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Certain immunologic features associated with idiopathic dilated cardiomyopathy (IDC) suggest an infectious and/or autoimmune etiology. In this regard, an association between the major histocompatibility complex class II allele, DR4, and increased risk for IDC was previously identified. In the present report, 43 additional patients with IDC and 236 control subjects were studied for major histocompatibility class II allele associations. DR alleles were identified by microcytotoxicity. No significant differences between control subjects and patients with IDC were seen, although the frequency of DR4 was increased among patients. DR4 subtyping (n = 9) was performed by 'dot blot' hybridization of allele-specific oligonucleotide probes to PCR-amplified genomic deoxyribonucleic acid. The DRB1(*)0401 and DRB1(*)0404 alleles were each found in 44% (n = 4) of patients with IDC, and DRB1(*)0407 was identified in 1 patient (11%). DQ and DP alleles were identified by restriction endonuclease codigestion of polymerase chain reaction-amplified deoxyribonucleic acid. The digested fragments were separated and identified by polyacrylamide gel electrophoresis. Differences between patients and control subjects were observed for DQA1(*)0501 (11% of patients vs 28% of control subjects, p

Coronary artery disease (CAD) is the leading cause of death in the United States. Increasing evidence suggests involvement of inflammation in the atherosclerotic process. We examined cytokines and other inflammatory markers in 865 patients with chest pain in whom coronary angiography revealed no evidence of CAD or CAD with or without concomitant myocardial infarction (MI). We developed a multiplexed immunoassay to simultaneously assess the plasma concentrations of 8 cytokines (interferon gamma, interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, IL-12, and tumor necrosis factor alpha), IL-2r, and soluble CD40 ligand in the patient groups. Concentrations of C-reactive protein (CRP) and IL-18 also were determined. Significant differences (P < .05) between no CAD and combined CAD groups were found for IL-2, IL-4, IL-6, IL-12, and IL-18. When the no CAD group was compared with the group with CAD with subsequent MI, significant differences were found for proinflammatory markers IL-6 (P pound .001), IL-8 (P = .017), and CRP (P pound .001). Cytokine profiles may have a role in differentiating patients with CAD with MI from those with chest pain due to other disorders and in deciphering the role of inflammation in the pathogenesis of CAD.

AbstractObjective: To evaluate soluble (s) ST2 as a biomarker of rejection, allograft vasculopathy and mortality after orthotopic heart transplantation (OHT).Methods: sST2 concentrations were measured in 241 patients following OHT.Results: Elevated sST2 was associated with cellular rejection (CR) 1R, with highest rates of CR in the 4th sST2 quartile (p  0.003). No significant association between sST2 and antibody-mediated rejection or allograft vasculopathy was found. sST2 30 ng/mL independently predicted death over 7-year follow-up (HR  2.01; 95 CI 1.15–3.51; p  0.01).Conclusion: Concentrations of sST2 are associated with the presence of CR and predict long-term mortality following OHT.

Peripartum (PP) cardiomyopathy (CM) is a rare condition of unknown etiology that occurs in late pregnancy or early postpartum. Initial evidence suggests that genetic factors may influence PPCM. This study evaluated and replicated genome-wide association of single nucleotide polymorphisms with PPCM.

Adrenergic activation is an important determinant of outcomes in chronic heart failure. Adrenergic activity is regulated in part by prejunctional 2C-adrenergic receptors (ARs), which exhibit genetic variation in humans. Bucindolol is a novel -AR blocking agent that also lowers systemic norepinephrine and thus is also a sympatholytic agent. This study investigated whether 2C-AR polymorphisms affect sympatholytic effects of bucindolol in patients with heart failure.

The completion of the Human Genome Project (HGP) holds promise for further insight into how genetic differences contribute to an individual's response to a medicine(s). Even before the completion of the HGP, cardiovascular medicine was thrust into the arena of pharmacogenomics by the observation that many drugs, cardiovascular and noncardiovascular, promote cardiac arrhythmias. It is now recognized that these adverse responses as well as beneficial responses to cardiovascular medicines can be influenced by alterations in the genes for metabolizing enzymes, drug transporters, and drug targets. To the present, much basic information regarding gene–drug interactions has accumulated, but translation to clinical care has been slow. It is anticipated that the pace of clinical cardiovascular pharmacogenomics will increase as the result of better‐designed studies and technological advances. The final adoption of this area of investigation into clinical practice will also be influenced by financial, psychosocial, and legal factors. Drug Dev. Res. 62:180–190, 2004. © 2004 Wiley‐Liss, Inc.

BackgroundRestenosis after percutaneous coronary intervention (PCI) constitutes a serious complication in the treatment of cardiovascular disease, but known risk factors do not fully account for the observed restenosis risk. Preliminary studies of infection or inflammation in restenosis report varied results. We tested whether C-reactive protein (CRP) or pathogen burden (seropositivity to 0, 1, 2, or 3 pathogens, of Chlamydia pneumoniae[Cpn], cytomegalovirus [CMV], or Helicobacter pylori[Hpy]) predict clinical restenosis after percutaneous coronary intervention (PCI). MethodsBlood samples were collected from 415 patients undergoing PCI, and levels of plasma CRP and antibodies to Cpn, CMV, and Hpy were measured. The patient's medical history, demographics, and procedural data were recorded. Patient end points were determined for as long as 6 months as a means of evaluating the incidence of clinical restenosis and major adverse cardiac events. ResultsThe average patient age was 62 years, and 80% of patients were male. Fifty-eight patients (14%) experienced clinical restenosis, whereas 17 patients (4%) died or had an acute myocardial infarction. After adjusting for 19 possible predictors, we found the pathogen burden (P-trend =.04, adjusted odds ratio [OR] 1.5 per number of pathogens) and minimum luminal diameter (P=.003, OR 1.8 per mm decrease) to be significant predictors of clinical restenosis. Male sex was a nonsignificant predictor of restenosis (P=.06, OR 2.2), but CRP was not significant after adjustment (P-trend =.10, OR 0.73 per tertile). ConclusionPathogen burden was associated with clinical coronary restenosis, an association that deserves further exploration and evaluation. CRP, a marker of inflammation, was not associated with an increased risk of restenosis. (Am Heart J 2002;144:491-500.)

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In patients with coronary artery disease (CAD), azithromycin therapy is associated with decreased cytokine levels and overall reduction of inflammation. Chlamydia pneumoniae(C.Pn) is a common pathogen that may be an important factor in the development and progression of atherosclerosis. Cell-adhesion molecules have an important role in recruitment of inflammatory cells during plaque development and are expressed by endothelial cells on activation. We sought to define the effect of treatment with azithromycin on circulating levels of soluble vascular cell-adhesion molecule (VCAM-1), intercellular adhesion molecule (ICAM-1), and E-selectin in patients with CAD. Plasma concentrations of VCAM-1, ICAM-1, and E-selectin were measured in 40 patients with documented CAD and a positive (≥1:16) immunoglobulin G (IgG) titer against C.Pn, 20 subjects with normal coronary arteries, and 14 healthy volunteers. Patients were assigned randomly to receive either 500 mg/wk of azithromycin or placebo for 3 months. Serum samples were obtained at baseline, at 3 months, and during the follow-up visit at 6 months. Patients with documented CAD exhibited elevation of VCAM-1 (535 ± 227 ng/ml; p = 0.0001) and E-selectin (69 ± 29 ng/ml; p = 0.006), but not ICAM-1 (321 ± 65 ng/ml) concentrations as compared with the patients with angiographically proven normal coronary arteries (252 ± 80; 50 ± 22; and 311 ± 40 ng/ml) and healthy controls (110 ± 18; 29 ± 2; and 238 ± 47 ng/ml, respectively). Prolonged treatment with azithromycin did not significantly affect the plasma levels of soluble VCAM-1, ICAM-1, and E-selectin. Soluble markers of endothelial activation are markedly increased in patients with documented CAD as compared with those with normal coronary arteries and healthy controls. Despite substantial heterogeneity in plasma E-selectin, ICAM-1, and VCAM-1 levels, long-term azithromycin treatment did not affect plasma levels of these adhesion molecules, indicative of endothelial activation, over a period of 6 months.

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Introduction:Mitochondrial DNA copy number (mtDNA-CN) is associated with cardiovascular disease (CVD) and mortality. Here we examine, in a high-risk CVD population, the association with prevalent coronary artery disease (CAD) and subsequent major adverse events (MACE) at 1-,5- and 10-year follow-up of mtDNA-CN.Methods:Consecutive subjects (n=2267) consenting to a blood sample drawn for the Intermountain INSPIRE biorepository at the time of a coronary angiogram from July 1994 to Sept 2003 were included. The mtDNA-CN was determined by multiplexed real-time polymerase chain reaction coamplifying a stable site of mt D- Loop and a region of a single copy genomic β-2-microglobulin gene(β2M). MtDNA-CN is given as the ratio of Mt to β2M DNA. The presence of severe CAD (>70% stenosis) was analyzed using multivariate logistic regression. The subsequent MACE (including all-cause mortality and non-fatal MI) outcomes were studied using multivariate Cox proportional hazard regression.Results:The average age of subjects was 62.3 ± 13.8, 35% were female, and 50% had prior CAD. Over half (55%) had severe CAD at the angiogram. As the mtDNA-CN increased, severe CAD decreased (58% for 1stquartile vs. 51% for 4thquartile). After adjustment for baseline differences, subjects with mtDNA-CN in the 1stquartile were 1.31 times more likely to have severe CAD than subjects with mtDNA-CN in the 4thquartile (95% CI: 1.01, 1.71; p=0.04). A total of 902(39.8%) had a subsequent MACE event within 10-years (193[8.5%] in 1-year and 548[24.2%] in 5-years). There was no association between mtDNA-CN and 1-year MACE. However, mtDNA-CN was associated with 5-year (p=0.006) and 10-year (p=0.003) MACE. After adjustment, subjects with mtDNA-CN in the 1stquartile were at 1.29 increased risk of 10-year MACE than subjects with mtDNA-CN in the 4thquartile (95% CI: 1.07, 1.56; p=0.008).Conclusions:In a coronary angiographic population, mtDNA-CN was associated with severe CAD and the risk of subsequent long-term MACE. These findings suggest that mtDNA-CN could be used as a clinical biomarker for risk. Moreover, understanding the factors impacting mtDNA-CN may also help in the prevention of secondary CVD outcomes.

Background:The SARS-CoV-2 B.1.1.7 variant, also known as the UK or alpha variant, carries the spike 69/70 deletion mutation and has been reported to be more contagious and possibly more virulent than other variants. This study examines follow-up cardiovascular outcomes for patients infected with deletion-carrying SARS-CoV-2 alpha variant.Methods:From October 2020 to May 2021, all positive SARS-CoV-2 samples at Intermountain Healthcare were tested for the 69/70 deletion (n=92822). Patient characteristics, COVID-19 treatments, and follow-up outcomes were extracted from Intermountain records. Cox hazard regression analysis with multivariable adjustment was used to determine risk of subsequent major cardiovascular adverse event outcomes (MACE), which included all-cause death, heart failure (HF), and hospitalization for coronary artery disease (CAD) or atrial fibrillation (AF).Results:Overall, 4.2% of patients testing positive for the SARS-CoV-2 virus carried the deletion mutation with prevalence increasing with time, ranging from 1.3% in October to 61.0% in May. Baseline characteristics, treatments, and outcomes stratified by non-mutant and deletion mutation status are shown in the Table. While the mutation did result in higher rates of COVID hospitalization (adjusted OR=1.68, p<0.001), there was no difference in overall MACE after adjustment by baseline characteristics and risk factors. There was a non-significant trend toward an increased rate of all-cause death in patients carrying the mutant variant (adjusted HR=1.90, p=0.12).Conclusions:The SARS-CoV-2 deletion mutant, while resulting in an increased risk of COVID hospitalization and a trend toward increased death, did not increase the risk of subsequent CVD. Because of the recent emergence of the variant the long-term effects are not known. Thus, it remains important to minimize risk of exposure. Moreover, long-term surveillance of subsequent CVD risk is warranted.

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We have previously reported a correlation between biopsy-proven rejection and the presence of IL-2-responsive lymphocytes for biopsy specimens from human cardiac allografts. We thus hypothesized a relationship between tissue expression of HLA class II antigen (DR) and the outgrowth of IL-2-responsive lymphocytes. Employing immunofluorescence DR staining with a propidium iodide counterstain in consecutive specimens from 41 patients, we found two patterns of DR expression: DR expressed on the vascular endothelial surface (donor antigens) and/or on myocardial infiltrating cells (presumably recipient antigens). Specimens were categorized by histologic diagnosis as “baseline nonrejecting controls” that were obtained 7.5±0.4 (mean ±SE) days posttransplantation, “nonrejecting” (obtained 59.9±5.8 days posttransplantation), “prerejecting” (obtained 47.7±6.3 days posttransplantation), and “rejecting” (obtained 101.3±10.1 days posttransplantation). Prerejecting specimens were histologically negative specimens obtained from patients a mean of 6.0±0.4 days before a biopsy-proven rejection episode. The percentage of specimens positive for interstitial DR staining were: < 1 for controls, 30 for nonrejecting specimens, 68 for prerejecting, and 46 for rejecting. For vascular DR staining, 25 of control specimens were positive, 56 of nonrejecting, 74 of prerejecting, and 73 of rejecting specimens. Culture positivity was seen for 38 of controls, 35 of nonrejecting specimens, 79 of prerejecting, and 70 of rejecting. Vascular DR staining was higher than interstitial staining for all specimen categories. For the vascular pattern, the mean score was significantly higher for culture-positive specimens compared to culture negative (0.87±0.1 vs. 0.59±0.1; P<0.01). A similar relationship was not found for the interstitial pattern. Lymphocyte growth occurred in conjunction with vascular DR upregulation significantly more frequently than in conjunction with interstitial DR expression (65 vs. 35 of culture-positive specimens, P<0.0001). These findings suggest a relationship be

Objectives. This study used a meta-analysis to examine HLA-DR frequencies in rheumatic heart disease and prospectively examined other class II allelic disease associations.

Objectives. The objectives of this study were to test prospectively for an association between Chlamydiaand atherosclerosis by comparing the incidence of the pathogen found within atherosclerotic plaques in patients undergoing directional coronary atherectomy with a variety of control specimens and comparing the clinical features between the groups.

Objectives. We sought to test whether C-reactive protein (CRP) and seropositivity to any of three infectious agents are associated with angiographic coronary artery disease (CAD) and clinical myocardial infarction (MI).

Objectives. We tested for an association between the angiotensin-converting enzyme (ACE) DD polymorphic genotype and myocardial infarction (MI) in a sample group composed exclusively of women.

AbstractObjective:To assess the potential for nosocomial measles transmission by measuring seropositivity among healthcare workers in Utah.Design:Blood specimens were collected for measurement of measles IgG antibody by enzyme immunoassay (EIA). Individuals with undetectable or equivocal antibody levels were considered at risk for infection. Employees were grouped according to the decade of their birth, and analyses of serological findings were done by the Mantel-Haenszel chi-square test for trend.Setting:The study was performed in a healthcare organization comprised of six urban and 10 rural hospitals.Participants:Employees (n = 5825) were tested regardless of age, history of disease, or immunization.Results:There were 599 employees (10.3%) who were nonimmune. A trend showing age-related differences in immunity was not noted among employees born prior to 1957 (4.7% nonimmune). However, for employees born after that time, there was a significant age-associated increase in the percentage of susceptible individuals (P= 0.00001). The rate of susceptibility was 8.1% for individuals born between 1957 and 1959, 16.3% for individuals born during the 1960s, and 33.7% for those born in the 1970s.Conclusions:We concluded that employees born after 1960 represent a material risk for transmission of measles in the hospital setting. Despite the low percentage of susceptibility among those born before 1957, the 144 susceptible individuals in this group also are at risk for measles transmission. Thus, during periods of increased measles prevalence, we would recommend screening all healthcare workers regardless of age and vaccinating those who are susceptible.

Introduction:Genetic factors are known to play an important role in NIDC with a large number of pathogenic mutations in multiple genes reported. TTNtvmutations are of interest because of their common and consistent appearance in NIDC series. However, the comparative severity and prognosis of TTNtv-associated NIDC is controversial.Methods:Consecutive patients with NIDC presenting to Intermountain Medical Center Specialty Clinics and entered into the INSPIRE Registry and DNA Bank were studied (N=231). Whole exome sequencing was performed using an Illumina Novaseq platform. Samples were processed with Sentieon analysis software using the GRCh38 human reference genome. Variant calls were annotated with ClinVar (September 2018 update). Presenting severity was assessed, and 5-year outcomes were defined, blinded to genotype, as recovered (LVEF>=50%), persistent LVEF 21-49%), or progressive (LVAD, transplant, VT/VF, heart failure death or LVEF<=20%).Results:DNA samples from a consecutive series of 231 NIDC patients (age=56 +/- 14 y, 42% women, 95% white) were analyzed. TTNtv?s were discovered in 17 patients; 7 had known and 10 had novel mutations (8 unique). 15/17 (88%) TTN+vs. 115/207 (56%) TTN-patients presented with severe NIDC (LVEF<=20%) (p=0.024). By 5-years, NIDC less often recovered (6% vs. 29%) and more likely was persistent (41% vs 46%) or progressive (53% vs. 25%) in TTN+vs. TTN-patients (p=0.021) (Table). Prognosis was similar with known and novel mutations. Potential causal co-factors were noted frequently in both groups (Table).Conclusion:In a consecutive series of NIDC patients, TTNtvpositivity was associated with a more severe presentation and a worse 5-year prognosis. Non-genetic predisposing factors are frequent in NIDC and may act in concert with genetic factors to precipitate heart failure.

Introduction:Omega-3 supplements are widely used for cardiovascular (CV) prevention. However, Brasky et-al* reported that levels of long-chain fatty acids correlated positively with the development of prostate cancer (PrCA), i.e., PrCA risk increased with increasing levels of docosahexaenoic acid (DHA) although not with eicosapentaenoic acid (EPA). Given potential public health implications of this report, we prospectively tested this finding in the INSPIRE Registry.Methods:Plasma samples from all men prospectively enrolled in the large, prospective INSPIRE Registry who developed incident PrCA during follow-up were selected and matched ~2:1 in a case-control design with men of similar age and entry date who were free of PrCA throughout follow-up. Plasma lipid fractions were analyzed by rapid throughput liquid chromatography-mass spectrometry. Levels in the 2 groups were compared by the Wilcoxon rank sum test. Our null hypothesis was that DHA and EPA levels are not related to increased PrCA risk.Results:We identified samples from 87 men (age: 67.3 +/- 8.6 y) who developed PrCA (at 4.6 +/- 3.7 y) and matched them to 149 samples from control men (age: 66.2 +/- 8.6 y); follow-up averaged 10.1 +/- 3.8 y and 13.5 +/- 3.7 y, respectively. Results are shown in the Table. Entry levels of both DHA (p=0.047) and EPA (p=0.012) were significantly lowerin PrCA patients than in controls.Conclusions:DHA and EPA levels were not found to be positively related to PrCA risk; rather, findings suggest protective potential. These results are in keeping with recent randomized trials of omega-3 supplementation (VITAL, REDUCE-IT), which did not note increased cancer or non-CV death risk. Moreover, our results go beyond supplementation to directly address the impact on PrCA risk of circulating omega-3 levels themselves. These results imply that supplementation may be based on potential CV benefits apart from concerns for PrCA risk.

Previous work has suggested an association between Chlamydia pneumoniaeinfection and coronary atherosclerosis, based on the demonstration of increased serologic titers and the detection of bacteria within atherosclerotic tissue. We sought to strengthen a possible etiologic link by comparing the incidence of Chlamydiainfection in coronary atherosclerotic tissue to that in coronary arteries of patients with non-atherosclerotic cardiovascular disease.