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Biomedical subjects

Patricia R Hebert

Publications and source records attributed to Patricia R Hebert.

13 recordsLinked to original sources
PubMed2007

Epistatic effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels.

Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) directly influence thrombus formation and degradation and thereby risk for arterial thrombosis. Activation of the renin-angiotensin system has been linked to the production of PAI-1 expression via the angiotensin II type 1 receptor (AT1R). In addition, bradykinin can induce the release of t-PA through a B2 receptor mechanism. In the present study, we aimed to investigate the epistatic effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels in a large population-based sample (n=2527). We demonstrated a strong significant interaction within genetic variations of the bradykinin B2 gene (P=0.002) and between ACE and bradykinin B2 (p=0.003) polymorphisms on t-PA levels in females. In males, polymorphisms in the bradykinin B2 and AT1R gene showed the most strong effect on t-PA levels (P=0.006). In both females and males, the bradykinin B2 gene interacted with AT1R gene on plasma PAI-1 levels (P=0.026 and P=0.039, respectively). In addition, the current study found a borderline significant interaction between PAI 4G5G and ACE I/D on plasma t-PA and PAI-1 levels. These results support the idea that the interplay between the renin-angiotensin, bradykinin, and fibrinolytic systems might play an important role in t-PA and PAI-1 biology.

Bradykinin↗
PubMed2006

The gender-specific role of polymorphisms from the fibrinolytic, renin-angiotensin, and bradykinin systems in determining plasma t-PA and PAI-1 levels.

Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) directly influence thrombus formation and degradation and thus risk for arterial thrombosis. We report here results from a genetic analysis of plasma t-PA and PAI-1 levels in a large population-based sample from the PREVEND study in Groningen, the Netherlands (n = 2,527). We measured polymorphisms from genes of the fibrinolytic system, the renin-angiotensin system (RAS), and the bradykinin system. We found that males had higher levels of natural-log transformed t-PA, and PAI-1 (P < 0.01) compared to females. When stratifying females by menopausal status, PAI-1 levels were only significantly different between pre-menopausal females and males (p < 0.001). Furthermore, we found that age, body mass index, and waist-to-hip ratio were significant predictors of t-PA and PAI-1 in both females and males, and that the regression relationships between these factors and plasma t-PA and PAI-1 were dependent on gender. In addition, we found that the PAI-1 4G/5G polymorphism was a significant predictor of PAI-1 levels in both females and males, that the angiotensin II type I receptor A1166C was a significant predictor of t-PA and PAI-1 levels in females, and that the bradykinin receptor B2 58CT polymorphism was a significant predictor of t-PA levels in females. In conclusion, this large population-based study showed that t-PA and PAI-1 levels are determined by several demographic and genetic factors involved in the fibrinolytic, RAS and bradykinin system. In addition, the results support the idea that the biology of t-PA and PAI-1 is different between females and males.

Adult↗
PubMed2004

Randomized trials of vitamin E in the treatment and prevention of cardiovascular disease.

BACKGROUND: Observational epidemiological studies consistently show that individuals who choose to take high amounts of vitamin E through diet or supplements experience cardiovascular benefits, for which basic research provides plausible mechanisms. However, because the size of the postulated benefit is small to moderate, the confounding inherent in observational studies is as great as the effect size. Before the availability of randomized evidence, about 1 in 4 adults was taking vitamin E supplements in the United States. METHODS: We conducted a computerized search of the English-language literature from 1990 to the present and found 7 large-scale randomized trials of the effectiveness vitamin E in the treatment and prevention of cardiovascular disease. Data were available on myocardial infarction, stroke, or cardiovascular death. RESULTS: Six of the 7 trials showed no significant effect of vitamin E on cardiovascular disease. In an overview, vitamin E had neither a statistically significant nor a clinically important effect on any important cardiovascular event (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.94-1.03) or its components: nonfatal myocardial infarction (OR, 1.00; 95% CI, 0.92-1.09), nonfatal stroke (OR, 1.03; 95% CI, 0.93-1.14), or cardiovascular death (OR, 1.00; 95% CI, 0.94-1.05). CONCLUSIONS: The ORs and CIs provide strong support for a lack of statistically significant or clinically important effects of vitamin E on cardiovascular disease. The use of agents of proven lack of benefit, especially those easily available over the counter, may contribute to underuse of agents of proven benefit and failure to adopt healthy lifestyles.

Adult↗
PubMed2004

Adverse effects of beta-blocker therapy for patients with heart failure: a quantitative overview of randomized trials.

BACKGROUND: Beta-blockers substantially improve survival in patients with chronic heart failure (HF) with left ventricular systolic dysfunction, but concerns about cardiovascular adverse effects may deter physicians from prescribing this therapy. We performed an overview of randomized beta-blocker trials in patients with HF to quantify the risks of these adverse effects. METHODS: Heart failure trials of beta-blockers were identified by electronic searches of the MEDLINE database from 1966 to 2002. The random-effects model was used to combine results from individual trials and calculate estimates of risks associated with therapy. RESULTS: beta-Blocker therapy was associated with significant absolute annual increases in risks of hypotension (11 per 1000; 95% confidence interval [CI], 0-22), dizziness (57 per 1000; 95% CI, 11-104), and bradycardia (38 per 1000; 95% CI, 21-54). There was no significant absolute risk of fatigue associated with therapy (3 per 1000; 95% CI, -2 to 9). beta-Blocker therapy was associated with a reduction in all-cause withdrawal of medication (14 per 1000; 95% CI, -2 to 29) as well as significant reductions in all-cause mortality (34 per 1000; 95% CI, 20-49), HF hospitalizations (40 per 1000; 95% CI, 22-58), and worsening HF (52 per 1000; 95% CI, 10-94). CONCLUSIONS: Although beta-blocker therapy was associated with hypotension, dizziness, and bradycardia, the absolute increases in risk were small, and overall fewer patients were withdrawn from beta-blocker therapy than from placebo. This information should alleviate concerns about prescribing this life-saving therapy to patients with HF.

Adrenergic beta-Antagonists↗
PubMed2004

Prolonged QTc interval and risks of total and cardiovascular mortality and sudden death in the general population: a review and qualitative overview of the prospective cohort studies.

BACKGROUND: In certain subgroups of patients, prolongation of the QTc interval may increase total and cardiovascular mortality due to life-threatening ventricular arrhythmias and sudden death. Nonetheless, whether modest prolongation of the QTc interval in the general population has clinical importance remains unclear. METHODS: We conducted a literature search from 1990 forward to identify all published prospective cohort studies evaluating the association between prolonged QTc interval and risks of total and cardiovascular mortality as well as sudden death. We reviewed each of the studies individually and then conducted a qualitative overview. RESULTS: The 7 prospective cohort studies identified included 36 031 individuals. There were 2677 (8.7%) individuals with prolonged QTc interval, defined as 440 milliseconds or greater. Whereas 1 study reported no association between prolonged QTc interval and mortality (relative risk, 1.02; 95% confidence interval, 0.70-1.49), the other 6 reported inconsistent associations overall as well as across subgroups defined by various characteristics including age, sex, and comorbidities. The reported associations for both cardiovascular mortality and sudden death were also inconsistent. In the overview, the only consistent findings were for the subgroup of patients with prior cardiovascular disease, in which relative risks ranged from 1.1 to 3.8 for total mortality, from 1.2 to 8.0 for cardiovascular mortality, and from 1.0 to 2.1 for sudden death. Further, in individuals without prior cardiovascular disease, associations were either absent or greatly attenuated; specifically, relative risks ranged from 0.9 to 1.6 for total mortality, from 1.2 to 1.7 for cardiovascular mortality, and from 1.3 to 2.4 for sudden death. CONCLUSIONS: There was no consistent evidence for increased risks of total or cardiovascular mortality or of sudden death, except perhaps for patients with prior cardiovascular disease. In the general population, if QTc interval prolongation is associated with any increase in mortality, that risk is likely to be small and difficult to detect reliably.

Cardiovascular Diseases↗
PubMed2004

An application of conditional logistic regression and multifactor dimensionality reduction for detecting gene-gene interactions on risk of myocardial infarction: the importance of model validation.

BACKGROUND: To examine interactions among the angiotensin converting enzyme (ACE) insertion/deletion, plasminogen activator inhibitor-1 (PAI-1) 4G/5G, and tissue plasminogen activator (t-PA) insertion/deletion gene polymorphisms on risk of myocardial infarction using data from 343 matched case-control pairs from the Physicians Health Study. We examined the data using both conditional logistic regression and the multifactor dimensionality reduction (MDR) method. One advantage of the MDR method is that it provides an internal prediction error for validation. We summarize our use of this internal prediction error for model validation. RESULTS: The overall results for the two methods were consistent, with both suggesting an interaction between the ACE I/D and PAI-1 4G/5G polymorphisms. However, using ten-fold cross validation, the 46% prediction error for the final MDR model was not significantly lower than that expected by chance. CONCLUSIONS: The significant interaction initially observed does not validate and may represent a type I error. As data-driven analytic methods continue to be developed and used to examine complex genetic interactions, it will become increasingly important to stress model validation in order to ensure that significant effects represent true relationships rather than chance findings.

Gene Expression Regulation↗
PubMed2003

An update on aspirin in the primary prevention of cardiovascular disease.

BACKGROUND: In 1988, the aspirin component of the Physicians' Health Study, a randomized, double-blind, placebo-controlled trial of 22 071 apparently healthy men was terminated early, due principally to a statistically extreme (P<.00001) 44% reduction in the risk of a first myocardial infarction (MI). The Cardio-Renal Drugs Advisory Committee recommended that the US Food and Drug Administration approve professional labeling of aspirin to prevent first MI. The agency did not act on this recommendation because the only other trial, the British Doctors' Trial of 5139 men, showed no significant benefits. Since that time, 3 additional randomized trials (which included men and women) of aspirin in the primary prevention of MI have been published. METHODS: A computerized search of the English literature from 1988 to the present revealed 5 published trials: the Physicians' Health Study (22 071 participants), the British Doctors' Trial (5139), the Thrombosis Prevention Trial (5085), the Hypertension Optimal Treatment Study (18 790), and the Primary Prevention Project (4495). RESULTS: Among the 55 580 randomized participants (11 466 women), aspirin was associated with a statistically significant 32% reduction in the risk of a first MI and a significant 15% reduction in the risk of all important vascular events, but had no significant effects on nonfatal stroke or vascular death. CONCLUSIONS: The current totality of evidence provides strong support for the initial finding from the Physicians' Health Study that aspirin reduces the risk of a first MI. For apparently healthy individuals whose 10-year risk of a first coronary event is 10% or greater, according to the US Preventive Services Task Force and the American Heart Association, the benefits of long-term aspirin therapy are likely to outweigh any risks.

Adult↗
PubMed2003

The renin-angiotensin system: the role of inhibitors, blockers, and genetic polymorphisms in the treatment and prevention of heart failure.

The renin-angiotensin system (RAS) plays an important role in the pathogenesis and worsening of heart failure (HF). Blocking this system with angiotensin converting enzyme (ACE) inhibitors in patients with HF and left ventricular dysfunction reduces mortality and morbidity and these drugs are currently recommended as standard therapy. A more recently developed class of drug, angiotensin receptor blockers (ARBs) block the RAS at the receptor level, and may therefore provide more complete blockade. ARBs, either singly or in combination with ACE inhibitors, are currently being compared to either ACE inhibitor therapy alone or to placebo in randomized trials of patients with or at high risk of developing HF. With respect to large trials published to date directly comparing ARB versus ACE inhibitor therapy, neither the Losartan Heart Failure Survival Study (ELITE II) nor the Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) found differences in mortality or morbidity between the treatment groups. As regards combination ARB/ACE inhibitor therapy versus ACE inhibitor therapy alone, one completed study, the Valsartan Heart Failure Trial (Val-HeFT), found no differences in mortality but a decrease in HF-related hospitalizations in the combined therapy group. Four additional long-term trials (VALIANT, CHARM, ONTARGET, and TRANSCEND) should complete the totality of evidence regarding the role of ARBs in the treatment of HF. Since genetic polymorphisms affecting drug metabolizing enzymes or drug receptors are known to influence responses to drugs, exploration of these effects on treatment responses to ARBs and ACE inhibitors may provide for more targeted treatment of HF.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2002

Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction.

CONTEXT: beta-Blocker therapy remains substantially underused in cardiac patients despite its proven mortality benefits. Reluctance to prescribe these agents may derive from concerns about their association with symptoms of depression, fatigue, and sexual dysfunction. OBJECTIVE: To determine the association of beta-blockers with depressive symptoms, fatigue, and sexual dysfunction by performing a quantitative review of randomized trials that tested beta-blockers in myocardial infarction, heart failure, and hypertension. DATA SOURCES: Randomized trials of beta-blockers used in the treatment of myocardial infarction, heart failure, or hypertension were identified by searching the MEDLINE database for English-language articles (1966-2001). In addition, we searched the reference lists of previously published trials and reviews of beta-blockers for additional studies. STUDY SELECTION: Criteria for inclusion of trials in the review were: random allocation of study treatments, placebo control, noncrossover design, enrollment of at least 100 patients, and a minimum of 6 months of follow-up. The initial search produced 475 articles, 42 of which met these criteria. Fifteen of these trials reported on depressive symptoms, fatigue, or sexual dysfunction and were selected for inclusion. DATA EXTRACTION: For each trial, 1 author abstracted the frequency of adverse events in the beta-blocker and placebo groups and the numbers of patients randomized to the treatment groups. Two other authors verified the counts of events, and all authors adjudicated any discrepancies. Two different types of information on adverse events were abstracted: patient-reported symptoms and withdrawal of therapy due to a specified symptom. We categorized the tested beta-blockers by generation (early vs late) and lipid solubility (high vs low to moderate). DATA SYNTHESIS: The 15 trials involved more than 35,000 subjects. beta-Blocker therapy was not associated with a significant absolute annual increase in risk of reported depressive symptoms (6 per 1000 patients; 95% confidence interval [CI], -7 to 19). beta-Blockers were associated with a small significant annual increase in risk of reported fatigue (18 per 1000 patients; 95% CI, 5-30), equivalent to 1 additional report of fatigue for every 57 patients treated per year with beta-blockers. beta-Blockers were also associated with a small, significant annual increase in risk of reported sexual dysfunction (5 per 1000 patients; 95% CI, 2-8), equivalent to one additional report for every 199 patients treated per year. None of the risks of adverse effects differed significantly by degree of beta-blocker lipid solubility. The risk associated with reported fatigue was significantly higher for early-generation than for late-generation beta-blockers (P =.04). CONCLUSION: The conventional wisdom that beta-blocker therapy is associated with substantial risks of depressive symptoms, fatigue, and sexual dysfunction is not supported by data from clinical trials. There is no significant increased risk of depressive symptoms and only small increased risks of fatigue and sexual dysfunction. The risks of these adverse effects should be put in the context of the documented benefits of these medications.

Adrenergic beta-Antagonists↗