiac intervention rose to 53%; 77% of patients had LVEF recovery to ≥50%, and 68% of these patients had recovery within 6 months of starting cardiac therapy; 76% of patients were able to continue their planned cancer therapy. CONCLUSIONS: With appropriate cardiac intervention, the majority of patients with LVEF decline from cancer therapy can achieve LVEF recovery and complete their cancer therapy.

Increased exhaled nitric oxide levels after exercise in patients with chronic systolic heart failure with pulmonary venous hypertension.

BACKGROUND: Fractional exhaled nitric oxide (eNO) is recognized as a marker of pulmonary endothelial function. Oxidative stress is associated with systemic endothelial nitric oxide production, but its correlation with eNO in heart failure (HF) patients has not been described. Previous studies have reported increased eNO levels after exercise in symptomatic HF patients but decreased levels with pulmonary arterial hypertension. Our objective was to prospectively examine the potential myocardial and functional determinants of exercise-induced rise of eNO in HF. METHODS AND RESULTS: Thirty-four consecutive ambulatory patients with chronic systolic HF (left ventricular ejection fraction [LVEF] ≤45%) underwent symptom-limited cardiopulmonary stress testing and echocardiography. eNO was determined immediately after exercise. Systemic endothelial dysfunction was assessed by asymmetric dimethylarginine (ADMA) and the L-arginine/ADMA ratio. In our study cohort (mean age 53 ± 13 years, 76% male, median LVEF 31%, interquartile range [IQR] 25%-40%), the mean eNO was 23 ± 9 ppb. eNO levels were higher in patients with diastolic dysfunction stages 2 or 3 than stage 1 or normal diastology (26.1 ± 9 vs 19.5 ± 7 ppb; P = .013). eNO had a positive correlation with estimated systolic pulmonary artery pressure (r = 0.57; P = .0009) and indexed left atrium volume (r = 0.43; P = .014), but it did not correlate with cardiopulmonary exercise test parameters, ADMA, or symptom score. CONCLUSIONS: In contrast to earlier reports, the increase in postexercise eNO observed in stable chronic systolic HF patients may be attributed to the presence of underlying pulmonary venous hypertension probably secondary to advanced diastolic dysfunction.

Widespread distribution of reticulon-3 in various neurodegenerative diseases.

Reticulons are a group of membrane-bound proteins involved in diverse cellular functions, and are suggested to act as inhibitors of ß-secretase enzyme 1 (BACE1) activity that cleaves amyloid precursor protein. Reticulons are known to accumulate in the dystrophic neurites of Alzheimer's disease (AD), and studies have suggested that alterations in reticulons, such as increased aggregation, impair BACE1 binding, increasing amyloid-ß production, and facilitating reticulon deposition in dystrophic neurites. To further characterize the cellular distribution of reticulon, we examined reticulon-3 expression in cases of AD, Parkinson's disease, and diffuse Lewy body disease. A more widespread cellular distribution of reticulon-3 was noted than in previous reports, including deposits in dystrophic neurites, neuropil threads, granulovacuolar degeneration, glial cells, morphologically normal neurons in both hippocampal pyramidal cell layer and cerebral neocortex, and specifically neurofibrillary tangles and Lewy bodies. These results are compatible with reticulon alterations as nonspecific downstream stress responses, consistent with its expression during periods of endoplasmic reticulum stress. This emphasizes the increasing recognition that much of the AD pathological spectrum represents a response to the disease rather than cause, and emphasizes the importance of examining upstream processes, such as oxidative stress, that have functional effects prior to the onset of structural alterations.

Soluble angiotensin converting enzyme 2 levels in chronic heart failure is associated with decreased exercise capacity and increased oxidative stress-mediated endothelial dysfunction.

The aim of this study was to explore the relationship between serum soluble angiotensin converting enzyme 2 (sACE2), parameters of cardiopulmonary exercise testing and plasma asymmetric dimethylarginine (ADMA), a marker of oxidative stress-induced endothelial dysfunction. This has not been previously evaluated. We assessed 50 consecutive ambulatory patients with chronic systolic heart failure and left ventricular ejection fraction (LVEF) ≤45%. Their blood samples were collected for sACE2 and ADMA tests before they underwent symptom-limited cardiopulmonary exercise testing and transthoracic echocardiography. The majority of our study subjects had New York Heart Association functional class II (74%) and III (18%) presentation, and 42% of patients had ischemic etiology. Median sACE2 activity was 10.36 (7.00-14.47) ng/mL and mean ADMA was 0.90 ± 0.22. sACE2 activity was inversely correlated with pVO2 (r = -0.42, P = 0.00283), exercise time (r = -0.35, P = 0.0138) and LVEF (r = -0.548, P < 0.001), and positively correlated with VE/VCO2 slope (r = 0.294, P = 0.0405), ΔDBP (r = 0.315, P = 0.0278), mitral E/Ea ratio (r = 0.442, P = 0.00158) and ADMA levels (r = 0.351, P = 0.0134). Meanwhile, we observed a negative correlation between ADMA and pVO2 (r = -0.424, P = 0.00227) and positive correlations between ADMA and VE/VCO2 slope (r = 0.515, P < 0.001), ΔDBP (r = 0.391, P = 0.00568), mitral E/Ea ratio (r = 0.426, P = 0.00219). In multivariate logistic regression analysis, sACE2 was independently associated with peak oxygen uptake (% predicted) after adjusting for body mass index (BMI) and mitral E/Ea ratio (odds ratio [OR] 0.81 (0.58-0.94), P = 0.041) and associated with oxygen pulse (VO2/HR) (%) after adjusting for age, gender, BMI and mitral E/Ea ratio (OR 0.83 [0.68-0.95], P = 0.025). Therefore in stable chronic systolic heart failure patients, higher sACE2 activity is independently associated with diminished exercise capacity and correlates with elevated systemic oxidative stress-mediated endothelial dysfunction.

Lean-Based Redesign of Multidisciplinary Rounds on General Medicine Service.

BACKGROUND: Multidisciplinary rounds (MDR) facilitate timely communication amongst the care team and with patients. We used Lean techniques to redesign MDR on the teaching general medicine service. OBJECTIVE: To examine if our Lean-based new model of MDR was associated with change in the primary outcome of length of stay (LOS) and secondary outcomes of discharges before noon, documentation of estimated discharge date (EDD), and patient satisfaction. DESIGN, SETTING, PATIENTS: This is a pre-post study. The preperiod (in which the old model of MDR was followed) comprised 4000 patients discharged between September 1, 2013, and October 22, 2014. The postperiod (in which the new model of MDR was followed) comprised 2085 patients between October 23, 2014, and April 30, 2015. INTERVENTION: Lean-based redesign of MDR. MEASUREMENTS: LOS, discharges before noon, EDD, and patient satisfaction. RESULTS: There was no change in the mean LOS. Discharges before noon increased from 6.9% to 10.7% (P < .001). Recording of EDD increased from 31.4% to 41.3% (P < .001). There was no change in patient satisfaction. CONCLUSIONS: Lean-based redesign of MDR was associated with an increase in discharges before noon and in recording of EDD.

Trauma- and Stressor-Related Disorders Among Children and Adolescents.

DSM-5 introduced a clustering of disorders designated "trauma- and stressor-related disorders." These disorders are unique in that the etiology is specified as part of the diagnostic criteria. In this review, the authors consider how some of these disorders manifest for children and adolescents. In posttraumatic stress disorder and related disorders, the child is exposed to one or more frightening, traumatic events. In attachment disorders, the child experiences severe social neglect. With this framework in mind, the authors consider details of several prominent trauma- and stressor-related disorders that arise in response to either excessive, unwanted input or inadequate, necessary input among children and adolescents.

Usefulness of elevated urine neopterin levels in assessing cardiac dysfunction and exercise ventilation inefficiency in patients with chronic systolic heart failure.

Neopterin is synthesized by macrophages upon stimulation with gamma-interferon, and high neopterin production is associated with cellular immune activation and increased production of reactive oxygen species (oxidant stress), but the clinical utility of urine neopterin levels in patients with heart failure (HF) has not been explored. Fifty-three ambulatory patients with chronic systolic HF (left ventricular [LV] ejection fraction ≤40%) underwent comprehensive echocardiographic evaluation and cardiopulmonary exercise testing. Urine neopterin levels were quantified by liquid chromatography with tandem mass spectrometric analyses and corrected to urine creatinine (Cr) levels. In our study cohort, median urine neopterin level was 60 µmol/mol Cr (interquartile range 40 to 86). There were modest correlations between urine neopterin levels and abnormalities in cardiac structure and function by echocardiography: LV ejection fraction (r = -0.33, p = 0.017), indexed LV end-diastolic volume (r = 0.31, p = 0.029), indexed LV end-systolic volume (r = 0.32, p = 0.024), and E/septal Ea (r = 0.28, p = 0.041). Although there was no significant correlation between urine neopterin and maximal oxygen uptake (peak VO2: r = -0.25, p = 0.07), there was a modest correlation between urine neopterin and maximal ventilation/carbon dioxide production ratio (VE/VCO2 max: r = 0.38, p = 0.005). In conclusion, increase in urine neopterin levels tracks with disease severity in patients with chronic systolic HF.

Pulmonary hypertension associated with advanced systolic heart failure: dysregulated arginine metabolism and importance of compensatory dimethylarginine dimethylaminohydrolase-1.

OBJECTIVES: This study sought to examine the hemodynamic determinants of dysregulated arginine metabolism in patients with acute decompensated heart failure and to explore possible mechanisms of arginine dysregulation in human heart failure. BACKGROUND: Accumulating methylated arginine metabolites and impaired arginine bioavailability have been associated with heart failure, but the underlying pathophysiology remains unclear. METHODS: This study prospectively determined plasma levels of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, and global arginine bioavailability ratio [GABR = arginine/(ornithine + citrulline)] by tandem mass spectrometry in subjects with advanced decompensated heart failure in the intensive care unit (n = 68) and with stable chronic heart failure (n = 57). RESULTS: Compared with chronic heart failure subjects, plasma ADMA was significantly higher (median [interquartile range]: 1.29 [1.04 to 1.77] µmol/l vs. 0.87 [0.72 to 1.05] µmol/l, p < 0.0001), and global arginine bioavailability ratio significantly lower (median [interquartile range]: 0.90 [0.69 to 1.22] vs. 1.13 [0.92 to 1.37], p = 0.002) in advanced decompensated heart failure subjects. Elevated ADMA and diminished global arginine bioavailability ratio were associated with higher systolic pulmonary artery pressure (sPAP) and higher central venous pressure, but not with other clinical or hemodynamic indices. We further observed myocardial levels of dimethylarginine dimethylaminohydrolase-1 were increased in chronic heart failure without elevated sPAP (<50 mm Hg), but diminished with elevated sPAP (≥50 mm Hg, difference with sPAP <50 mm Hg, p = 0.02). CONCLUSIONS: Dysregulated arginine metabolism was observed in advanced decompensated heart failure, particularly with pulmonary hypertension and elevated intracardiac filling pressures. Compared with hearts of control subjects, we observed higher amounts of ADMA-degradation enzyme dimethylarginine dimethylaminohydrolase-1 (but similar amounts of ADMA-producing enzyme, protein methyltransferase-1) in the human failing myocardium.

Retinoblastoma protein phosphorylation at multiple sites is associated with neurofibrillary pathology in Alzheimer disease.

The re-expression of multiple cell cycle markers representing various cell cycle phases in postmitotic pyramidal neurons suggests that neurons in Alzheimer disease (AD) attempt to re-enter the cell cycle. Entry into the cell cycle requires activation of G1 to S phase cell cycle proteins, among which retinoblastoma protein (pRb) is a key regulator. pRb inhibits the transcription of cell cycle proteins in the nucleus of healthy cells by interaction and consequent blocking of the active site of E2F, dependent upon the phosphate stoichiometry and combination of the locations of their 16 potential phosphorylation sites on pRb. Therefore, to determine whether pRb is involved in the aberrant cell cycle phenotype in AD neurons, a systematic immunocytochemical evaluation of the phosphorylation status of pRb protein using antibodies specific for multiple phosphorylation sites (i.e., pSpT249/252, pS612, pS795, pS807, pS811 and pT821) was carried out in the hippocampal regions of brains from AD patients. Increased levels of phospho-pRb (ppRb) for all these phosphorylation sites were noted in the brains of AD patients as compared to control cases. More importantly, redistribution of ppRb from the nucleus to the cytoplasm of susceptible neurons, with significant localization in neurofibrillary tangles and neuritic plaques, was observed. Additional studies revealed extensive co-localization between phospho-p38 and ppRb, implicating that p38 activation may contribute to cell cycle abnormalities through pRb phosphorylation. Taken together, these data supports the concept of neuronal cell cycle re-entry in AD and indicates a crucial role for pRb in this process.

c-Jun phosphorylation in Alzheimer disease.

The c-Jun N-terminal kinase (JNK) pathway is known to be activated by oxidative stress and can lead to either defensive-protective adaptations in the cell or apoptosis. The JNK pathway is activated in Alzheimer disease (AD), as demonstrated in studies showing higher levels of phospho-JNK in affected neurons in AD brains than in controls. c-Jun, a transcription factor, is the downstream effector of JNK, whose activation requires phosphorylation of Ser63/Ser73. In this study, we characterized and compared the localization of c-Jun phosphorylated at either Ser63 or Ser73 in the hippocampi of AD cases with that in age-matched controls. Phospho-c-Jun (Ser73) was found to be strongly associated with neurofibrillary tangles and granulovacuolar degeneration (GVD) in addition to the nuclei in neurons in the hippocampal regions of the AD brain, but was virtually absent in most controls. Phospho-c-Jun (Ser63) was also found to be associated with GVD in AD brains. Indeed, phospho-c-Jun (Ser73) immunostaining was much more extensive than that of phospho-c-Jun (Ser63), with all the phospho-c-Jun (Ser63)-positive neurons also being phospho-c-Jun (Ser73) positive. Significant overlap between phospho-c-Jun and phospho-JNK suggested a mechanistic link. In addition, the neurons showing increased levels of phospho-c-Jun (Ser73) in the cytoplasmic GVD were negative for TUNEL, suggesting a mechanism protecting the cells from death. Overall, this study demonstrated specific alterations in c-Jun phosphorylation and distribution in AD which is not necessarily linked to apoptosis but rather may represent an adaptation process in the face of oxidative stress.