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Biomedical subjects

W E Cascio

Publications and source records attributed to W E Cascio.

At least 19 recordsLinked to original sources
PubMed2005

A LabVIEW model incorporating an open-loop arterial impedance and a closed-loop circulatory system.

While numerous computer models exist for the circulatory system, many are limited in scope, contain unwanted features or incorporate complex components specific to unique experimental situations. Our purpose was to develop a basic, yet multifaceted, computer model of the left heart and systemic circulation in LabVIEW having universal appeal without sacrificing crucial physiologic features. The program we developed employs Windkessel-type impedance models in several open-loop configurations and a closed-loop model coupling a lumped impedance and ventricular pressure source. The open-loop impedance models demonstrate afterload effects on arbitrary aortic pressure/flow inputs. The closed-loop model catalogs the major circulatory waveforms with changes in afterload, preload, and left heart properties. Our model provides an avenue for expanding the use of the ventricular equations through closed-loop coupling that includes a basic coronary circuit. Tested values used for the afterload components and the effects of afterload parameter changes on various waveforms are consistent with published data. We conclude that this model offers the ability to alter several circulatory factors and digitally catalog the most salient features of the pressure/flow waveforms employing a user-friendly platform. These features make the model a useful instructional tool for students as well as a simple experimental tool for cardiovascular research.

Animals↗
PubMed2001

Electrical properties and conduction in reperfused papillary muscle.

The reversibility of ischemia-induced changes of extracellular K(+) concentration ([K(+)](o)), resting membrane potential (E(M)), and passive cable-like properties, ie, extracellular resistance and cell-to-cell electrical coupling, and their relationship to recovery of conduction and contraction is described in 25 reperfused rabbit papillary muscles. No-flow ischemia caused extracellular K(+) accumulation, depolarization of E(M), an increase in whole-tissue (r(t)), external (r(o)), and internal (r(i)) longitudinal resistances, and failure of conduction and contraction. Muscles were reperfused 10 minutes after the onset of ischemia related cell-to-cell electrical uncoupling, ie, 26+/-1 minutes after arrest of perfusion. In 11 muscles, incomplete reflow occurred with only partial recovery of [K(+)](o) and r(t). In the remaining 14 muscles, reperfusion caused a rapid and parallel decrease in [K(+)](o), r(t), and r(o). When complete tissue reperfusion occurred, cell-to-cell electrical uncoupling was largely reversible. Thus, cell-to-cell electrical uncoupling did not indicate irreversible injury. Reperfusion induced a depolarizing current widening the difference between the K(+) equilibrium potential and the E(M). This difference decreased after longer periods of reperfusion. Conduction was restored and conduction velocity approached preischemic values as cell-to-cell electrical interaction was reestablished and E(M) recovered. The recovery of r(o) preceded r(i), decreasing the ratio of the extracellular to intracellular resistance early in reperfusion, an effect predicted to influence the amplitude of the extracellular voltage field and electrocardiographic ST segments during reperfusion.

Animals↗
PubMed2001

Diffuse alveolar damage after exposure to an oil fly ash.

Epidemiological investigation has established an association between exposure to particulate matter (PM) and both human mortality and diverse indices of human morbidity. However, attributing adverse health effects of specific individuals to PM exposure in these studies is not possible. Consequently, their clinical presentation remains ill-defined. We describe a 42-yr-old male with both respiratory damage, abnormal blood end points, and cardiac effects following an exposure to an emission source air pollution particle aerosolized during the cleaning of his domestic oil-burning stove. Early symptoms of shortness of breath and wheezing progressed over 2 wk to hypoxic respiratory failure necessitating mechanical ventilation. Blood indices were abnormal. Thoracoscopic biopsy demonstrated particle-laden macrophages and diffuse alveolar damage. Symptomatic and objective improvement rapidly followed initiation of corticosteroids. He developed typical anginal symptoms within 2 wk of discharge; however, coronary angiography did not identify any significant narrowing of the epicardial coronary arteries. This patient presents with the aggregate of potential injuries described by epidemiological methods to be associated with air pollution particle exposure.

Adult↗
PubMed2001

Association of ventricular premature complexes with electrocardiographic-estimated left ventricular mass in a population of African-American and white men and women (The Atherosclerosis Risk in Communities.

Increased left ventricular (LV) mass is often found in adults and is a powerful predictor of cardiovascular mortality. To test the hypothesis that an electrocardiographic estimate of LV mass--the Cornell voltage--is associated with ventricular premature complexes (VPCs) in free-living adults, a cross-sectional analysis of the predictors of VPCs on a 2-minute rhythm strip in a population-based sample of 13,606 middle-aged, African-American and white men and women from 4 US communities in the Atherosclerosis Risk in Communities Study baseline examinations was performed. In adults without known coronary artery disease, the prevalence of VPCs increases monotonically with increasd Cornell voltages within ethnicity and gender groups. Independent of systemic hypertension, serum electrolytes, age, heart rate, educational attainment, gender, and ethnicity, a millivolt increase in Cornell voltage was associated with a 20% to 30% increase in the prevalence odds ratio of VPCs on the 2-minute electrocardiogram. Thus, Cornell voltage is associated with VPCs on a 2-minute electrocardiogram. The association is consistent in African-Americans, whites, men, and women.

Aged↗
PubMed2001

Influence of dynamic gap junction resistance on impulse propagation in ventricular myocardium: a computer simulation study.

The gap junction connecting cardiac myocytes is voltage and time dependent. This simulation study investigated the effects of dynamic gap junctions on both the shape and conduction velocity of a propagating action potential. The dynamic gap junction model is based on that described by Vogel and Weingart (J. Physiol. (Lond.). 1998, 510:177-189) for the voltage- and time-dependent conductance changes measured in cell pairs. The model assumes that the conductive gap junction channels have four conformational states. The gap junction model was used to couple 300 cells in a linear strand with membrane dynamics of the cells defined by the Luo-Rudy I model. The results show that, when the cells are tightly coupled (6700 channels), little change occurs in the gap junction resistance during propagation. Thus, for tight coupling, there are negligible differences in the waveshape and propagation velocity when comparing the dynamic and static gap junction representations. For poor coupling (85 channels), the gap junction resistance increases 33 MOmega during propagation. This transient change in resistance resulted in increased transjunctional conduction delays, changes in action potential upstroke, and block of conduction at a lower junction resting resistance relative to a static gap junction model. The results suggest that the dynamics of the gap junction enhance cellular decoupling as a possible protective mechanism of isolating injured cells from their neighbors.

Action Potentials↗
PubMed2001

Myocardial ischemia: what factors determine arrhythmogenesis?

In ischemic myocardium, cellular architecture and heterogeneous changes in metabolic and ionic conditions interact to cause spatial and temporal heterogeneity of electrical properties predisposing to lethal ventricular arrhythmias. Yet, the details of their interaction, vis-à-vis the initiation and maintenance of reentry, remain poorly understood. Future studies are needed to address the mechanisms of the initial premature beat, reentry, and formation of wavebreaks contributing to ventricular fibrillation. New experimental methods including mathematical and transgenic mouse models are promising techniques to study these phenomena and thereby provide new insights into the fundamental mechanisms of ischemia-related arrhythmias.

Animals↗
PubMed2001

Effect of fluoxetine on carvedilol pharmacokinetics, CYP2D6 activity, and autonomic balance in heart failure patients.

The objective of this study was to examine the pharmacokinetic and pharmacodynamic consequences of concomitant administration of fluoxetine and carvedilol in heart failure patients. Fluoxetine (20 mg) or matching placebo was administered in a randomized, double-blind, two-period crossover study to 10 patients previously identified as extensive metabolizers of CYP2D6 substrates. Patients were maintained on a carvedilol dose of 25 or 50 mg bid and given fluoxetine/placebo for a minimum of 28 days. Plasma was collected over the 12-hour carvedilol dosing interval, and the concentrations of the R(+) and S(-) enantiomers of carvedilol were measured. CYP2D6 phenotype was assessed during each study period using dextromethorphan (30 mg). Changes in autonomic modulation between study periods were measured by heart rate variability in the time and frequency domains using ambulatory electrocardiographic monitoring. Compared to placebo, fluoxetine coadministration resulted in a 77% increase in mean (+/- SD) R(+) enantiomer AUC0-12 (522 +/- 413 vs. 927 +/- 506 ng.h/mL, p = 0.01) and a nonsignificant increase in S(-) enantiomer AUC (244 +/- 185 vs. 330 +/- 179 ng.h/mL, p = 0.17). Mean apparent oral clearance for both enantiomers decreased significantly with fluoxetine administration (R(+): 10.3 +/- 7.2 vs. 4.5 +/- 2.2 mL/min/kg; S(-): 22.5 +/- 12.3 vs. 12.6 +/- 7.4 mL/min/kg; p = 0.004 and 0.03, respectively). No differences in adverse effects, blood pressure, or heart rate were noted between treatment groups, and there were no consistent changes in heart rate variability parameters. In conclusion, fluoxetine administration resulted in a stereospecific inhibition of carvedilol metabolism, with the R(+) enantiomer increasing to a greater extent than the S(-) enantiomer. However, this interaction was of little clinical significance in our sample population.

Adrenergic beta-Antagonists↗
PubMed2000

Mitochondrial calcium transients in adult rabbit cardiac myocytes: inhibition by ruthenium red and artifacts caused by lysosomal loading of Ca(2+)-indicating fluorophores.

A cold/warm loading protocol was used to ester-load Rhod 2 into mitochondria and other organelles and Fluo 3 into the cytosol of adult rabbit cardiac myocytes for confocal fluorescence imaging. Transient increases in both cytosolic Fluo 3 and mitochondrial Rhod 2 fluorescence occurred after electrical stimulation. Ruthenium red, a blocker of the mitochondrial Ca(2+) uniporter, inhibited mitochondrial Rhod 2 fluorescence transients but not cytosolic Fluo 3 transients. Thus the ruthenium red-sensitive mitochondrial Ca(2+) uniporter catalyzes Ca(2+) uptake during beat-to-beat transients of mitochondrial free Ca(2+), which in turn may help match mitochondrial ATP production to myocardial ATP demand. After ester loading, substantial amounts of Ca(2+)-indicating fluorophores localized into an acidic lysosomal/endosomal compartment. This lysosomal fluorescence did not respond to electrical stimulation. Because fluorescence arose predominantly from lysosomes after the cold loading/warm incubation procedure, total cellular fluorescence failed to track beat-to-beat changes of mitochondrial fluorescence. Only three-dimensionally resolved confocal imaging distinguished the relatively weak mitochondrial signal from the bright lysosomal fluorescence.

Adenosine Triphosphate↗
PubMed2000

Validation of a short rhythm strip compared to ambulatory ECG monitoring for ventricular ectopy.

Premature ventricular contractions (PVCs) are associated with an increased risk of cardiovascular disease and mortality. Many epidemiologic studies measure a continuous short rhythm strip to ascertain PVCs as a screening tool to identify persons at highest risk. Despite its widespread use in epidemiologic studies, the rhythm strip has not been completely validated. Therefore, a continuous 2-min rhythm strip was measured on 242 consecutive individuals referred for ambulatory ECG monitoring. Prevalence of at least one PVC on the 2-min rhythm strip was compared to a gold standard, the average number of PVCs per hr on ambulatory recording. The prevalence of any PVCs on the 2-min rhythm strip was 19%. As average PVCs per hr increased on the ambulatory ECG recording, sensitivity increased while specificity slowly decreased. Sensitivity ranged from 26-100% and specificity ranged from 81-100% across the distribution of average PVCs per hr on ambulatory monitoring. Area under the receiver operator characteristic (ROC) curve of the 2-min rhythm strip compared to 24-hr results was 0.943. Area under ROC curves were not statistically different (P > 0.05) by age, gender, hypertension status, or history of myocardial infarction. In this clinical population, utilizing the 2-min rhythm strip as an indicator of average PVCs per hr had excellent specificity and moderate to low sensitivity across most of the distribution of average PVCs per hr. The use of a short rhythm strip to detect PVCs may be considered useful in epidemiologic investigations of cardiovascular disease and mortality for detecting high frequency PVCs in populations. The use of a short rhythm strip as a screening tool to detect PVCs in clinical practice is not warranted, based on our findings and the existing literature. However, an awareness that PVCs on a 2-min rhythm strip consistently identify high frequency PVCs on 24-hr recordings should be helpful to clinicians.

Adult↗
PubMed2000

Effect of rates of perfusion on dominant frequency and defibrillation energy in isolated fibrillating hearts.

This study assessed the influence of rates of reperfusion on excitability of the myocardium using dominant frequency (DF) (in Hz) of VF and the relationship of DF to the minimum defibrillation energy (MDE) (in J). Our hypothesis was that increasing flow during reperfusion increases DF that raises MDE. Initially, six Langendorff perfused swine hearts were serially fibrillated and perfusion arrested for 4 minutes followed by reperfusion and defibrillation to establish reproducibility of the model. The epicardial ECG was analyzed for DF. In subsequent studies (n = 8), no flow VF was followed by 1-minute reperfusion at normal flow or 10% flow (low flow) and shocked with increasing energy via epicardial pads until defibrillation. The DF at onset of no flow VF was 9.5 +/- 1.4 and decreased to 3.6 +/- 1.4 after 4 minutes. Reperfusion at normal flow increased the DF of VF compared to low flow after 1 minute (10.8 +/- 1.1 vs 4.5 +/- 1.1 Hz, P = 0.0002) and was associated with increased defibrillation energy requirements (13.5 +/- 5.0 vs 7.3 +/- 6.2 J, P = 0.047). In summary, defibrillation energy requirements are lower when myocardial excitability is reduced during low flow reperfusion.

Animals↗
PubMed1999

Calcium channel blockers and mortality in elderly patients with myocardial infarction.

BACKGROUND: Although calcium channel blockers are a useful therapy in relieving angina, lowering blood pressure, and slowing conduction of atrial fibrillation, growing evidence has cast doubt on their safety in patients with coronary disease. OBJECTIVE: To examine the association between calcium channel blocker therapy at hospital discharge and mortality in a population-based sample of elderly patients hospitalized with acute myocardial infarction. DESIGN: Retrospective cohort study using data from medical charts and administrative files. SETTING: All acute care hospitals in 46 states. PATIENTS: All Medicare patients with a principal diagnosis of acute myocardial infarction consecutively discharged from the hospital alive during 8-month periods between 1994 and 1995 (N = 141,041). MAIN OUTCOME MEASURE: Mortality at 30 days and 1 year. RESULTS: Calcium channel blockers were widely prescribed at hospital discharge to elderly patients with myocardial infarction between 1994 and 1995 (n = 51,921), the most commonly prescribed being diltiazem (n = 21,175), nifedipine (n = 12,670), amlodipine (n = 11,683), and verapamil (n = 3639). After adjusting for illness severity and concomitant medication use, patients who were prescribed calcium channel blockers at hospital discharge did not have increased risk for 30-day or 1-year mortality, with the exception of the few (n = 116) treated with bepridil. Bepridil differs from other calcium channel blockers because of its tendency to prolong repolarization, and its association with proarrhythmic effects in elderly patients. CONCLUSION: We did not identify a mortality risk in a large consecutive sample of elderly patients with myocardial infarction, which supports the need for additional prospective trials examining calcium channel blocker therapy for ischemic heart disease.

Aged↗
PubMed1999

Mitochondrial dysfunction in the pathogenesis of necrotic and apoptotic cell death.

Mitochondria are frequently the target of injury after stresses leading to necrotic and apoptotic cell death. Inhibition of oxidative phosphorylation progresses to uncoupling when opening of a high conductance permeability transition (PT) pore in the mitochondrial inner membrane abruptly increases the permeability of the mitochondrial inner membrane to solutes of molecular mass up to 1500 Da. Cyclosporin A (CsA) blocks this mitochondrial permeability transition (MPT) and prevents necrotic cell death from oxidative stress, Ca2+ ionophore toxicity, Reye-related drug toxicity, pH-dependent ischemia/reperfusion injury, and other models of cell injury. Confocal fluorescence microscopy directly visualizes onset of the MPT from the movement of green-fluorescing calcein into mitochondria and the simultaneous release from mitochondria of red-fluorescing tetramethylrhodamine methylester, a membrane potential-indicating fluorophore. In oxidative stress to hepatocytes induced by tert-butylhydroperoxide, NAD(P)H oxidation, increased mitochondrial Ca2+, and mitochondrial generation of reactive oxygen species precede and contribute to onset of the MPT. Confocal microscopy also shows directly that the MPT is a critical event in apoptosis of hepatocytes induced by tumor necrosis factor-alpha. Progression to necrotic and apoptotic cell killing depends, at least in part, on the effect the MPT has on cellular ATP levels. If ATP levels fall profoundly, necrotic killing ensues. If ATP levels are at least partially maintained, apoptosis follows the MPT. Cellular features of both apoptosis and necrosis frequently occur together after death signals and toxic stresses. A new term, necrapoptosis, describes such death processes that begin with a common stress or death signal, progress by shared pathways, but culminate in either cell lysis (necrosis) or programmed cellular resorption (apoptosis) depending on modifying factors such as ATP.

Animals↗
PubMed1999

Confocal microscopy of the mitochondrial permeability transition in necrotic and apoptotic cell death.

Opening of a high-conductance pore in the mitochondrial inner membrane induces onset of the mitochondrial permeability transition (mPT). Cyclosporin A and trifluoperazine inhibit this pore and block necrotic cell death in oxidative stress, Ca2+ ionophore toxicity, Reye-related drug toxicity, pH-dependent ischaemia/reperfusion injury and other models of cell injury. Confocal fluorescence microscopy directly visualizes the increased mitochondrial membrane permeability of the mPT from the movement of calcein from the cytosol into the matrix space. Pyridine nucleotide oxidation, increased mitochondrial Ca2+ and mitochondrial generation of reactive oxygen species (ROS) all contribute to the onset of the mPT in situ. Confocal microscopy also shows directly that the mPT is a critical link in apoptotic signalling by tumour necrosis factor-alpha at a point downstream of caspase 8 and upstream of caspase 3. Cyclosporin A blocks this mPT, preventing release of pro-apoptotic cytochrome c from mitochondria and subsequent apoptotic cell killing. Progression to necrosis or apoptosis after the mPT depends on the availability of ATP, which blocks necrosis but promotes the apoptotic programme. Given the pathophysiological importance of the mPT, development of agents to modulate the mPT represents an important new goal for pharmaceutical drug discovery.

Animals↗
PubMed1998

Electrodeposited iridium oxide pH electrode for measurement of extracellular myocardial acidosis during acute ischemia.

In the present paper, fabrication, characterization, and physiological applications of a solid-state pH electrode are described. The pH sensing layer was based on an anodic electrodeposited iridium oxide film (AEIROF). Sputtered platinum electrodes (1 mm diameter) fabricated on flexible Kapton films or platinum wires were used as planar or cylindrical supports. Each electrode site was coated with Nafion to attenuate the interference of anionic redox species and to protect the electrode surface during in vivo measurements. Performance of the AEIROF was evaluated, for the first time, as a pH electrode and proved to have a slightly super-Nernstian response with slope of -63.5 +/- 2.2 mV/pH unit for both wire and planar sputtered platinum electrodes. Linear pH responses were obtained in the pH range 2-10. The electrodes have a working lifetime of at least 1 month with accuracy of about 0.02 pH unit and fast response time. The electrodes showed very low sensitivities for different species, such as Na+, K+, Li+, NH4+, Ca2+, Mg2+, dissolved oxygen, lactate, ascorbate, and urate, which are important for physiological applications. The electrodes were applied in extracellular pH measurements during brief regional ischemia in a swine heart and no-flow ischemia in an isolated rabbit papillary muscle. A first report on extracellular pH, K+, and lactate simultaneous measurements during no-flow ischemia using the AEIROF pH electrode and the previously described K+ and lactate electrodes is presented as well.

Acidosis↗
PubMed1998

The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy.

Using confocal microscopy, onset of the mitochondrial permeability transition (MPT) in individual mitochondria within living cells can be visualized by the redistribution of the cytosolic fluorophore, calcein, into mitochondria. Simultaneously, mitochondria release membrane potential-indicating fluorophores like tetramethylrhodamine methylester. The MPT occurs in several forms of necrotic cell death, including oxidative stress, pH-dependent ischemia/reperfusion injury and Ca2+ ionophore toxicity. Cyclosporin A (CsA) and trifluoperazine block the MPT in these models and prevent cell killing, showing that the MPT is a causative factor in necrotic cell death. During oxidative injury induced by t-butylhydroperoxide, onset of the MPT is preceded by pyridine nucleotide oxidation, mitochondrial generation of reactive oxygen species, and an increase of mitochondrial free Ca2+, all changes that promote the MPT. During tissue ischemia, acidosis develops. Because of acidotic pH, anoxic cell death is substantially delayed. However, when pH is restored to normal after reperfusion (reoxygenation at pH 7.4), cell death occurs rapidly (pH paradox). This killing is caused by pH-dependent onset of the MPT, which is blocked by reperfusion at acidotic pH or with CsA. In isolated mitochondria, toxicants causing Reye's syndrome, such as salicylate and valproate, induce the MPT. Similarly, salicylate induces a CsA-sensitive MPT and killing of cultured hepatocytes. These in vitro findings suggest that the MPT is the pathophysiological mechanism underlying Reye's syndrome in vivo. Kroemer and coworkers proposed that the MPT is a critical event in the progression of apoptotic cell death. Using confocal microscopy, the MPT can be directly documented during tumor necrosis factor-alpha induced apoptosis in hepatocytes. CsA blocks this MPT and prevents apoptosis. The MPT does not occur uniformly during apoptosis. Initially, a small proportion of mitochondria undergo the MPT, which increases to nearly 100% over 1-3 h. A technique based on fluorescence resonance energy transfer can selectively reveal mitochondrial depolarization. After nutrient deprivation, a small fraction of mitochondria spontaneously depolarize and enter an acidic lysosomal compartment, suggesting that the MPT precedes the normal process of mitochondrial autophagy. A model is proposed in which onset of the MPT to increasing numbers of mitochondria within a cell leads progressively to autophagy, apoptosis and necrotic cell death.

Animals↗
PubMed1998

An application of methods for clustered binary responses to a cardiovascular study with small sample size.

This paper discusses statistical methods for a cardiovascular study in which each of eight animals had a dichotomous outcome observed for each of several treatments. There were five treatments in all: shunt, control, two doses of a test drug for potentially causing an unfavorable cardiovascular event, and a combination of the test drug and a counteracting agent. Exact conditional methods were used through LogXact, a statistical software for exact logistic regression and an alternative framework for performing a large class of nonparametric tests performed by StatXact. The results agreed reasonably with asymptotic methods even though the sample size was small.

Animals↗