Biomedical subjects
Publications and source records attributed to Richard S Schofield.
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BACKGROUND: Pulmonary artery hypertension can complicate the early postoperative care of patients with left ventricular assist devices (LVADs). Inhaled nitric oxide (INO) is frequently used to manipulate pulmonary resistance after LVADs have been placed. We evaluated the effect of oral sildenafil therapy on pulmonary artery pressure, systemic pressure, and nitric oxide utilization. METHODS: After Institutional Review Board approval, the records of 10 consecutive adult patients with LVADs and pulmonary hypertension who received sildenafil were reviewed. Demographics, surgical history, INO use, inotrope requirements, and hemodynamic response to oral sildenafil at multiple intervals were collected. Hemodynamic data were analyzed with a two-way analysis of variance of repeated measures with correction for multiple comparisons. RESULTS: There were 8 men and 2 women with 6 Heartmate XVE LVADs and 4 Thoratec LVADs (both, Thoratec, Pleasanton, California). When weaning was attempted, 8 patients who received INO demonstrated rebound pulmonary hypertension or increased right heart dysfunction. All patients were on inotropic therapy with dobutamine and milrinone. Sildenafil produced a significant reduction in pulmonary artery systolic pressure within 90 minutes of oral administration (p = 0.042). Significant changes in systolic blood pressure, mean arterial pressure, systemic vascular resistance, and heart rate were not observed. All 8 patients receiving INO were weaned within 12 hours without recurrent pulmonary hypertension. All 10 patients were weaned from inotropic support within 72 hours. No patient suffered right-side heart failure requiring intervention. CONCLUSIONS: Oral sildenafil represents a useful adjunctive therapy for patients with LVADs. In our series, it provided additional reduction of pulmonary artery pressure, and facilitated weaning from INO and inotropes without deleterious hemodynamic consequences.
Heart failure (HF) is characterized by neurohormonal activation of the sympathetic nervous and renin-angiotensin systems. Genetic polymorphisms in these systems could alter the prognosis in HF. We hypothesized the genetic polymorphisms in the sympathetic nervous and renin-angiotensin systems are associated with adverse outcomes, defined as death or heart transplantation in patients with HF. A total of 227 patients with HF were enrolled from a tertiary care clinic and followed for outcomes for < or =4 years. Eight polymorphisms in 6 genes were genotyped: beta(1)-adrenergic receptor (ADRB1, S49G, R389G), beta(2)-adrenergic receptor (ADRB2, G16R, Q27E), alpha(2c)-adrenergic receptor (ADRA2C, insertion/deletion 322-325), angiotensinogen (AGT, M235T), angiotensin receptor type 1 (AGTR1, 1166A>C), and angiotensin-converting enzyme (ACE, insertion/deletion in intron 16). Most patients were treated according to consensus guidelines. Male gender (hazard ratio 2.24, 95% confidence interval 1.27 to 3.94), higher New York Heart Association functional class (hazard ratio 2.54, 95% confidence interval 1.84 to 3.52), and 2 copies of ADRB2 Arg16Gln27 haplotype (hazard ratio 1.91, 95% confidence interval 1.09 to 3.36) increased the risk of adverse outcomes. In contrast, a higher serum sodium level (hazard ratio 0.91, 95% confidence interval 0.86 to 0.97) and higher creatinine clearance (hazard ratio 0.99, 95% confidence interval 0.98 to 0.99) decreased the risk of adverse outcomes. None of the other genotypes/haplotypes were associated with adverse outcomes. In conclusion, ADRB2 Arg16Gln27 haplotype may significantly increase the risk of adverse outcomes in patients with HF receiving contemporary HF pharmacotherapy.
Data exist linking elevated epithelial neutrophil activating peptide (ENA-78) concentrations with myriad inflammatory conditions. ENA-78 is encoded by the CXCL5 gene which has recently been shown to be polymorphic in nature (rs352046 and rs425535). No functional data on these polymorphisms exist. We investigated whether CXCL5 polymorphisms are associated with differences in plasma ENA-78 concentrations or leukocyte production of ENA-78 from cultured leukocytes in relatively healthy adults. We genotyped 114 adults for the above polymorphisms. Variant alleles at both loci were highly linked (D'=1, r2=0.94). The rs352046 variant allele was associated with significantly higher ENA-78 plasma concentrations. A genotype effect was also demonstrated for this polymorphism and leukocyte production of ENA-78. Both polymorphisms were predicted to have functional consequences by in silico analyses, with the rs352046 polymorphism found to occur at a transcription factor binding site for myeloid zinc finger proteins and the rs425535 polymorphism found to be located in an exon splicing enhancer site. Our findings add to the strength of CXCL5 as candidate gene in future disease-gene and pharmacogenetic association studies.
OBJECTIVES: The purpose of this study was to investigate the possibility that some patients with coronary artery disease (CAD) but negative exercise or chemical stress test results might have mental stress-induced ischemia. The study population consisted solely of those with negative test results. BACKGROUND: Mental stress-induced ischemia has been reported in 20% to 70% of CAD subjects with exercise-induced ischemia. Because mechanisms of exercise and mental stress-induced ischemia may differ, we studied whether mental stress would produce ischemia in a proportion of subjects with CAD who have no inducible ischemia with exercise or pharmacologic tests. METHODS: Twenty-one subjects (14 men, 7 women) with a mean age of 67 years and with a documented history of CAD were studied. All subjects had a recent negative nuclear stress test result (exercise or chemical). Subjects completed a speaking task involving role playing a difficult interpersonal situation. A total of 30 mCi 99mTc-sestamibi was injected at one minute into the speech, and imaging was started 40 min later. A resting image obtained within one week was compared with the stress image. Images were analyzed for number and severity of perfusion defects. The summed difference score based on the difference between summed stress and rest scores was calculated. Severity was assessed using a semiquantitative scoring method from zero to four. RESULTS: Six of 21 (29%) subjects demonstrated reversible ischemia (summed difference score > or =3) with mental stress. No subject had chest pain or electrocardiographic changes during the stressor. Mean systolic and diastolic blood pressure and heart rate all increased between resting and times of peak stress. CONCLUSIONS: Mental stress may produce ischemia in some subjects with CAD and negative exercise or chemical nuclear stress test results.
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.
STUDY OBJECTIVES: To investigate whether atorvastatin decreases serum or leukocyte-produced CD40 ligand (CD40L) levels and whether these effects are dependent on reduction in low-density lipoprotein cholesterol (LDL) levels in people without overt dyslipidemia. DESIGN: Prospective pilot study. SETTING: University research center. SUBJECTS: Twenty-five normocholesterolemic volunteers (mean age 32 +/- 11 yrs; 15 women, 10 men) without cardiovascular disease. INTERVENTION: After a 2-week drug-free run-in period, subjects received atorvastatin 80 mg/day orally for 16 weeks. MEASUREMENTS AND MAIN RESULTS: All lipoprotein level measurements were performed with the subject in the fasting state. The CD40L concentrations were measured by immunofluorescence detection in serum and leukocyte culture supernates after 24-hour incubation, and treatment effect was analyzed. Baseline mean +/- SD total cholesterol, LDL, high-density lipoprotein cholesterol, and triglyceride levels were 179 +/- 33, 97 +/- 29, 62 +/- 20, and 102 +/- 69 mg/dl, respectively. Mean changes in each of these levels, respectively, after 16 weeks of atorvastatin were -34%, -59%, +3%, and -23%. The median serum CD40L level was lower at 16 weeks (2.3 ng/ml, interquartile range [IQR] 1.2-5.0 ng/ml) than at baseline (3.0 ng/ml, IQR 2.1-3.7 ng/ml), but the change was not significant (p=0.24). However, atorvastatin significantly lowered CD40L produced from leukocytes by 57% (21 pg/mg of protein [IQR 10-38 pg/mg] vs 49 pg/mg [IQR 21-149 pg/mg], p=0.045). Effects were independent of reduction in cholesterol levels. CONCLUSION: Although atorvastatin did not significantly lower serum CD40L levels, significant reduction in leukocyte production was seen independent of degree of LDL reduction. These pilot data suggest a potential benefit in normocholesterolemic individuals that should be further investigated, and that leukocyte CD40L concentrations should be considered in the drug response.
STUDY OBJECTIVES: To determine the frequency and type of complementary and alternative medicine (CAM) use among healthy volunteers participating in research, and to investigate the potential for interactions between commonly used CAM modalities and various drugs. DESIGN: Prospective evaluation. SETTING: University general clinical research center. SUBJECTS: Sixty healthy adults participating in an ongoing drug study. MEASUREMENTS AND MAIN RESULTS: The clinical study database was queried to determine the use and type of existing and newly started CAM throughout the study period. Baseline characteristics were compared between users and nonusers of CAM to identify differences between them. Potential CAM-drug interactions were classified based on curated databases and primary literature sources. Of the 60 subjects enrolled, 30 (50%) used CAM during the study. Of these, 26 (87%) were using CAM at study entry. Baseline CAM users were on average 7 years older than nonusers (p=0.03) and had high-density lipoprotein cholesterol concentrations 10 mg/dl higher than those of nonusers (p=0.04). The group using CAM had more women and nonsmokers than the other group. Several potential CAM-drug interactions were identified. CONCLUSION: Because of high rates of CAM use (50% of the subjects were using biologically based CAM) and the many potential CAM-drug interactions, CAM use should be rigorously addressed in clinical practice and research. Failure to capture this information may have clinical repercussions through pharmacokinetic and pharmacodynamic interference of clinical response and clinical trial results. Clinicians and researchers may be able to identify those most likely to use CAM by their baseline characteristics; this would help target those patients and research subjects for more thorough assessment and follow-up.
STUDY OBJECTIVE: To investigate the immunomodulatory effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) by determining whether atorvastatin alters the production of specific endothelium-derived immunoactive proteins and whether its treatment effects depend on its concentration and/or inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase. DESIGN: In vitro study using a multiplexing method for protein measurement. SETTING: University laboratory. MEASUREMENTS AND MAIN RESULTS: Human umbilical vein endothelial cells were cultured to approximately 80% confluence and treated with atorvastatin 1-50 microM alone or with mevalonate for 24 hours. Untreated cells served as controls. Culture-conditioned media were removed and multiplex assayed for protein content of epithelial neutrophil-activating peptide-78, interleukin-8, monocyte chemotactic protein-1, interleukin-6, interleukin-10, fibroblast growth factor, and granulocyte colony stimulating factor. Atorvastatin significantly reduced the production of epithelial neutrophil-activating peptide-78, interleukin-6, interleukin-8, and monocyte chemotactic protein-1 (p<0.001 to p<0.05) in a concentration-dependent manner without affecting basal production of interleukin-10, fibroblast growth factor, and granulocyte colony stimulating factor. The treatment effects of atorvastatin were reversed with concurrent mevalonate therapy. CONCLUSION: By inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, atorvastatin lowered concentrations of several inflammatory molecules derived from basal-state endothelial cells in a concentration-dependent manner. The in vivo importance of these immunomodulatory effects needs further investigation.
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.
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.
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A retrospective analysis was performed on 52 patients with heart failure to determine the change in beta-blocker therapy after cardiac resynchronization therapy (CRT). After 6 months of CRT, the number of patients receiving beta-blocker therapy increased from 36 to 44, with improved clinical outcomes and larger beta-blocker doses, indicating that these 2 therapies may work together to improve outcomes by allowing the use of larger doses of beta blockers while correcting ventricular dyssynchrony.
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.
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.
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.
Anabolic-androgenic steroids are synthetic derivatives of testosterone that some athletes have used to enhance muscle mass and improve their athletic performance. Ephedrine is a potent sympathomimetic agent that can lead to cardiomyopathy similar to that seen with catecholamine excess. Adverse cardiovascular events attributed to anabolic steroid and ephedra use, such as arrhythmias, myocardial infarction, cardiomyopathy, and sudden death, are rarely reported. Bodybuilders have used gamma-hydroxybutyrate, a potent secretagogue of growth hormone, to promote muscle development. Although dilated cardiomyopathy is a known complication of excess growth hormone levels, it has not been associated with use of gamma-hydroxybutyrate. A healthy 40-year-old man was admitted to our hospital for new-onset congestive heart failure and severe acute hepatitis that developed several months after he began using anabolic-androgenic steroids, ephedra, and gamma-hydroxybutyrate supplements. Analysis with an objective causality assessment scale revealed a probable adverse drug reaction between the patient's use of anabolic steroids, ephedra, and gamma-hydroxybutyrate and the development of his cardiomyopathy and acute liver injury.
The objective of this study was to investigate the effects of 12 weeks of standard cardiac rehabilitation on endothelial function, oxidative stress, and antioxidant defenses in patients with coronary artery disease. Twelve weeks of endurance exercise training led to an improvement in endothelial function as measured by brachial artery flow-mediated dilation (7.9% at baseline vs 11.1% at 12 weeks). Exercise training resulted in increased plasma nitrite and nitrate levels, increased plasma superoxide dismutase activity, and decreased oxidative stress.