Dianne Gallup

A Branched-Chain Amino Acid-Related Metabolic Signature that Differentiates Obese and Lean Humans and Contributes to Insulin Resistance

Metabolomic profiling of obese versus lean humans reveals a branched-chain amino acid (BCAA)-related metabolite signature that is suggestive of increased catabolism of BCAA and correlated with insulin resistance. To test its impact on metabolic homeostasis, we fed rats on high-fat (HF), HF with supplemented BCAA (HF/BCAA), or standard chow (SC) diets. Despite having reduced food intake and a low rate of weight gain equivalent to the SC group, HF/BCAA rats were as insulin resistant as HF rats. Pair-feeding of HF diet to match the HF/BCAA animals or BCAA addition to SC diet did not cause insulin resistance. Insulin resistance induced by HF/BCAA feeding was accompanied by chronic phosphorylation of mTOR, JNK, and IRS1Ser307 and by accumulation of multiple acylcarnitines in muscle, and it was reversed by the mTOR inhibitor, rapamycin. Our findings show that in the context of a dietary pattern that includes high fat consumption, BCAA contributes to development of obesity-associated insulin resistance.

Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events

BACKGROUND The intensity of antiplatelet therapy during percutaneous coronary intervention (PCI) is an important determinant of PCI-related ischemic complications. Cangrelor is a potent intravenous adenosine diphosphate (ADP)-receptor antagonist that acts rapidly and has quickly reversible effects. METHODS In a double-blind, placebo-controlled trial, we randomly assigned 11,145 patients who were undergoing either urgent or elective PCI and were receiving guideline-recommended therapy to receive a bolus and infusion of cangrelor or to receive a loading dose of 600 mg or 300 mg of clopidogrel. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours after randomization; the key secondary end point was stent thrombosis at 48 hours. The primary safety end point was severe bleeding at 48 hours. RESULTS The rate of the primary efficacy end point was 4.7% in the cangrelor group and 5.9% in the clopidogrel group (adjusted odds ratio with cangrelor, 0.78; 95% confidence interval [CI], 0.66 to 0.93; P=0.005). The rate of the primary safety end point was 0.16% in the cangrelor group and 0.11% in the clopidogrel group (odds ratio, 1.50; 95% CI, 0.53 to 4.22; P=0.44). Stent thrombosis developed in 0.8% of the patients in the cangrelor group and in 1.4% in the clopidogrel group (odds ratio, 0.62; 95% CI, 0.43 to 0.90; P=0.01). The rates of adverse events related to the study treatment were low in both groups, though transient dyspnea occurred significantly more frequently with cangrelor than with clopidogrel (1.2% vs. 0.3%). The benefit from cangrelor with respect to the primary end point was consistent across multiple prespecified subgroups. CONCLUSIONS Cangrelor significantly reduced the rate of ischemic events, including stent thrombosis, during PCI, with no significant increase in severe bleeding. (Funded by the Medicines Company; CHAMPION PHOENIX ClinicalTrials.gov number, NCT01156571.).

Sex differences in mortality following acute coronary syndromes.

CONTEXT Conflicting information exists about whether sex differences modulate short-term mortality following acute coronary syndromes (ACS). OBJECTIVES To investigate the relationship between sex and 30-day mortality in ACS, and to determine whether this relationship was modified by clinical syndrome or coronary anatomy using a large database across the spectrum of ACS and adjusting for potentially confounding clinical covariates. DESIGN, SETTING, AND PARTICIPANTS A convenience sample of patients pooled from 11 independent, international, randomized ACS clinical trials between 1993 and 2006 whose databases are maintained at the Duke Clinical Research Institute, Durham, North Carolina. Of 136 247 patients, 38 048 (28%) were women; 102 004 (26% women) with ST-segment elevation myocardial infarction (STEMI), 14 466 (29% women) with non-STEMI (NSTEMI), and 19 777 (40% women) with unstable angina. MAIN OUTCOME MEASURE Thirty-day mortality following ACS. RESULTS Thirty-day mortality was 9.6% in women and 5.3% in men (odds ratio [OR], 1.91; 95% confidence interval [CI], 1.83-2.00). After multivariable adjustment, mortality was not significantly different between women and men (adjusted OR, 1.06; 95% CI, 0.99-1.15). A significant sex by type of ACS interaction was demonstrated (P < .001). In STEMI, 30-day mortality was higher among women (adjusted OR, 1.15; 95% CI, 1.06-1.24), whereas in NSTEMI (adjusted OR, 0.77; 95% CI, 0.63-0.95) and unstable angina, mortality was lower among women (adjusted OR, 0.55; 95% CI, 0.43-0.70). In a cohort of 35 128 patients with angiographic data, women more often had nonobstructive (15% vs 8%) and less often had 2-vessel (25% vs 28%) and 3-vessel (23% vs 26%) coronary disease, regardless of ACS type. After additional adjustment for angiographic disease severity, 30-day mortality among women was not significantly different than men, regardless of ACS type. The relationship between sex and 30-day mortality was similar across the levels of angiographic disease severity (P for interaction = .70). CONCLUSIONS Sex-based differences existed in 30-day mortality among patients with ACS and vary depending on clinical presentation. However, these differences appear to be largely explained by clinical differences at presentation and severity of angiographically documented disease.

Extended Valganciclovir Prophylaxis to Prevent Cytomegalovirus After Lung Transplantation: A Randomized, Controlled Trial

BACKGROUND Cytomegalovirus (CMV) is the most prevalent opportunistic infection after lung transplantation. Current strategies do not prevent CMV in most at-risk patients. OBJECTIVE To determine whether extending prophylaxis with oral valganciclovir from the standard 3 months to 12 months after lung transplantation is efficacious. DESIGN Randomized, clinical trial. Patients were randomly assigned by a central automated system to treatment or placebo. Patients and investigators were blinded to treatment status. (ClinicalTrials.gov registration number: NCT00227370) SETTING Multicenter trial involving 11 U.S. lung transplant centers. PATIENTS 136 lung transplant recipients who completed 3 months of valganciclovir prophylaxis. INTERVENTION 9 additional months of oral valganciclovir (n = 70) or placebo (n = 66). MEASUREMENTS The primary end point was freedom from CMV disease (syndrome or tissue-invasive) on an intention-to-treat basis 300 days after randomization. Secondary end points were CMV disease severity, CMV infection, acute rejection, opportunistic infections, ganciclovir resistance, and safety. RESULTS CMV disease occurred in 32% of the short-course group versus 4% of the extended-course group (P < 0.001). Significant reductions were observed with CMV infection (64% vs. 10%; P < 0.001) and disease severity (110 000 vs. 3200 copies/mL, P = 0.009) with extended treatment. Rates of acute rejection, opportunistic infections, adverse events, CMV UL97 ganciclovir-resistance mutations, and laboratory abnormalities were similar between groups. During the 6 months after study completion, a low incidence of CMV disease was observed in both groups. LIMITATION Longer-term effects of extended prophylaxis were not assessed. CONCLUSION In adult lung transplant recipients who have received 3 months of valganciclovir, extending prophylaxis by an additional 9 months significantly reduces CMV infection, disease, and disease severity without increased ganciclovir resistance or toxicity. A beneficial effect with regard to prevention of CMV disease seems to extend at least through 18 months after transplantation.

Music, imagery, touch, and prayer as adjuncts to interventional cardiac care: the Monitoring and Actualisation of Noetic Trainings (MANTRA) II randomised study

BACKGROUND Data from a pilot study suggested that noetic therapies-healing practices that are not mediated by tangible elements-can reduce preprocedural distress and might affect outcomes in patients undergoing percutaneous coronary intervention. We undertook a multicentre, prospective trial of two such practices: intercessory prayer and music, imagery, and touch (MIT) therapy. METHODS 748 patients undergoing percutaneous coronary intervention or elective catheterisation in nine USA centres were assigned in a 2x2 factorial randomisation either off-site prayer by established congregations of various religions or no off-site prayer (double-blinded) and MIT therapy or none (unmasked). The primary endpoint was combined in-hospital major adverse cardiovascular events and 6-month readmission or death. Prespecified secondary endpoints were 6-month major adverse cardiovascular events, 6 month death or readmission, and 6-month mortality. FINDINGS 371 patients were assigned prayer and 377 no prayer; 374 were assigned MIT therapy and 374 no MIT therapy. The factorial distribution was: standard care only, 192; prayer only, 182; MIT therapy only, 185; and both prayer and MIT therapy, 189. No significant difference was found for the primary composite endpoint in any treatment comparison. Mortality at 6 months was lower with MIT therapy than with no MIT therapy (hazard ratio 0.35 (95% CI 0.15-0.82, p=0.016). INTERPRETATION Neither masked prayer nor MIT therapy significantly improved clinical outcome after elective catheterisation or percutaneous coronary intervention.

The STEDMAN project: biophysical, biochemical and metabolic effects of a behavioral weight loss intervention during weight loss, maintenance, and regain.

The Study of the Effects of Diet on Metabolism and Nutrition (STEDMAN) Project uses comprehensive metabolic profiling to probe biochemical mechanisms of weight loss in humans. Measurements at baseline, 2 and 4 weeks, 6 and 12 months included diet, body composition, metabolic rate, hormones, and 80 intermediary metabolites measured by mass spectrometry. In 27 obese adults in a behavioral weight loss intervention, median weight decreased 13.9 lb over the first 6 months, then reverted towards baseline by 12 months. Insulin resistance (HOMA) was partially ameliorated in the first 6 months and showed sustained improvement at 12 months despite weight regain. Ghrelin increased with weight loss and reverted to baseline, whereas leptin and PYY fell at 6 months and remained persistently low. NPY levels did not change. Factors possibly contributing to sustained improvement in insulin sensitivity despite weight regain include adiponectin (increased by 12 months), IGF-1 (increased during weight loss and continued to increase during weight regain), and visceral fat (fell at 6 months but did not change thereafter). We observed a persistent reduction in free fatty acids, branched chain amino acids, and related metabolites that may contribute to improved insulin action. These findings provide evidence for sustained benefits of weight loss in obese humans and insights into mechanisms.

Implementing rapid HIV testing with or without risk-reduction counseling in drug treatment centers: Results of a randomized trial

OBJECTIVES We examined the effectiveness of risk reduction counseling and the role of on-site HIV testing in drug treatment. METHODS Between January and May 2009, we randomized 1281 HIV-negative (or status unknown) adults who reported no past-year HIV testing to (1) referral for off-site HIV testing, (2) HIV risk-reduction counseling with on-site rapid HIV testing, or (3) verbal information about testing only with on-site rapid HIV testing. RESULTS We defined 2 primary self-reported outcomes a priori: receipt of HIV test results and unprotected anal or vaginal intercourse episodes at 6-month follow-up. The combined on-site rapid testing participants received more HIV test results than off-site testing referral participants (P<.001; Mantel-Haenszel risk ratio=4.52; 97.5% confidence interval [CI]=3.57, 5.72). At 6 months, there were no significant differences in unprotected intercourse episodes between the combined on-site testing arms and the referral arm (P=.39; incidence rate ratio [IRR]=1.04; 97.5% CI=0.95, 1.14) or the 2 on-site testing arms (P=.81; IRR=1.03; 97.5% CI=0.84, 1.26). CONCLUSIONS This study demonstrated on-site rapid HIV testings value in drug treatment centers and found no additional benefit from HIV sexual risk-reduction counseling.

Rationale and design of the cangrelor versus standard therapy to achieve optimal management of platelet inhibition PHOENIX trial

BACKGROUND Despite robust efficacy in the reduction of ischemic events in patients who require percutaneous coronary intervention (PCI), current P2Y(12) inhibitors have limitations. In particular, they require hours to be effective, and they can only be administered orally. Cangrelor is an intravenous, potent, and reversible P2Y(12) inhibitor with fast onset and offset of action. We designed CHAMPION PHOENIX to evaluate the efficacy and safety of cangrelor in patients with atherosclerosis undergoing PCI. TRIAL DESIGN The CHAMPION PHOENIX is a randomized, double-blind, double-dummy, superiority trial comparing cangrelor with clopidogrel standard of care in approximately 10,900 patients who have not previously received a P2Y(12) inhibitor and who require PCI, including patients with stable angina and with acute coronary syndromes (with or without ST-segment elevation). The primary objective of the study is to demonstrate that cangrelor will reduce the incidence of the composite of death, myocardial infarction (MI), ischemia-driven revascularization, or stent thrombosis in the 48 hours after randomization compared with clopidogrel without excessive periprocedural bleeding. The key secondary objective is to demonstrate that cangrelor will reduce the incidence of stent thrombosis. Myocardial infarction will be defined according to the universal MI definition, adapting the definition of PCI-related (type 4a) MI. Bleeding will be assessed according to the thrombolysis in myocardial infarction, GUSTO, and Bleeding Academic Research Consortium (BARC) scales. CONCLUSION The CHAMPION PHOENIX may establish the role of cangrelor in the care of patients who require PCI across the spectrum of stable and unstable coronary diseases in the setting of current treatment strategies.

Does the presence of thrombus seen on a coronary angiogram affect the outcome after percutaneous coronary angioplasty? An angiographic trials pool data experience

OBJECTIVES This study aimed to determine whether pre-existing angiographic thrombus was associated with adverse in-hospital and six-month outcomes after percutaneous coronary interventions. BACKGROUND There are conflicting data about whether pre-existing thrombus is an independent predictor of adverse in-hospital and short-term outcome after coronary interventions. METHODS The Angiographic Trials Pool, a data set derived from eight prospective randomized trials, was analyzed. The study population consisted of 7,917 patients who underwent coronary interventions between 1986 and 1995. Two trials were excluded because they did not collect information regarding thrombus. Patients from the other six trials were divided on the basis of the presence or absence of thrombus. RESULTS In patients with (n = 2,752) and without (5,165) thrombus, in-hospital mortality following angioplasty was low (0.8 vs. 0.6%, p = 0.207). Several adverse outcomes were higher in patients with thrombus: death/myocardial infarction (8.4 vs. 5.5%, p < or = 0.001), in-hospital abrupt closure (5.9 vs. 3.9%, p < or = 0.001) and an in-hospital composite of death, myocardial infarction and/or repeat revascularization (15.4 vs. 11.2%, p < or = 0.001). Six-month mortality was low and comparable between the two groups (2.1 vs. 1.8%, p = 0.34), but the incidence of six-month death/myocardial infarction was higher in patients with thrombus (11.7 vs. 8.7%, p < or = 0.0001). CONCLUSIONS Percutaneous coronary angioplasty can be performed with low mortality in patients with pre-existing thrombus, although these patients are at higher risk of in-hospital and six-month death/myocardial infarction. Continued efforts are required to optimize the outcome in these high risk patients.

Periodontal disease in patients with chronic coronary heart disease: Prevalence and association with cardiovascular risk factors.

Aim There are reported links between periodontal disease (PD) and cardiovascular (CV) risk but data are lacking, especially from populations with established coronary heart disease (CHD). This study describes self-reported indicators of PD and associations with CV risk factors in a global stable CHD population. Methods and results A total of 15,828 participants in the global STABILITY trial underwent a physical examination, blood sampling, and completed a lifestyle questionnaire. They reported remaining number of teeth (none, 1–14, 15–20, 21–25 or 26–32 (all)) and frequency of gum bleeding (never/rarely, sometimes, often or always). Adjusted linear and logistic regression models assessed associations between tooth loss, gum bleeding, and socioeconomic and CV risk factors. A total of 40.9% of participants had <15 remaining teeth; 16.4% had no teeth; and 25.6% reported gum bleeding with large differences in prevalence among countries, regions and ethnic groups. Less tooth loss was associated with lower levels of glucose, low-density lipoprotein (LDL) cholesterol, systolic blood pressure, waist circumference and hs-CRP; higher estimated glomerular filtration rate; decreased odds for diabetes and smoking, and increased odds for higher education, alcohol consumption and work stress. Gum bleeding was associated with higher LDL cholesterol and systolic blood pressure; decreased odds for smoking, but increased odds for higher education, alcohol consumption and stress. Conclusion Self-reported indicators of PD were common in this chronic CHD population and were associated with an increasing socioeconomic and CV risk factor burden. However, causality between self-reported PD and CV risk and outcome needs further investigation.