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ABSTRACT: Approximately 20% of patients with idiopathic dilated cardiomyopathy (iDCM) have autoantibodies (AAbs) specific to cardiac troponin-I (cTnI). However, there has been no work evaluating active cellular autoimmunity. We aimed to identify a cTnI-stimulated cellular autoimmune response and to correlate our findings with cTnI AAb production.
Samples were obtained from stable ambulatory iDCM patients and healthy controls. Peripheral blood monocytes were incubated with cTnI, and cellular proliferation was measured using flow cytometry. AAbs against cTnI were detected by enzyme-linked immunosorbent assay.
A positive cellular proliferative response to cTnI was identified in 20.5% (9/44) patients with iDCM and 5.7% (2/35) of healthy controls (p < 0.05). Positive cTnI AAbs were identified in 20% (7/35) of healthy controls and 13.6% (6/44) of patients with iDCM (p = NS). The presence of cTnI AAbs did not correlate with a positive cellular proliferative response. However, patients with iDCM who had an AAb response to cTnI were less likely to be taking a statin (p < 0.05).
A cellular autoimmune response to cTnI is demonstrated in a subset of patients with iDCM. However, the presence of a cellular response did not correlate with the presence of AAbs to the same antigen.
Clinical and Translational Science 10/2011; 4(5):317-22. · 1.13 Impact Factor
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Jason M Lappé,
Benjamin D Horne,
Svati H Shah,
Heidi T May,
Joseph B Muhlestein,
Donald L Lappé,
Abdallah G Kfoury,
John F Carlquist,
Deborah Budge,
Rami Alharethi,
Tami L Bair,
William E Kraus,
Jeffrey L Anderson
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ABSTRACT: Red cell distribution width (RDW) is associated with morbidity and mortality in coronary artery disease (CAD), but the connection of RDW with chronic inflammation is equivocal.
In 1,489 patients with CAD and 8.4-15.2 years of follow-up all-cause mortality and RDW were studied using Cox regression. RDW and its associations with inflammation, liver function, renal function, and body mass were assessed. A population of 449 normal (No-CAD) patients also was evaluated.
RDW predicted all-cause mortality in a step-wise manner (HR=1.37 per quintile; 95% CI=1.29, 1.46; p-trend<0.001). A significant but meaningless correlation between RDW and high-sensitivity C-reactive protein (hsCRP) was identified (r=0.181; p<0.001). With full adjustment, RDW remained significant (p-trend<0.001) and the strongest predictor of mortality among all factors included in the model. RDW also strongly predicted all-cause mortality in the normal control population (HR=1.33 per quintile, CI=1.15, 1.55; p-trend<0.001), but hsCRP did not predict mortality among normal controls.
RDW was associated with mortality in patients with CAD and may provide clinically useful prognostication. Although RDW was correlated with hsCRP, they were independent predictors of mortality. RDW has been incorporated into risk prediction tool using data from basic chemistries available at: http://intermountainhealthcare.org/IMRS.
Clinica chimica acta; international journal of clinical chemistry 07/2011; 412(23-24):2094-9. · 2.54 Impact Factor
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ABSTRACT: Autoimmune mechanisms, particularly through generation of autoantibodies, may contribute to the pathophysiology of idiopathic dilated cardiomyopathy (iDCM). The precise role of cellular autoimmune responses to cardiac-specific antigens has not been well described in humans. The purpose of this study was to characterize the cellular autoimmune response to cardiac troponin I (cTnI), specifically, the release of cytokines by peripheral blood mononuclear cells (PBMCs), in subjects with iDCM and healthy control subjects.
We performed enzyme-linked immunospot assays on PBMCs isolated from subjects with iDCM and healthy control subjects to examine the ex vivo interferon-gamma (IFN-γ) and interleukin-10 (IL-10) production in response to cTnI exposure. Thirty-five consecutive subjects with iDCM (mean age 53 ± 11 years, 60% male, left ventricular ejection fraction 23 ± 7%) and 26 control subjects (mean age 46 ± 13 years, 46% male) were prospectively enrolled. IFN-γ production in response to cTnI did not differ between the groups (number of secreting cells 26 ± 49 vs 38 ± 53, respectively; P = .1). In contrast, subjects with iDCM showed significantly higher IL-10 responses to cTnI compared with control subjects (number of secreting cells 386 ± 428 vs 152 ± 162, respectively; P < .05). Among iDCM subjects, heightened IL-10 response to cTnI was associated with reduced systemic inflammation and lower prevalence of advanced diastolic dysfunction compared with those with normal IL-10 response to cTnI.
Our preliminary findings suggest that a heightened cellular autoimmune IL-10 response to cTnI is detectable in a subset of patients with iDCM, which may be associated with reduced systemic levels of high-sensitivity C-reactive protein and lower prevalence of advanced diastolic dysfunction.
Journal of cardiac failure 05/2011; 17(5):359-65. · 3.25 Impact Factor
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ABSTRACT: Dilated cardiomyopathy is a devastating disease associated with poor outcomes. Although the etiology of this disease remains largely unknown, so-called "idiopathic" dilated cardiomyopathy (iDCM) is associated with evidence of an autoimmune process that may be contributing to the pathophysiology of this disease. Indeed, iDCM shares many characteristics with other autoimmune diseases, including an association with systemic and organ-specific inflammation, an association with viral infections, a genetic predisposition, and a correlation with specific human leukocyte antigen subtypes. Additionally, numerous pathologic cardiac-specific autoantibodies have been associated with iDCM, including those against alpha-myosin, the beta(1)-adrenoceptor, and cardiac troponin I. This review highlights the emerging evidence regarding autoimmune characteristics of iDCM, and summarizes the data of specific immunomodulatory therapies used to target autoimmune mechanisms in the treatment of patients with this devastating disease.
Journal of cardiac failure 09/2008; 14(6):521-30. · 3.25 Impact Factor
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ABSTRACT: In patients with acute coronary syndrome (ACS), elevated levels of soluble CD40 ligand (sCD40L) are associated with increased risk of cardiovascular events. We evaluated sCD40L levels and future cardiovascular events in patients not experiencing ACS.
Serum sCD40L levels were measured in 909 patients undergoing angiography. A three-way matching scheme (age, gender and catheterization time period) identified 303 patients with coronary artery disease (CAD) who experienced a cardiac event within 1 year (CAD/event), 303 patients with CAD free of events (CAD/no event) and 303 patients without CAD and free of events (no CAD).
Average age was 64 +/- 11 years; 74% were males. Median (+/- SE) sCD40L levels were higher for no CAD patients (335 +/- 60 pg/ml) compared to CAD (248 +/- 65 pg/ml, p = 0.01) and to CAD/event (233 +/- 63 pg/ml, p < 0.001). There was no significant difference in median sCD40L levels between CAD/no event and CAD/event patients. Higher sCD40L quartiles were associated with a significant decrease in the risk of CAD/event versus no CAD (quartile 4 versus quartile 1: odds ratio = 0.59, p = 0.03). There was a nonsignificant trend towards a decreased risk of CAD as compared to no CAD, and for CAD/event versus CAD.
In non-ACS patients, higher sCD40L levels were associated with a decreased risk of CAD. This novel interaction of sCD40L raises interesting questions for CAD pathogenesis.
Cardiology 01/2008; 109(3):196-201. · 1.71 Impact Factor
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Jason M Lappé,
Joseph B Muhlestein,
Donald L Lappé,
Rodney S Badger,
Tami L Bair,
Ruth Brockman,
Thomas K French,
Linda C Hofmann,
Benjamin D Horne,
Susan Kralick-Goldberg,
Nan Nicponski,
Janette A Orton,
Robert R Pearson,
Dale G Renlund,
Holly Rimmasch,
Colleen Roberts,
Jeffrey L Anderson
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ABSTRACT: Despite recent advances in the treatment and prevention of cardiovascular disease, a treatment gap for secondary prevention medications still exists.
To develop and implement a program ensuring appropriate prescription of aspirin, statins, beta-blockers, angiotensin-converting enzyme inhibitors, and warfarin at hospital discharge.
A nonrandomized before-after study comparing patients hospitalized before (1996-1998) and after (1999-2002) implementation of a discharge medication program (DMP). Patients were followed for up to 1 year.
The 10 largest hospitals in the Utah-based Intermountain Health Care system.
In the pre-DMP and DMP time periods, 26,000 and 31,465 patients, respectively, were admitted to cardiovascular services (n = 57,465).
Prescription of indicated medications at hospital discharge; postdischarge death or readmission.
By 1 year, the rate of prescription of each medication increased significantly to more than 90% (P < 0.001); this rate was sustained. At 1 year, unadjusted absolute event rates for readmission and death, respectively, were 210 per 1000 person-years and 96 per 1000 person-years before DMP implementation and 191 per 1000 person-years and 70 per 1000 person-years afterward. Relative risk for death and readmission at 30 days decreased after DMP implementation; hazard ratios (HRs) for death and readmission were 0.81 (95% CI, 0.73 to 0.89) and 0.92 (CI, 0.87 to 0.99) (P < 0.001 and P = 0.017, respectively). At 1 year, risk for death continued to decrease (hazard ratio, 0.79 [CI, 0.75 to 0.84]; P < 0.001) while risk for readmission stabilized (hazard ratio, 0.94 [CI, 0.90 to 0.98]; P = 0.002), probably because survivors had more opportunities to be readmitted.
The study design was observational and nonrandomized, and the authors could not control for potential confounders or determine the extent to which secular trends accounted for the observed improvements.
A relatively simple quality improvement program aimed at enhancing the prescription of appropriate discharge medications among cardiovascular patients is feasible and can be sustained within an integrated multihospital system. Such a program may be associated with improvements in cardiovascular readmission rates and mortality.
Annals of internal medicine 10/2004; 141(6):446-53. · 16.73 Impact Factor
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ABSTRACT: Restenosis after percutaneous transluminal coronary intervention (PCI) remains a serious complication in the treatment of coronary artery disease. Although beta-adrenergic receptor blockers (BBs) effectively reduce many cardiac events, no large prospective studies have examined the association of BBs with restenosis.
We prospectively evaluated the association of BBs (prescribed at hospital discharge) with clinical restenosis in 4840 patients who underwent stent placement (60%), balloon angioplasty (32%), or rotational atherectomy (8%). Clinical restenosis was defined as repeat target lesion revascularization or coronary artery bypass grafting within 6 months of PCI. Other end points included 9-month clinical restenosis, repeat target lesion PCI (only), long-term (5-year) target lesion repeat-PCI, and major adverse cardiac events (MACE). Multivariable regression adjusted the effect of BBs on clinical restenosis for 15 covariables.
The average patient age was 63 years, 75% were men, and 37% received a BB prescription. The incidence of clinical restenosis was 12% overall and was lower among those prescribed a BB (10.0% for BB, 13.5% for none, adjusted odds ratio [OR] 0.76, P =.004). Other predictors of decreased restenosis included stent use, age, and smoking; predictors of increased restenosis included diabetes, atherectomy, and number of treated vessels. BBs also reduced 9-month clinical restenosis (10.3% vs 13.5%, OR 0.75, P =.004), MACE (16.5% vs 20.9%, OR 0.75, P <.001), 6-month target lesion restenosis (7.8% vs 10.2%, OR 0.75, P =.006), and 5-year target lesion restenosis (12.0% vs 14.0%, OR 0.83, P =.046).
beta-Adrenergic receptor blockers prescribed after PCI reduced the risk of clinical restenosis, target lesion restenosis, and MACE in this cohort of 4840 patients. The mechanism by which beta-blockers conferred a protective effect against restenosis remains to be determined.
American heart journal 05/2003; 145(5):875-81. · 4.65 Impact Factor
