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Introduction: Cardiovascular disease (CVD) is a disease of aging. While men with hemophilia were initially thought to be protected from CVD, it is now clear that atherothrombotic events do occur. ...The objective of this study is to determine the prevalence of CVD and CV risk factors in older men with moderate and severe hemophilia.
Methods: A U.S. national cross-sectional study began enrollment in 10/2012. Included are men with moderate or severe congenital hemophilia A or B (FVIII or IX level ≤ 5%), age 54-73. Men with an additional bleeding disorder (besides liver dysfunction) were excluded. After informed consent, CV risk factors, medications, and thrombotic event history were obtained from patient interview and chart review. A fasting blood sample was assayed centrally.
Results: As of 7/24/2015, 194 of 200 planned subjects were recruited with enrollment to be completed by 9/2015 and analysis by 12/2015. Planned interim analysis on 165 subjects from 19 U.S. Hemophilia Treatment Centers is presented here. The majority were white (148; 89.7%) or African American (14; 8.5%). Mean age was 61 years (SD: 5; range: 54-73). Most used factor on demand, with only 30.3% (50/165) on prophylaxis, defined as ≥2 doses of FVIII or ≥ 1 dose FIX/week. Eight (4.9%) had a current inhibitor. Viral infection was common; 61.2% had hepatitis C, and 28.5% HIV.
Hypertension (HTN) was reported in 61.2% of subjects, dyslipidemia in 35.1%, and diabetes (DM) in 21.8%; 49.1% had ever smoked, 55.2% denied engaging in at least moderate physical activity and 43.0% had a family history of CVD. Average BMI was 28 kg/m2 (30.3% obese) and waist circumference 96 cm (32.1% enlarged). Fasting blood work showed an abnormally elevated: creatinine in 26.7% subjects (mean, SD) (1.1 mg/dl, 0.5), CRP in 9.7% (5.2 mg/L, 13.7), total cholesterol in 23.0% (174.1 mg/dl, 38.8), triglycerides in 27.9% (129.1 mg/dl, 68.3), LDL in 21.8% (105.1 mg/dl, 34.7); and low HDL in 42.4% (43.2 mg/dl, 11.8).
A minority, 14 subjects (8.5%) reported prior angina or atrial fibrillation/flutter; 5 (3.0%) leg deep venous thrombosis; 4 (2.4%) myocardial infarction (MI) or pulmonary embolism; 3 (1.8%) coronary artery stent placement; 2 (1.2%) transient ischemic event (TIA); and 1 (0.6%) coronary artery angioplasty, CABG, or peripheral arterial disease history.
The prevalence rate of CVD (defined as angina, MI, TIA, or ischemic or embolic stroke) was 9.7% (16 subjects), significantly lower than the 23% prevalence of CVD in similar aged men without hemophilia in the longitudinal Atherosclerosis Risk in Communities (ARIC) cohort (p-value <0.001). None of the men with CVD were on antiplatelet or anticoagulant medications.
Compared to never smokers, ever smokers had a significant odds ratio (OR) of 3.5 (95% CI 1.1-11.3) of CVD. For HTN, dyslipidemia, and DM, the OR (95% CI) of CVD were 2.0 (0.6-6.6), 2.0 (0.7-5.6), and 1.2 (0.4-4.0), respectively. Positive family history (OR 1.4 (0.5-3.8)) and low-level physical activity (1.1 (0.4-3.3)) also suggested some association with increased CVD risk. Higher triglycerides (1.2 (0.4-3.7)) and lower HDL (1.4 (0.5-3.9)) tended to increase CVD risk, but obesity was not a risk factor.
Men using prophylaxis appeared less likely to have CVD (3/50, 6.0%) than men not on prophylaxis (13/115, 11.3%), OR 0.5 (0.1-1.8), although the difference was not statistically significant. HIV+ men (2/47, 4.3%) were also less likely to have CVD compared to non-HIV+ men (14/115, 12.2%), OR 0.3 (0.07-1.5), but not significantly so. Current use of anti-HTN medications (42.4% of all subjects), cholesterol lowering agents (17.6%), and DM medications (13.3%) did not decrease CVD risk. Analysis of cause and effect is limited by the cross-sectional design.
Conclusions: In this interim analysis of an ongoing national cross-sectional study, older men with moderate to severe hemophilia commonly report risk factors for CVD, including HTN (61.2%), dyslipidemia (35.2%) and renal insufficiency (26.7%). Despite this, the prevalence of reported CVD is low at 9.7%, suggesting that men with hemophilia may be protected from forming pathogenic thrombi. Smoking significantly increased the OR of CVD events among men with hemophilia. More data are needed to determine if the approach to prophylaxis or other therapies should be altered in this population. We plan to formally compare the prevalence of CVD and CV risk factors with similarly aged men in the ARIC database once enrollment is complete.
Sood:Bayer: Research Funding. Ragni:Vascular Medicine Institute: Research Funding; Tacere Benitec: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Research Funding; Biogen: Research Funding; Alnylam: Research Funding; Bristol Myers Squibb: Research Funding; Bayer: Research Funding; Genentech Roche: Research Funding; SPARK: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Dimension: Research Funding. Quon:Baxter: Other: Advisory Board, Speakers Bureau; Bayer: Other: Advisory Board; Biogen: Other: Advisory Board, Speakers Bureau; Novo Nordisk: Other: Advisory Board, Speakers Bureau; Grifols: Speakers Bureau. Shapiro:Baxalta, Novo Nordisk, Biogen, ProMetic Life Sciences, and Kedrion Biopharma: Consultancy; Baxalta, Novo Nordisk, Biogen,: Membership on an entity's Board of Directors or advisory committees; Biogen: Speakers Bureau; Bayer Healthcare, Baxalta, Biogen, CSL Behring, Daiichi Sankyo, Kedrion Biopharma, Octapharma, OPKO, ProMetic Life Sciences, PTC Therapeutics, and Selexys: Research Funding. Cuker:Bracco: Consultancy; Genzyme: Consultancy; T2 Biosystems: Research Funding; CSL Behring: Consultancy. von Drygalski:CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hematherix Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gill:Baxalta, Bayer, and CSL-Behring: Membership on an entity's Board of Directors or advisory committees. Leissinger:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding. Konkle:Pfizer: Consultancy; CSL Behring: Consultancy; Octapharma: Research Funding; Baxalta: Consultancy, Research Funding; Biogen: Consultancy, Research Funding; Novo Nordisk: Consultancy.
We have examined transcription in an early diverging eukaryote by analyzing the effect of the fungus-derived toxin alpha-amanitin on the transcription of protein-coding genes of the protist ...Trichomonas vaginalis. In contrast to that typical in eukaryotes, the RNA polymerase that transcribes T. vaginalis protein-coding genes is relatively resistant to alpha-amanitin (50% inhibition = 250 microg alpha-amanitin/ml). We have also characterized the gene encoding the largest subunit of RNA polymerase II, the subunit that binds alpha-amanitin. This protein is 41% identical to the mouse RNA polymerase II. Sequence analysis of the 50-amino-acid region thought to bind alpha-amanitin shows that this region of the trichomonad RNA polymerase II lacks many of the conserved amino acids present in the putative binding site, in agreement with the observed insensitivity to this inhibitor. Similar to other RNA polymerase IIs analyzed from ancient eukaryotes, the T. vaginalis RNA polymerase II lacks the typical heptapeptide (Tyr-Ser-Pro-Thr-Ser-Pro-Ser) repeat carboxyl-terminal domain (CTD) that is a hallmark of higher eukaryotic RNA polymerase IIs. The trichomonad enzyme, however, does contain a short modified CTD that is rich in the amino acid residues that compose the repeat. These data suggest that T. vaginalis protein-coding genes are transcribed by a RNA polymerase II that is relatively insensitive to alpha-amanitin and that differs from typical eukaryotic RNA polymerase IIs as it lacks a heptapeptide repeated CTD.
An elongated beta-subunit of the lysosomal enzyme beta-hexosaminidase was found in fibroblast strains derived from two patients with juvenile Sandhoff disease and two asymptomatic individuals sharing ...an unusual isoenzyme pattern: a low level of residual A (alpha beta) isoenzyme activity (3-6% of normal for the juvenile Sandhoff and 9-10% for the asymptomatic strains) without B (beta beta) isoenzyme activity. The elongated beta-subunit was abnormal in other ways: It reacted with antiserum against the unfolded polypeptide, it was not phosphorylated on mannose residues, it was not processed to the mature form, and it was degraded rapidly. The increased length of the beta-subunit was caused by two different mutations. Cells from two juvenile Sandhoff and one asymptomatic individuals had the previously described G—-A transition in intron 12 that creates a splice site, causing an in-frame insertion of 24 intronic nucleotides into mRNA (Nakano, T., and Suzuki, K. (1989) J. Biol. Chem. 264, 5155-5158). The second mutation was found in cells from the asymptomatic girl whose A+B- isoenzyme pattern had been designated “Hexosaminidase Paris” (Dreyfus, J. C., Poenaru, L., Vibert, M., Ravise, N., and Boue, J. (1977) Am. J. Hum. Genet. 29, 287-293); duplication of a region straddling the junction of intron 13 and exon 14 generates an alternate splice site, causing an in-frame insertion of 18 nucleotides into mRNA. Although the two new splice sites are used preferentially, the normal sites may be used to some extent, accounting for the residual A isoenzyme activity.
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