Estrogen and different aspects of vascular disease in women and men.
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Aorta↗
Biomedical subjects
Daniel F Pauly
Publications and source records attributed to Daniel F Pauly.
Sustained restoration of autonomic balance with long- but not short-acting metoprolol in patients with heart failure.
BACKGROUND: The purpose of this study was to compare the effects of immediate-release (IR) metoprolol and extended-release (XL) metoprolol on measures of heart rate variability in chronic systolic heart failure patients. METHODS AND RESULTS: Thirteen metoprolol-treated heart failure patients were randomized to a 2-way crossover study of equal daily doses of metoprolol IR and metoprolol XL, each administered for 3 weeks. After each 3-week interval, patients underwent 24-hour Holter and ambulatory blood pressure monitoring. Over the entire 24-hour period, the ratio of high to total variability (normalized measure of parasympathetic activity) was significantly greater (P < .05), the ratio of low to total variability (normalized measure of sympathetic activity) was significantly lower (P < .05), and the ratio of high to low variability (index of parasympathetic to sympathetic balance) was greater (P < .08) for metoprolol XL compared with metoprolol IR. Over the entire 24-hour period, both systolic and diastolic blood pressure were significantly lower for metoprolol XL compared with metoprolol IR (P < .0001, and .0005, respectively). CONCLUSION: These data suggest that with twice daily dosing, metoprolol IR is inferior to metoprolol XL in its effects on heart rate variability, autonomic balance, and blood pressure in patients with heart failure.
Adrenergic beta-Antagonists↗
Discordant beta-blocker effects on clinic, ambulatory, resting, and exercise hemodynamics in patients with hypertension.
STUDY OBJECTIVES: To determine the correlation between ambulatory and clinic blood pressure in assessing antihypertensive response to beta-blockade, to test whether blood pressure response to metoprolol is associated with the heart rate response, and to determine whether exercise and resting heart rate responses to metoprolol are correlated. DESIGN: Post hoc analysis of a prospective cohort study. SETTING: University-affiliated general clinical research center. PATIENTS: Fifty-one patients aged 35-65 years with uncomplicated hypertension. Intervention. All patients received metoprolol at a dosage titrated to achieve a diastolic blood pressure below 90 mm Hg. MEASUREMENTS AND MAIN RESULTS: Clinic and 24-hour ambulatory blood pressure measurements were obtained and exercise treadmill testing was performed before and after metoprolol treatment. Based on ambulatory blood pressure data, 24 patients (47%) responded (defined as at least a 10% reduction in diastolic blood pressure) to metoprolol compared with 36 patients (71%) based on clinic blood pressure data (p=0.027). Clinic blood pressure was associated with a 67% false-positive rate (responsive blood pressure by clinic data that was actually nonresponsive by ambulatory data). Blood pressure responders and nonresponders exhibited similar reductions in exercise heart rate (24% and 23%, p=0.74). However, responses to metoprolol measured by exercise heart rate versus resting heart rate were not significantly correlated (r=0.24, p=0.105). CONCLUSION: Reliance on clinic blood pressure or resting heart rate for making beta-blocker treatment decisions may yield less than optimal assessment of the antihypertensive response or degree of beta-blockade.
Adrenergic beta-Antagonists↗
Management of heart failure after cardiac resynchronization therapy: integrating advanced heart failure treatment with optimal device function.
Cardiac resynchronization therapy (CRT) is an established adjunctive treatment for patients with systolic heart failure (HF) and ventricular dyssynchrony. The majority of recipients respond to CRT with improvements in quality of life, New York Heart Association functional class, 6-min walk test, and ventricular function. Management of HF after CRT may include up-titration of neurohormonal blockade and an exercise prescription through cardiac rehabilitation to further improve and sustain clinical outcomes. Diagnostic data provided by the CRT device may help to facilitate and optimize treatment. Initial nonresponder rates remain problematic. We suggest a simple step-by-step management and troubleshooting strategy that integrates device function with advanced HF therapy in patients who do not initially respond to CRT. This algorithm represents a new, comprehensive, collaborative approach between the HF and electrophysiology specialists to further improve and sustain outcomes in the field of CRT.
Adrenergic beta-Antagonists↗
Atrial fibrillation as a cause of left ventricular dysfunction after cardiac transplantation.
We report 3 cases of late-onset atrial fibrillation several years after cardiac transplantation, each involving left ventricular systolic dysfunction in the absence of cardiac rejection or cardiac allograft vasculopathy. Although the etiology of late-onset atrial fibrillation in cardiac transplant recipients is not clear, its presence in the absence of cardiac rejection or coronary allograft vasculopathy can result in left ventricular systolic dysfunction, and therefore should be considered in the differential diagnosis of cardiac allograft failure. The onset of atrial fibrillation years after a heart transplant is not necessarily an indication of rejection. Aggressive rate control and restoration of normal sinus rhythm may improve allograft function in such cases.
Atrial Fibrillation↗
Cardiac function and heart failure.
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Animals↗
beta-Adrenergic receptor polymorphisms and responses during titration of metoprolol controlled release/extended release in heart failure.
OBJECTIVE: beta-Blockers require careful initiation and titration when used in patients with heart failure. Some patients tolerate beta-blocker therapy initiation without difficulty, whereas in other patients this period presents clinical challenges. We tested the hypothesis that polymorphisms at codons 389 (Arg389Gly) and 49 (Ser49Gly) of the beta(1)-adrenergic receptor would be associated with differences in initial tolerability of beta-blocker therapy in patients with heart failure. We also tested whether polymorphisms in the beta(2)-adrenergic receptor, G-protein alpha s subunit (G(s)alpha), and cytochrome P450 (CYP) 2D6 genes or S-metoprolol plasma concentrations were associated with beta-blocker tolerability. METHODS: Sixty-one beta-blocker-naive patients with systolic heart failure were prospectively enrolled. Patients began taking 12.5 to 25 mg metoprolol controlled release/extended release with titration every 2 weeks (as tolerated) to 200 mg/d or the maximum tolerated dose over a period of 8 to 10 weeks. Decompensation was the composite of death, heart failure hospitalization, increase in other heart failure medications, or need to discontinue metoprolol. End points were assessed during the titration period. RESULTS: The overall rate of decompensation was not different between the codon 49 or 389 genotypes. However, a significantly greater percentage of patients with the Gly389 variant required increases in heart failure medications as compared with Arg389 homozygotes (48% versus 14%, respectively; P = .006). Similarly, patients with the Ser49 homozygous genotype were significantly more likely to require increases in concomitant heart failure therapy as compared with Gly49 carriers (41% versus 11%, respectively; P = .03). Neither CYP2D6 genotypes nor metoprolol pharmacokinetics differed between patients with and those without a decompensation event. There was no association between the beta(2)-adrenergic receptor or G(s)alpha polymorphisms with decompensated heart failure. CONCLUSIONS: Patients with the Gly389 variant and Ser49Ser genotype were significantly more likely to require increases in heart failure medications during beta-blocker titration and thus may require more frequent follow-up during titration.
Cytochrome P-450 CYP2D6↗
Early outcomes of a care coordination-enhanced telehome care program for elderly veterans with chronic heart failure.
Veterans with chronic heart failure (HF) are frequently elderly, have numerous comorbid chronic medical illnesses, frequent hospitalizations, and have high rates of cardiovascular events. Within the Veterans Health Administration (VHA), primary care providers are required to manage the majority of HF patients because access to cardiac specialty care within the VHA may be limited. We designed and implemented a care-coordinated, nurse-directed home telehealth management program for veterans with difficult-to-manage or new onset chronic systolic HF. An in-home telehealth message device was provided to the patient at enrollment, and patients received daily HF-specific education via the nurse coordinator and/or the device throughout their continuum of care. We collected demographic characteristics, clinical characteristics, and outcome data at the time of enrollment and at nearly 6 months after enrollment. A total of 92 patients were enrolled, with complete data available on 73. The mean patient age was 67 years, the mean left ventricular ejection fraction (LVEF) was 23%, and nearly all patients (99%) were men. After enrollment, significant improvements were found in blood pressure (129/73 to 119/69 mm Hg, p < 0.05), weight (196 to 192 pounds, p < 0.01), and shortness of breath rating (0-10 scale, 4.0 to 2.7, p = 0.02). Average daily doses of fosinopril (24 to 35 mg/d, p < 0.01) and metoprolol (84 to 94 mg/d, p = 0.05) were also improved. The total number of inpatient hospital days were reduced while on the home telehealth program (from 630 for the previous year to 122 for the duration of the program) with only 31% of the hospitalizations related to HF while on the program. Our nurse-directed, care coordinated home telehealth management program was associated with improved early outcomes in a group of elderly male veterans with chronic HF.
Aged↗
Beta1-adrenergic receptor polymorphisms and left ventricular remodeling changes in response to beta-blocker therapy.
OBJECTIVE: Large variability exists in the improvement in left ventricular (LV) function from beta-blocker treatment. We hypothesized that polymorphisms at codon 389 (Arg389Gly) and 49 (Ser49Gly) in the beta1-adrenergic receptor (AR) gene were associated with LV reverse remodeling changes in response to beta-blocker therapy among heart failure patients. METHODS: We prospectively enrolled 61 beta-blocker naive patients with systolic heart failure. Patients underwent baseline echocardiography followed by metoprolol CR/XL. The dose was doubled on a biweekly basis up to 200 mg/day or attainment of maximum tolerated dose. Echocardiography was repeated after the patient received the target or highest tolerated dose for 3 months. RESULTS: Among patients with the Arg389Arg genotype, ejection fraction (EF) increased from 23+/-5 to 29+/-10 (P=0.008). Gly389 carriers did not demonstrate any significant change in EF (22+/-9 to 23+/-11; P=0.45). There was a significant between-group difference in EF by genotype (P=0.04). The Arg389Arg genotype was also associated with significantly greater reductions in LV end-diastolic and end-systolic diameters compared to Gly389 carriers. Patients with the Gly49 variant also had a significantly greater reduction in LV end-diastolic diameter compared to Ser49 homozygotes. Multiple regression analysis modeling revealed that the codon 389 polymorphism was a significant predictor of an improvement in EF and both codon 49 and 389 polymorphisms were significant predictors of final LV end-diastolic diameter. CONCLUSIONS: Heart failure patients with the Arg389Arg genotype and Gly49 carriers had greater improvements in LV remodeling from beta-blocker treatment.
Adrenergic beta-Antagonists↗
Ischemic heart disease: metabolic approaches to management.
The number of patients with coronary artery disease and its risk factors is increasing in Western nations. New treatments for these patients may soon include a class of agents known as the metabolic modulators. This group of agents consists of the partial fatty acid oxidation inhibitors trimetazidine and ranolazine, as well as dichloroacetate, which promotes carbohydrate utilization. Metabolic modulators also include the nutriceuticals L-carnitine and D-ribose. The available evidence regarding the benefits of each of these five agents is reviewed.
Acetanilides↗
Pharmacokinetics and CYP2D6 genotypes do not predict metoprolol adverse events or efficacy in hypertension.
OBJECTIVE: Beta-Blocker use can be associated with adverse effects that may have an impact on adherence or harm patients. The commonly prescribed beta-blocker metoprolol is metabolized by the polymorphic cytochrome P450 (CYP) 2D6 enzyme, resulting in widely variable drug exposure. We investigated whether metoprolol plasma concentrations, CYP2D6 polymorphisms, or genotype-derived phenotype was associated with adverse effects or efficacy in patients with hypertension. METHODS: Fifty hypertensive patients received metoprolol by use of a dose-titration algorithm until target blood pressure was reached, intolerable side effects occurred, or maximal daily dose was achieved. CYP2D6 genotype was determined by methods based on polymerase chain reaction-restriction fragment length polymorphism and included 19 allelic variants. Patients were assigned to standard phenotype groups on the basis of genotype. Patients were also assigned activity scores based on functional activity of the alleles. General and dose-limiting adverse events and blood pressure responses were analyzed in relation to metoprolol steady-state pharmacokinetic profile and CYP2D6 genotype-derived phenotype. RESULTS: Poor metabolizers had a significantly longer elimination half-life, higher S-metoprolol area under the plasma concentration-time curve (AUC), and lower oral clearance (P < or = .007 for all parameters). There was a 29.6-fold variability in AUC among extensive metabolizers, which was largely explained by CYP2D6 activity scores (P = .032 for ordered differences in AUC by activity score among extensive metabolizers). Overall general and dose-limiting adverse event rates were 46% and 14%, respectively. General adverse event rates did not differ by AUC quartile (66.7% [95% confidence interval (CI), 35.4%-88.7%] and 41.7% [95% CI, 16.5%-71.4%] in the lowest and highest quartiles, respectively; P = .09 among all quartiles). Dose-limiting adverse event rates were also not different by AUC quartile (16.7% [95% CI, 2.9%-49.1%] and 8.3% [95% CI, 0.4%-40.2%] in the lowest and highest quartiles; P = .35 among all quartiles). Furthermore, adverse event rates did not differ by activity scores or between extensive, intermediate, or poor metabolizers. Antihypertensive response rate and blood pressure changes also were not influenced by differences in plasma concentrations or CYP2D6 genotypes. CONCLUSIONS: As expected, CYP2D6 genotype-phenotype correlates with differences in metoprolol pharmacokinetics. However, there was no association between variable pharmacokinetics or CYP2D6 genotype and beta-blocker-induced adverse effects or efficacy.
Adrenergic beta-Antagonists↗
Dobutamine-related asthma in a patient awaiting cardiac transplantation: the eosinophilic dilemma.
Long-term continuous intravenous inotrope infusion is frequently used as a pharmacologic bridge to cardiac transplantation in patients with end-stage congestive heart failure. We report a case of severe eosinophil-associated asthma after 6 weeks of therapy with the inotrope dobutamine in a patient awaiting cardiac transplantation. Review of the laboratory data revealed a steady increase in eosinophils during the period of treatment with dobutamine. Once the patient was switched to an alternative inotrope, milrinone, the eosinophil count returned to normal, and the asthma exacerbation resolved.
Asthma↗
Genetic variation in lectin-like oxidized low-density lipoprotein receptor 1 (LOX1) gene and the risk of coronary artery disease.
BACKGROUND: We examined the association of 3 polymorphisms in the lectin-like oxidized LDL receptor-1 (LOX1 or OLR1) gene with coronary artery disease in the Women's Ischemia Syndrome Evaluation (WISE) study population. METHODS AND RESULTS: The WISE sample comprised 589 white and 122 black women who underwent angiography for suspected ischemia. The sample was divided into 3 groups: <20% stenosis (38.7%), 20% to 49% stenosis (24.9%), and >or=50% stenosis (35.3%). The three LOX1 polymorphisms (intron 4/G-->A, intron 5/T-->G, and 3' UTR/T-->C) were in linkage disequilibrium and thus behaved as a single polymorphism. The frequency of the 3'UTR/T allele was significantly higher in whites than blacks (49% versus 19%; P<0.0001). Among white women, the frequency of the 3'UTR/T allele carriers (TC+TT genotypes) increased gradually from 67.9% to 75.0% and 79.2% in the <20%, 20% to 49%, and >or=50% stenosis groups, respectively (chi2 trend=6.23; P=0.013). Logistic regression analyses indicated that APOE (odds ratio, 1.90; P=0.007) and LOX1 (odds ratio, 1.67; P=0.025) genotypes were independently associated with the risk of disease and that there was no interaction between the two genes. The 3'UTR/T allele carriers also had significantly higher IgG anti-oxLDL levels than individuals carrying the CC genotype (0.94+/-0.20 versus 0.86+/-0.16; P=0.032). Furthermore, our electrophoretic mobility shift assay data show that the 3'UTR polymorphic sequence affects the binding of a putative transcription factor in an allele-specific manner. CONCLUSIONS: Our data suggest that common genetic variation in the LOX1 gene may be associated with the risk of coronary artery disease in white women.
3' Untranslated Regions↗
Sustained use of nesiritide to aid in bridging to heart transplant.
Patients with end-stage heart failure awaiting heart transplant are often maintained on continuous intravenous inotropic therapy. However, this therapy alone is often inadequate for maintenance of appropriate pulmonary artery pressure and stable clinical course. Nesiritide, B-type natriuretic peptide, is a recently released intravenous vasodilator for short-term use in patients with decompensated heart failure. This report details experience in four patients in whom this agent was used to bridge to transplant for prolonged periods (11-35 days) with added clinical benefit and without obvious tolerance. This suggests that new strategies for pretransplant management may be needed.
Adult↗
Beta 1-adrenergic receptor polymorphisms and antihypertensive response to metoprolol.
OBJECTIVES: Marked interpatient variability exists in blood pressure response to beta-blocker monotherapy. We tested the hypothesis that 2 common polymorphisms in the gene for beta(1)-adrenergic receptor are associated with antihypertensive response to metoprolol in patients with uncomplicated hypertension. METHODS: Forty hypertensive men and women aged 35 to 65 years were studied. Baseline studies included 24-hour ambulatory blood pressure monitoring. Patients took 50 mg metoprolol twice daily with weekly titration to response or 200 mg twice daily. After a minimum of 4 weeks at stable dose, treatment phase 24-hour ambulatory blood pressure monitoring was repeated. The codon 49 and 389 genotypes for beta(1)-adrenergic receptor were determined by polymerase chain reaction with restriction fragment length polymorphism. Multilinear regression was performed to determine the impact of genotype and other variables on blood pressure response to metoprolol. RESULTS: Patients homozygous for Arg at codon 389 had a nearly 3-fold greater reduction in daytime diastolic blood pressure (-13.3% +/- 8.4% versus -4.5% +/- 8.2%, P =.0018) compared with those who carried the variant allele. The haplotype pair (diplotype) for beta(1)-adrenergic receptor was also a significant predictor of response, with patients having the Ser49Arg389/Ser49Arg389 diplotype demonstrating a decline in blood pressure of 14.7 mm Hg versus 0.5 mm Hg in patients with the Gly49Arg389/Ser49Gly389 diplotype. In multiregression analysis, baseline daytime diastolic blood pressure, codon 389 genotype, and codon 49 genotype were significant predictors of blood pressure after treatment. CONCLUSIONS: Our data suggest that beta(1)-adrenergic receptor polymorphisms are important determinants of antihypertensive response to metoprolol. In the future, codon 49 and 389 genotypes or beta(1)-adrenergic receptor haplotypes might be used to predict the diastolic blood pressure response to metoprolol in patients with hypertension.
Adrenergic beta-1 Receptor Antagonists↗
APOE polymorphism and angiographic coronary artery disease severity in the Women's Ischemia Syndrome Evaluation (WISE) study.
Genetic variation in the apolipoprotein E (APOE) gene is a significant determinant of variation in plasma cholesterol levels and it also affects the risk of coronary artery disease (CAD). We examined the association of the APOE polymorphism with CAD severity in women from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE) study. Quantitative coronary angiography was used to classify subjects as having normal/minimal CAD (<20% stenosis), mild CAD (20-49% stenosis) and significant CAD (>or=50% stenosis). The women with or=50% stenosis were further stratified according to the number of vessel disease they have (one, two, or three). In white subjects, the frequency of APOE*4 carriers (3/4 and 4/4 genotypes) was significantly higher in the combined mild/significant CAD group (>or=20% stenosis) compared with the normal/minimal CAD group (<20% stenosis) (31.3 vs. 19.2%; P=0.025) with an adjusted OR of 2.40 (95% CI: 1.47-3.93; P=0.0005). Furthermore, the APOE*4 allele was found to be significantly associated with the increased vessel disease number (chi(2)=8.04; P=0.0046). This association of the APOE*4 allele with CAD severity was present only in women with family history of CAD. APOE polymorphism also showed significant associations with increasing plasma total cholesterol (P=0.01) and low-density lipoprotein (LDL)-cholesterol (P<0.001) in whites. These data support the hypothesis that the APOE*4 allele is an independent risk factor not only for the presence of CAD and hyperlipidemia, but also for the angiographic severity of CAD in white women with a family history of disease.
Alleles↗
The role of carnitine in myocardial dysfunction.
L-Carnitine (carnitine) may have a role in the treatment of various cardiac disorders because of its actions on cardioprotection from hypoxia and oxidative stress. Studies on the role of carnitine administration to patients with myocardial infarction (MI), angina, and congestive heart failure generally have been positive. In general, treatment with carnitine (1.5 to 6 g/d for up to 1 year) results in a beneficial effect of fewer deaths and less heart failure when administered to patients after MI. Compared with placebo, carnitine use resulted in smaller increases in left ventricular end-systolic and end-diastolic volumes over time. In shorter term studies (1 to 3 months), carnitine therapy may have positive effects on symptoms of heart failure and angina in the post-MI period. Carnitine also seems to improve exercise tolerance and oxygen consumption in moderate to severe heart failure. Only preliminary results are available; results of a long-term (3-year) study should be reported soon. Studies specific to the dialysis population have generally shown that carnitine may have a beneficial effect on a number of cardiac parameters. Because cardiac disease is the most common form of death in patients with end-stage renal disease, these findings may be particularly important for this population. Moreover, because the relationship between conventional cardiac risk factors and cardiac disease is less clear in this population, the role of therapies that address pathological states specific to the dialysis population is worthy of study. Because a dialysis-related carnitine disorder is common among these patients, L-carnitine supplementation would be among these specific therapies.
Cardiomyopathies↗
Vascular effects of sildenafil in hypertensive cardiac transplant recipients.
BACKGROUND: Sildenafil is commonly used in the treatment of erectile dysfunction in hypertensive male cardiac transplant recipients (CTR); however, little is known about the vascular effects of sildenafil in these patients. METHODS: Central and peripheral arterial blood pressure (BP), heart rate, and brachial artery reactivity were determined in 15 hypertensive male CTR before and after oral sildenafil (50 mg) administration. RESULTS: Sildenafil improved brachial and aortic systolic BP, pulse pressure, aortic augmentation index, left ventricular tension time index, travel time of the reflected aortic pressure wave, and brachial artery reactivity (P <.01 for each comparison). No patient became hypotensive with sildenafil despite continuation of usual antihypertensive medications. CONCLUSIONS: Sildenafil (50 mg) is well tolerated in hypertensive CTR and improves BP, aortic augmentation index, and endothelial function. By decreasing the amplitude of the reflected pressure wave and delaying its return to the heart, sildenafil reduces left ventricular afterload and systolic stress.
Aged↗