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At least 505 records · Page 28Linked to original sources
PubMed1993

Sustained augmentation of parasympathetic tone with angiotensin-converting enzyme inhibition in patients with congestive heart failure.

OBJECTIVES: The objective of this investigation was to evaluate the changes in parasympathetic tone associated with long-term angiotensin-converting enzyme inhibitor therapy in patients with congestive heart failure. BACKGROUND: Angiotensin-converting enzyme inhibitors provide hemodynamic and symptomatic benefit and are associated with improved survival in patients with congestive heart failure. Angiotensin II, whose production is ultimately inhibited by these agents, exerts significant regulatory influence on a variety of target organs including the central and peripheral nervous systems. Accordingly, it would be anticipated that angiotensin-converting enzyme inhibitors would significantly alter the autonomic imbalance characteristic of patients with congestive heart failure and that this influence over neural mechanisms of cardiovascular control may significantly contribute to the hemodynamic benefit and improved survival associated with angiotensin-converting enzyme inhibitor therapy. METHODS: In the current investigation, changes in autonomic tone associated with long-term administration of an angiotensin-converting enzyme inhibitor were measured using spectral analysis of heart rate variability in 13 patients with congestive heart failure who were enrolled in a double-blind randomized placebo-controlled trial of the angiotensin-converting enzyme inhibitor zofenopril. Both placebo and treatment groups were balanced at baseline study in terms of functional class, ventricular performance and autonomic tone. RESULTS: After 12 weeks of therapy with placebo, there was no change in total heart rate variability, parasympathetically governed high frequency heart rate variability or sympathetically influenced low frequency heart rate variability. In contrast, therapy with zofenopril was associated with a 50% increase in total heart rate variability (p = 0.09) and a significant (p = 0.03) twofold increase in high frequency heart rate variability, indicating a significant augmentation of parasympathetic tone. CONCLUSIONS: These results demonstrate that long-term treatment of patients having congestive heart failure with an angiotensin-converting enzyme inhibitor is associated with a restoration of autonomic balance, which derives in part from a sustained augmentation of parasympathetic tone. Such augmentation of vagal tone is known to be protective against malignant ventricular arrhythmias in patients with ischemic heart disease and therefore may have similar benefit in the setting of ventricular failure, thus contributing to the improved survival associated with angiotensin-converting enzyme inhibitor therapy in patients with congestive heart failure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

Clinical trials of diuretic therapy in heart failure: research directions and clinical considerations.

Diuretic drugs have historically been developed for the treatment of sodium and water retention in edematous disorders. The latter have traditionally been an amalgam of congestive heart failure, nephrotic syndrome, cirrhosis and chronic renal failure. With a > 50-year tradition of this approach to development, diuretic drugs have not been evaluated specifically for their safety and efficacy profile in patients with congestive heart failure. Yet, they are the most frequently prescribed drug class for this disorder. Furthermore, they remain the only drug class in congestive heart failure not subjected to large scale clinical trials. Sodium and water retention within this group of patients is related primarily to functional rather than to structural renal abnormalities. The reduction of glomerular filtration rate, increase in aldosterone secretion and abnormal profile of atrial natriuretic factor, all produce sodium retention and can be related to the severity of heart failure. Diuretic drugs have not been scrutinized in a manner similar to that of other drugs for the management of heart failure. Controversy persists regarding direct vascular effects, objective end points of assessment and the magnitude of adverse effects such as activation of neurohormonal pathways. These issues may be addressed by the establishment of reasonable objective end points, better stratification of patients in clinical trials and prospective trials in large clinical series. Even mortality studies should be considered.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

A prospective evaluation of glucose reagent teststrips in the prehospital setting.

Reagent teststrip determination of blood glucose has been shown to be accurate for hospital and home testing and is commonly used in prehospital care despite the lack of studies in this arena. This prospective, multicenter study examines the ability of glucose reagent teststrips to detect hypoglycemia when used under field conditions compared with simultaneously drawn control samples for laboratory glucose determination. Also examined was the accuracy of the teststrips in the laboratory glucose range less than or equal to 200 mg/dL. One hundred eighty-one pairs of data were analyzed. Hypoglycemia was defined as laboratory glucose less than or equal to 60 mg/dL. The teststrips correctly identified 31 of 33 patients in this range (sensitivity = 94%), and 125 of 148 patients without hypoglycemia (specificity = 85%). The two false negative readings were 70 and 90 mg/dL. Reagent teststrips were within +/- 40 mg/dL of the laboratory value in 70% of cases. The correlation coefficient (Spearman r) between teststrip and laboratory glucose in the range less than or equal to 200 mg/dL was .80. Using teststrip readings of 90 mg/dL or less as a measure of hypoglycemia yields 100% sensitivity with a specificity of 57%. We conclude glucose reagent teststrips are a useful adjunct for use in the prehospital setting and may be valuable for the detection of hypoglycemia.

Analysis of Variance↗
PubMed1995

Acute myocardial and vascular responses to specific angiotensin II antagonism in the spontaneously hypertensive rat.

As the AT1 receptor is the primary angiotensin II receptor in the myocardium and vasculature, we assessed the acute myocardial and vascular response to the AT1 angiotensin II antagonist losartan in the spontaneously hypertensive rat (SHR) to determine the contribution of angiotensin II in this genetic form of hypertension. In a preliminary dose response study, which evaluated losartan at 1.0, 3.0, and 10 mg/kg, 10 mg/kg uniformly lowered blood pressure. In a second group of experiments, 10 mg/kg also completely attenuated the pressor effects of angiotensin II administration. In nine adult SHR, intravenous losartan, 10 mg/kg, was given, with hemodynamics measured immediately and at steady-state intervals to delineate the hemodynamic response to angiotensin II antagonism. Losartan significantly lowered systolic, diastolic, and mean blood pressures, yet heart rate was unchanged. Cardiac function, as assessed by cardiac output and blood flow acceleration, demonstrated only transient increases which were not sustained during steady-state blood pressure reduction. Significant increases of peak blood flow and pulse pressure were sustained throughout the blood pressure response. At immediate and steady-state determinations, system vascular resistance and characteristic aortic impedance were significantly reduced with losartan (both P < .01). In addition, concomitant reduction of the wave reflectance index also occurred, achieving significance at steady state (P < .05). These changes demonstrate that the AT1 angiotensin II receptor contributes to both central and peripheral vasoconstriction in the spontaneously hypertensive rat. Absence of sustained increase of cardiac output and blood flow acceleration are consistent with inhibition of the previously reported positive inotropic effect of angiotensin II.

Angiotensin II↗
PubMed1996

Influence of pressure overload and ACE inhibitor therapy on constitutive protein mRNA expression in the spontaneously hypertensive rat.

Despite use as constitutive protein standards to quantify mRNA, data are limited regarding alteration of cyclophilin or glyceraldehyde-3-phosphate dehydrogenase (G3PDH) in hypertension or angiotensin converting enzyme (ACE) inhibitor treatment. We assessed these standards in 6 month old Wistar-Kyoto rats (WKY, n = 16), compared to age-matched spontaneously hypertensive rats (SHR, n = 14). Additional SHR (n = 8) had received enalapril for 3 to 4 months at evaluation. Left ventricular (LV) and kidney RNA was extracted for dot blot cyclophilin and G3PDH cDNA hybridization. Cyclophilin and G3PDH mRNA densitometries were expressed as a ratio. Cyclophilin/G3PDH for the WKY, untreated SHR, and enalapril SHR were 1.56 +/- 0.33, 1.45 +/- 0.42, and 1.49 +/- 0.51, respectively, for the LV, and 1.52 +/- 0.09, 1.43 +/- 0.22, and 1.38 +/- 0.22, respectively, for the kidney. Differences were not significant. Relative expression of cyclophilin/G3PDH was unaffected by genetic SHR hypertension, or long term enalapril. Thus, either constitutive mRNA may be confidently used to index structural or functional protein responses, at the transcriptional level, in the SHR.

Amino Acid Isomerases↗
PubMed1992

Serum and growth factors stimulate ribosomal RNA processing in Syrian hamster embryo cells: divergence of this signalling pathway from immediate-early gene expression.

Growth factor stimulation of cells results in multiple intracellular biochemical changes including increases in calcium levels, phosphatidylinositol turnover, protein phosphorylation, immediate-early gene transcription and intracellular pH alterations. We report here that serum and growth factor stimulation of Syrian hamster embryo (SHE)-derived cell lines increases the ribosomal RNA (rRNA) processing rates. In addition, in several transformed SHE cell lines, the immediate-early response of fos/actin transcription could be separated from the immediate-early rRNA processing response. These results indicate that in these cell lines a mutation(s) which uncouples these responses has occurred. This is the first report describing (i) rRNA processing as an immediate-early effect following growth factor stimulation and (ii) the identification of a mutation(s) which can uncouple two immediate-early signalling responses.

Actins↗
PubMed1996

Three-dimensional magnetic resonance microscopy of materials.

Several aspects of magnetic resonance microscopy are examined employing three-dimensional (3D) back-projection reconstruction techniques in combination with either simple Bloch-decay methods or MREV-8 multiple-pulse line narrowing techniques in the presence of static field gradients. Applications to the areas of ceramic processing, catalyst porosity measurements and the characterization of polymeric materials are presented. The focus of the discussion centers on issues of sensitivity and resolution using this approach compared with other methods. Advantages and limitations of 3D microscopy over more commonly employed slice selection protocols are discussed, as well as potential remedies to some of the inherent limitations of the technique.

Ceramics↗
PubMed1995

Structure-activity studies of phosphorylated peptide inhibitors of the association of phosphatidylinositol 3-kinase with PDGF-beta receptor.

Phosphorylated pentapeptides derived from Tyr751 of the PDGF-beta receptor (pTyr751-Val-Pro-Met-Leu, pTyr = phosphotyrosine) were prepared to examine their ability to inhibit the association of the C-terminal SH2 domain of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) with the PDGF-beta receptor. Peptidic analogs were prepared to examine the importance of the amine and carboxy terminus and specific amino acids via alanine/D-amino acid scans and site specific modifications. Several of these peptides had submicromolar activity. In particular, it was shown that neutralization of the amine and carboxy terminus led to analogs with enhanced activity. In addition, it was determined that only minimal modifications were allowed for pTyr and Met, while the other positions were quite tolerant of modification.

Alanine↗
PubMed1995

Enantioselective inhibition of the epidermal growth factor receptor tyrosine kinase by 4-(alpha-phenethylamino)quinazolines.

4-Benzylaminoquinazolines can be potent reversible inhibitors of the EGFR tyrosine kinase at the ATP binding site. Examination of benzylic methylation reveals that an (R)-methyl group is four- to six-fold activating, with an optimal Ki of 630 pM for compound 11. In sharp contrast, (S)-methylation causes a > 30 to 500-fold loss of inhibitory activity, showing that the ATP-binding site of the receptor has very low tolerance for even moderate out-of-plane bulk in certain directions. It is suggested that the best of these inhibitors can induce a conformation of the kinase not available to poorer inhibitors.

Adenosine Triphosphate↗
PubMed1994

Pulmonary hypertension and systemic hypotension as limitations to exercise in chronic heart failure.

The authors have previously shown that the resistance ratio (RR) is increased in patients with congestive heart failure (CHF), and that the patients with the highest RRs have an increased mortality. The authors hypothesized that CHF patients with the lowest maximum oxygen consumption and the most impaired Weber functional classification would have the highest RR. Eighty-four patients with chronic CHF underwent seated ergometric exercise to exhaustion. Hemodynamic and respiratory gas exchange parameters were measured at rest and peak exercise. Weber functional classifications (A through E) were determined from maximum oxygen consumptions, and patients were stratified to evaluate the RR. The RR increased progressively across Weber classifications at rest (A vs E; P < .001) and with maximum exercise (A vs E; P < .002). At rest, elevation in the RR was related to an increase in the pulmonary pressure gradient (A vs E; P < .002) secondary to increased mean pulmonary arterial pressures. With peak exercise, this elevation was secondary to a decrease in the systemic pressure gradient (A vs E; P < .001). Further analysis revealed that the progressive decrease in the systemic pressure gradient was due to progressively lower mean arterial pressures (A vs E; P < .001). Elevation of the RR, both at rest and peak exercise, predicts a more impaired exercise functional status in patients with chronic CHF. Increases in the RR at peak exercise were related to decreases in mean arterial pressure, most likely limiting perfusion to exercising skeletal muscle. The mechanism of poor exercise blood pressure response in these patients is unclear. Possible explanations include abnormal systemic baroreceptor function with inappropriate vascular adaptation, and a poor cardiac output response to a relative increase in right ventricular afterload in systemic vasodilation seen with exercise.

Adult↗
PubMed2006

Binding thermodynamics of substituted diaminopyrimidine renin inhibitors.

Renin is an aspartyl protease involved in the production of angiotensin II, a potent vasoconstrictor. Renin inhibitors can prevent blood vessel constriction and therefore could be useful for the treatment of hypertension. High-throughput screening efforts identified a small molecule renin inhibitor with a core substituted diaminopyrimidine ring. Parallel medicinal chemistry efforts based on this lead resulted in compound 1. A complex of 1 bound to renin was crystallized, and structural data were obtained by X-ray diffraction. The structure indicated that there were adjacent unoccupied binding pockets. Synthetic efforts were initiated to extend functionality into these pockets so as to improve affinity and adjust pharmacokinetic parameters. Thermodynamics data for inhibitor binding to renin were also collected using isothermal titration calorimetry. These data were used to help guide inhibitor optimization by suggesting molecular alterations to improve binding affinity from both thermodynamic and structural perspectives. The addition of a methoxypropyl group extending into the S3 subpocket improved inhibitor affinity and resulted in greater binding enthalpy. Initial additions to the pyrimidine ring template that extended into the large hydrophobic S2 pocket did not improve affinity and dramatically altered the thermodynamic driving force for the binding interaction. Binding of the core template was enthalpically driven, whereas binding of initial inhibitors with S2 extensions was both enthalpically and entropically driven but lost significant binding enthalpy. Additional electrostatic interactions were then incorporated into the S2 extension to improve binding enthalpy while taking advantage of the favorable entropy.

Calorimetry↗
PubMed2006

Quantification of bleomycin-induced murine lung damage in vivo with micro-computed tomography.

RATIONALE AND OBJECTIVES: We explored noninvasive, in vivo cone-beam microcomputed tomography (micro-CT) to visualize and quantify fibrotic and inflammatory damage over the entire lung volume of mice. MATERIALS AND METHODS: We used bleomycin to induce pulmonary damage in vivo and compared the results from micro-CT with histologic measurements. Ten C57BL/6 mice were given 5 U/kg bleomycin intratracheally. Seven surviving mice were scanned with micro-CT before administration of bleomycin, and again before sacrifice. The resulting images were analyzed for lung volume measurements. After the final scan, all lungs were examined histologically and pulmonary damage was quantified. Damaged lung tissue regions were matched between micro-CT images and histologic sections for each mouse. RESULTS: The percent lung damage calculated from micro-CT and histology were correlated (r(2) = 0.49, r = 0.64 with P = 0.12), and the means of their respective distributions were not different (P > 0.05). CONCLUSION: This study shows that micro-CT is a promising alternative to predicting lung damage caused by bleomycin. CT image volumes of the thorax allow for global tissue sampling, which may be useful when following nonuniform lung damage that can occur from intratracheal administration of bleomycin.

Animals↗
PubMed2006

Description and implementation of a quality control program in an imaging-based clinical trial.

RATIONALE AND OBJECTIVES: The American College of Radiology Imaging Network is participating in the National Lung Screening Trial, a large, multicenter, randomized controlled trial, comparing multidetector helical computed tomography (MDCT) versus chest radiography (CXR) in screening for lung cancer. Because the threshold for detection of disease is an inherent function of image quality, and consistent image quality is necessary to track changes in suspicious findings, our purpose was to develop an image quality control (QC) program across all clinical sites for both modalities. MATERIALS AND METHODS: The primary goals of the QC program include standardization of imaging protocols, certification of imaging equipment, and ongoing, periodic evaluation of the equipment calibration and image quality. Minimum standards for equipment and standardized cross-platform acquisition protocols are achieved via radiologist and physicist attestation forms and web-distributed technique charts, respectively. Imaging equipment performance standards are implemented through an initial machine certification process that includes equipment calibration. Ongoing assessment of equipment performance and calibration, as well as adherence to established imaging protocols. is accomplished via periodic submission of calibration records and phantom images. Participant-specific image acquisition parameters are entered into a web-based centralized database and variations from established protocols are automatically flagged for review. Participant radiation dose can be estimated from the image acquisition parameters applied to the imaging equipment calibration measurements. A radiologist visual review committee also evaluates participant images for diagnostic quality. Data are collected from 23 independent centers, representing 14 models of MDCT scanners from four manufacturers, and CXR systems that include film-screen, computed radiography, and direct digital radiography systems. RESULTS: Widespread imaging protocol variation in extant clinical practice-as well as variability in equipment technology, image acquisition parameters, manufacturer terminology, and user interface-have required careful standardization as a prerequisite to trial participation and ongoing image QC. Acceptable ranges for image acquisition parameters have been refined to accommodate continuously evolving equipment platforms and the scope of participant size and body habitus. CONCLUSION: Standardization of imaging protocols is a critical component of image-based clinical trials, predicated on ongoing dialogue between sites and a centralized review committee.

Artificial Intelligence↗
PubMed2007

A quality guarantee in acute coronary syndromes: the American College of Cardiology's Guidelines Applied in Practice program taken real-time.

BACKGROUND: Wide variation exists in the management of acute coronary syndromes (ACSs), which includes an apparent underutilization of evidence-based therapies. We have previously demonstrated that application of the American College of Cardiology Guidelines Applied in Practice (GAP) tools can improve quality indicator rates and outcomes of patients hospitalized with ACS. OBJECTIVE: To determine whether a real-time system for monitoring key quality-of-care indicators using GAP would improve both process indicators and outcomes beyond those of the initial implementation of GAP. DESIGN: Prospective patient identification, prospective chart coding, retrospective data abstraction. PATIENTS: All patients with ACS admitted (N = 3189) to our institution between January 1, 1999, and December 2004; 2019 studied before real-time implementation from January 1, 1999, to June 30, 2002, and 1170 studied during real-time implementation from July 1, 2002, to December 31, 2004. MAIN OUTCOME MEASURE: The effect of real-time monitoring of key quality indicators on inhospital therapy and outcomes, and 6-month outcomes in patients admitted with ACS. RESULTS: The real-time GAP implementation correlated with more frequent use of inhospital angiotensin-converting enzyme inhibitors (72.7% vs 63.7%, P < .0001), beta blockers (93.0% vs 89.7%, P = .0016), statins (81.2% vs 65.9%, P < .0001), antiplatelet agents (69.2% vs 22.5%, P < .0001), and glycoprotein IIb/IIIa inhibitors (35.5% vs 26.7%, P < .0001). There were fewer episodes of inhospital congestive heart failure (3.85% vs 8.77%, P < .0001) and major bleeding events (3.2% vs 7.9%, P < .0001) after the real-time system was adopted. Real-time GAP also resulted in higher discharge rates of aspirin (92.1% vs 86.5%, P < .0001), beta blockers (86.8% vs 79.1%, P < .0001), statins (81.2% vs 64.7%, P < .0001), and angiotensin-converting enzyme inhibitors (67.1% vs 55.5%, P < .0001). Real-time GAP implementation was associated with fewer rehospitalizations for heart disease (19.8% vs 25.2%, P = .0014), myocardial infarction (3.5% vs 5.4%, P = .0243), and combined death/cerebrovascular accident/myocardial infarction (9.5% vs 13.9%, P = .0009) during the first 6 months after discharge. CONCLUSION: The institution of a formal system to review and "guarantee" key quality-of-care indicators real time in the hospital is associated with improved outcomes in patients admitted with ACS. The combination of American College of Cardiology's GAP program and its real-time implementation leads to higher use of evidence-based therapies and correspondingly better outcomes than those associated with the initial GAP implementation.

Angina, Unstable↗
PubMed2006

Changes in access to primary care for Medicaid beneficiaries and the uninsured: the emergency department perspective.

Reductions in scope of benefits and stricter premium and co-payment policies in the Oregon Health Plan (OHP) led to a large drop in OHP enrollment. Outpatient psychiatric benefits were eliminated for approximately 25% of enrollees. One measure of access to care is ED use. We used administrative data from our ED from August 1, 2001, through June 30, 2004, comparing ED use before vs after the March 1, 2003, cutbacks. Before the cutbacks, 38% of ED visits were by OHP beneficiaries, falling to 32% afterward. Visits by the uninsured rose from 18% before to 22% afterward. The proportion of visits for psychiatric conditions covered by OHP fell from 41% [corrected] to 31% [corrected], although the proportion by uninsured patients rose from 16% to 23%. These findings suggest a worrisome reduction in access to medical care for uninsured Oregonians and unstable access for OHP enrollees, especially for behavioral health conditions.

Cohort Studies↗
PubMed2006

Treatment of coronary artery perforations complicating percutaneous coronary intervention with a polytetrafluoroethylene-covered stent graft.

Coronary artery perforation is a rare, but dreaded, complication of percutaneous coronary intervention. Conventional treatment, including reversal of anticoagulation and prolonged balloon inflation, is associated with a high incidence of death, Q-wave myocardial infarction, and emergency coronary bypass surgery. Although a number of case reports have demonstrated the feasibility of sealing coronary perforations with synthetic material-covered stent grafts, the efficacy of this treatment has not been reported in a large, multicenter series. We used a retrospective international registry to examine the outcomes of the polytetrafluoroethylene-coated JOSTENT coronary stent graft (CSG) in 41 cases of coronary perforations. Perforations were relatively severe: 16.7% Ellis grade 1, 54.2% grade 2, and 29.1% grade 3. Of the 41 patients, > 1/3 (n = 14) experienced life-threatening complications before stent graft implantation, including pericardial tamponade (12.2%), cardiogenic shock (9.8%), and cardiac arrest (2.4%). A total of 52 CSGs were used to treat the 41 perforations (mean 1.3 per lesion). All CSGs were placed successfully, with 92.9% of the perforations sealed completely and 7.1% partially. One patient developed abrupt vessel closure after CSG deployment, resulting in an overall procedure success rate of 96.4%. No in-hospital Q-wave myocardial infarctions, emergency coronary bypass surgeries, or deaths resulted. The CSG may be a reliable and highly effective treatment option for sealing coronary perforations complicating percutaneous coronary interventions.

Aged↗