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.

Immunosenescence in patients with chronic systolic heart failure.

AIM: Chronic heart failure (CHF) is characterized by hemodynamic compromise, neurohormonal and immune activation. We sought to examine the presence and severity of immunosenescence and its relation with the stages of CHF. METHODS: We enrolled 86 consecutive stable systolic CHF patients and examined the relationship of leukocyte and lymphocyte subpopulation counts by flow cytometry with their functional status according to New York Heart Association (NYHA) class. RESULTS: Patients with advanced heart failure were characterized by significantly increased neutrophil and reduced lymphocyte counts. T-helper cells were increased, whereas B-cells and T cytotoxic cells were decreased. T-helper cells exhibited significant differentiation and aging across the NYHA classes; naïve T-cells, CD4 + CD45RA +, were significantly reduced in NYHA Class IV and memory T-cells, CD4 + CD45RO +, were significantly increased. CONCLUSION: Patients with CHF develop intense T-cell differentiation and aging. The presence of significant immunosenescence in advanced CHF may indicate a population at increased risk for adverse events.

Changes in the monocytic subsets CD14(dim)CD16(+) and CD14(++)CD16(-) in chronic systolic heart failure patients.

Different monocytic subsets are important in inflammation and tissue remodelling, but although heart failure (HF) is associated with local and systemic inflammation, their roles in HF are yet unknown. We recruited 59 chronic systolic HF patients (aged 58 ± 13 years, 45 males and 14 females) and 29 age-matched controls with no pervious heart disease. Compared to the controls, we found no change in the distribution of the CD14(+)CD16(+) monocytic subset, whereas the classical CD14(++)CD16(-) subset was decreased by 11% (P < 0.001), and the nonclassical CD14(dim)CD16(+) subset was expanded by 4% (P < 0.001) in HF patients and was inversely associated with severe HF (P = 0.015), as assessed by increased end-diastolic dimension (EDD). Compared to the control group, serum TNFα, IL-1ß, IL-10, and IL-13 levels were significantly elevated in the HF patients. Specifically, IL-13 levels were positively correlated to the CD1CD14(dim)CD16(+) monocytic subset (r = 0.277, P = 0.017), and intracellular staining of IL-13 demonstrated that some of these monocytes produce the cytokine in HF patients, but not in the controls. We suggest that the inverse association between EDD values and the expansion of CD14(dim)CD16(+) monocytes that can produce IL-13 could be explained as a measure to counterbalance adverse remodelling, which is a central process in HF.

Long-term statin therapy in patients with systolic heart failure and normal cholesterol: effects on elevated serum markers of collagen turnover, inflammation, and B-type natriuretic peptide.

BACKGROUND: The role of statin therapy in heart failure (HF) is unclear. The amino-terminal propeptide of procollagen type III (PIIINP) predicts outcome in HF, and yet there are conflicting reports of statin therapy effects on PIIINP. OBJECTIVES: This study determined whether there was an increase in serum markers of inflammation, fibrosis (including PIIINP), and B-type natriuretic peptide (BNP) in patients with systolic HF and normal total cholesterol and determined the effects of long-term treatment with atorvastatin on these markers. METHODS: Fifty-six white patients with systolic HF and normal cholesterol levels (age 72 [13] years; 68% male; body mass index 27.0 [7.3] kg/m(2); ejection fraction 35 [13]%; 46% with history of smoking) were randomly allocated to atorvastatin treatment for 6 months, titrated to 40 mg/d (A group) or not (C group). Age- and/or sex-matched subjects without HF (N group) were also recruited. Biomarkers were measured at baseline (all groups) and 6 months (A and C groups). RESULTS: Serum markers of collagen turnover, inflammation, and BNP were significantly elevated in HF patients compared with normal participants (all P < 0.05). There were correlations between these markers in HF patients but not in normal subjects. Atorvastatin treatment for 6 months caused a significant reduction in the following biomarkers compared with baseline: BNP, from median (interquartile range) 268 (190-441) pg/mL to 185 (144-344) pg/mL; high-sensitivity C-reactive protein (hs-CRP), from 5.26 (1.95 -9.29) mg/L to 3.70 (2.34-6.81) mg/L; and PIIINP, from 4.65 (1.86) to 4.09 (1.25) pg/mL (all P < 0.05 baseline vs 6 months). Between-group differences were significant for PIIINP only (P = 0.027). There was a positive interaction between atorvastatin effects and baseline hs-CRP and PIIINP (P < 0.01). CONCLUSIONS: Long-term statin therapy reduced PIIINP in this small, selected HF population with elevated baseline levels. Further evaluation of statin therapy in the management of HF patients with elevated PIIINP is warranted.