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Biomedical subjects

M F O'Rourke

Publications and source records attributed to M F O'Rourke.

At least 19 recordsLinked to original sources

Arterial stiffness.

BACKGROUND: Arterial stiffness is an important determinant of pulse pressure, and of left ventricular load and coronary perfusion pressure. ASSESSMENTS OF STIFFNESS: Precise quantification is elusive, since stiffness is different in different arteries and even in the same artery at different pressures. Proximal elastic arteries and peripheral muscular arteries respond differently to aging change and to drugs. Various other terms are used to express stiffness, such as distensibility and compliance. Various indirect indices are also used, including pulse wave velocity, characteristic impedance and augmentation index. INCREASES IN STIFFNESS: While the literature is confusing, it is well established that stiffness of central arteries increases with aging and with elevated blood pressure. Effects of other diseases and of vasoactive agents are less clear-cut.

Aging

Cardiovascular ageing and heart failure.

Increase in arterial stiffness with age causes elevation of systolic blood pressure, which is the most common antecedent of heart failure in older people. Heart failure results from systolic and diastolic dysfunction; in either case, reducing mechanical load is the basis for preventing and treating heart failure.

Adolescent

An airline cardiac arrest program.

BACKGROUND: As many as 1000 lives are lost annually from cardiac arrest in commercial aircraft. Ventricular fibrillation (VF), the most common mechanism, can be treated effectively only with prompt defibrillation, whereas the current policy of most airlines is to continue cardiopulmonary resuscitation pending aircraft diversion. The objective of this study was to assess the impact of making semiautomatic external defibrillators (AEDs) available for use on airline passengers with cardiac arrest. METHODS AND RESULTS: AEDs were installed on international Qantas aircraft and at major terminals, selected crew were trained in their use, and all crew members were trained in cardiopulmonary resuscitation. Supervision was provided by medical volunteers or (remotely) by airline physicians. During a 64-month period, AEDs were used on 109 occasions: 63 times for monitoring an acutely ill passenger and 46 times for cardiac arrest. Twenty-seven episodes of cardiac arrest occurred in aircraft, often (11 of 27 [41%]) unwitnessed, and they were usually (21 of 27 [78%]) associated with asystole or pulseless idioventricular rhythm. All 19 arrests in terminals were witnessed; VF was present in 17 (89%). Overall, defibrillation was initially successful in 21 of 23 cases (91%). Long-term survival from VF was achieved in 26% (2 of 6 in aircraft and 4 of 17 in terminals). The ability to monitor cardiac rhythm aided decisions on diversion, which was avoided in most passengers with asystole or idioventricular rhythm. CONCLUSIONS: AEDs in aircraft and terminals, with appropriate crew training, are helpful in the management of cardiac emergencies. Survival from VF is practicable and is comparable with the most effective prehospital ambulance emergency services. Costly aircraft diversions can be avoided in clearly futile situations, enhancing the cost-effectiveness of the program.

Aircraft

Decreased binding and autophosphorylation of the epidermal growth factor receptor in ethanol-fed rats.

We have shown previously that binding and processing of epidermal growth factor are impaired in livers of ethanol-fed rats. In the current study, we examined these ethanol-induced alterations in greater detail by studying both high and low affinity epidermal growth factor binding as well as the ability of added ligand to stimulate receptor autophosphorylation. We also measured the binding of anti-receptor antibody to intact and permeabilized cells in order to determine more accurately the levels of receptor protein. Hepatocytes were isolated from ethanol-fed and pair-fed control rats. Ligand binding, antibody binding, and ligand-induced receptor autrophosphorylation were measured in the respective cell populations. In ethanol-fed animals, binding to both high and low affinity states of the hepatic epidermal growth factor receptor was decreased by 40-50% (P < 0.01). This ethanol-induced decrease in ligand binding was accompanied by a reduced ability of epidermal growth factor to stimulate receptor autophosphorylation (32% decrease, P < 0.01). In contrast, binding of anti-receptor antibody was not altered in ethanol-fed animals. In conclusion, chronic ethanol feeding decreased epidermal growth factor binding with a concomitant decrease in the ability of the receptor tyrosine kinase to phosphorylate tyrosine residues. These changes were not accompanied by an actual decrease in receptor protein content. These findings could be relevant to modified responses to this growth factor in the livers of chronic ethanol-fed animals.

Animals

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Communication

Towards optimization of wave reflection: therapeutic goal for tomorrow?

1. The conventional approach to drug therapy of hypertension and heart failure considers only effects of such drugs on peripheral resistance, cardiac output and heart rate. 2. A more complete approach needs to consider the pulsatile nature of cardiac ejection and so the influence of arterial stiffness and wave reflection properties and the effects of drugs on these. 3. Wave reflection normally aids cardiac function when full body height is achieved and arterial distensibility is high. However, with ageing or in hypertension the arteries stiffen and wave reflection returns early, augmenting systolic pressure, increasing pulse pressure and reducing the capacity for coronary perfusion. 4. In mature or older adults, delay of or reduction in wave reflection is an important therapeutic strategy for management of hypertension, angina pectoris and cardiac failure. 5. Beneficial effects of such therapy cannot always be gauged from conventional recordings of blood pressure, but can be inferred from analysis of pulse waveform.

Aging

Pulse wave analysis.

PULSE WAVE ANALYSIS IN HISTORICAL TIMES: Interpretation of the arterial pulse has been an important part of the medical examination from ancient times. Graphic methods for clinical pulse wave recording were introduced by Marey in Paris and by Mahomed in London last century. Mahomed showed how such recordings could be used to detect asymptomatic hypertension, and used them to chart the natural history of essential hypertension and to distinguish between this condition and chronic nephritis. Interest in arterial pulse analysis, as applied by Mahomed, lapsed with the introduction of the cuff sphygmomanometer 100 years ago. MODERN PULSE WAVE ANALYSIS: Analysis of the arterial pulse is now regaining favour as limitations of the cuff sphygmomanometer are better recognized (including the ability only to measure extremes of the pulse in the brachial artery). In addition, high-fidelity tonometers have been introduced for very accurate, non-invasive measurement of arterial pulse contour, and there is now a better understanding of arterial hemodynamics, and appreciation of disease and aging effects in humans. It is now possible to record the pulse wave accurately in the radial or carotid artery, to synthesize the ascending aortic pulse waveform, to identify systolic and diastolic periods and to generate indices of ventricular-vascular interaction previously only possible with invasive arterial catheterization. Pressure pulse wave analysis now permits more accurate diagnosis and more logical therapy than was ever possible in the past.

Aging

Comparative PET studies of the distribution of (-)-3,4-methylenedioxy-N-[11C]methamphetamine and (-)-[11C]methamphetamine in a monkey brain.

Carbon-11 labeled (-)-methamphetamine and (-)-3,4-methylenedioxy-N-methamphetamine were synthesized by methylation of the corresponding desmethyl precursors with [11C]H3I in 40-60% yield in a synthesis time of 30 min from EOB with a specific activity of 0.5-1.2 Ci/microM. PET studies in a Rhesus monkey revealed that the uptakes of both compounds in different brain regions were similar, and the retention of radioactivity in these brain regions remained constant throughout the study for the former while it was washed out slowly for the latter. The half-life of (-)-3,4-methylenedioxy-N-methamphetamine in monkey brain was approximately 70 min. Analyses of arterial plasma by HPLC revealed that 50% of radioactivity in the plasma remained as (-)-methamphetamine while only 3% remained as (-)-3,4-methylenedioxy-N-methamphetamine at 60 min post-injection. These results suggest that the uptakes of both compounds in monkey brain are probably not receptor mediated. Rather, blood flow, lipophilicity of the compounds or other transport mechanisms may play a role in their uptakes.

3,4-Methylenedioxyamphetamine

PET study of the distribution of [11C]fluoxetine in a monkey brain.

No-carrier-added [11C]fluoxetine (2) was synthesized by methylation of norfluoxetine (1) with [11C]H3I in 20% radiochemical yield in a synthesis time of 40 min from EOB with a specific activity of 0.48 Ci/microM (EOB). In vivo study in mouse indicated that the uptake of 2 in mouse tissues was high and the radioactivity remained constant throughout the study. The uptake of 2 in mouse brain was 4%/g. PET study in a Rhesus monkey also showed that the uptakes of 2 in different brain regions were similar and the retention of radioactivity in these regions remained constant throughout the study (80 min). Analysis of arterial plasma by HPLC showed that only 20% of radioactivity in the plasma remained as 2 at 30 min post-injection. These results suggest that the uptake of fluoxetine in monkey brain is probably not receptor mediated. Rather, blood flow, lipophilicity or other transport mechanisms may play a role in its uptake.

Animals

Haemodynamic basis for the development of left ventricular failure in systolic hypertension and for its logical therapy.

In youth, properties of the human arterial system are such that pulse pressure generated by ventricular ejection is low, and the major component of wave reflection returns to the heart after the aortic valve has shut, so making no contribution to ventricular load, but boosting pressure throughout diastole and so aiding coronary perfusion. That constitutes optimal arterial function and optimal vascular/ventricular interaction. With ageing, the aorta and elastic arteries stiffen, so that aortic pulse pressure is markedly increased. This is a consequence of a direct stiffening effect on the aorta itself, and of an indirect effect caused by early return of wave reflection consequent upon stiffening of the whole arterial system with an increase in its pulse wave velocity. There is a change in contour of the aorta pressure wave with wave generation of a late systolic peak and disappearance of the diastolic wave; the reflected wave moves from diastole and systole. Because the lowest diastolic pressure remains relatively constant [1,10], increased pulse pressure causes a substantial increase in aortic systolic pressure. Increased aortic systolic pressure is associated with increased left ventricular pressure and leads to left ventricular hypertrophy. Sustained elevation in systolic pressure and persistent left ventricular hypertrophy are associated with progressive degenerative changes in the hypertrophied myocytes such that these weaken, developing less force with each contraction. The weakened, hypertrophied fibres lengthen and the ventricle dilates, with force and cardiac output initally being maintained at greater muscle length and ventricular volume through the Frank-Starling mechanism. Ultimately compensation is lost. The hypertrophied ventricle normally functions as a flow source, which is capable of generating flow even against very high pressure. With the development of cardiac failure through muscle weakening, the ventricle comes to act as a pressure source, with ventricular output very sensitive to pressure and to changes in pressure. The normal ventricle functions in an intermediate position, even though it is closer in behaviour to a flow than to a pressure source. Wave reflection adds to pressure but subtracts from flow. In youth, wave reflection returns to the heart during diastole when the aortic valve is shut. Negative flow is not possible, so wave reflection is apparent only as a secondary pressure wave in the ascending aorta. In older subjects, when the left ventricle is beating powerfully, return of wave reflection during systole has less obvious an effect on the ascending aortic flow wave, but causes an obvious secondary boost to pressure in the ascending aorta and left ventricle. Hence, under normal circumstances, wave reflection at the heart is apparent as a positive secondary pressure wave, either because the aortic valve is shut when this wave returns, or because the ventricle possesses enough power that it virtually overcomes any negative influence on flow when reflection returns during systole. When the myocardium weakens and the heart fails, the heart starts to behave like a pressure source, and wave reflection starts to have a far greater effect on flow; wave reflection is manifested more as a negative influence on flow than as a positive influence on pressure. As heart failure develops, there is a progressive change in flow wave contour, with early deceleration of aortic flow and ultimately, abbreviation of systolic ejection duration with fall in stroke volume. Early wave reflection is the major factor in the genesis of systolic hypertension. Early wave reflection remains a major factor when heart failure develops, although its effect is apparent in reduction of late systolic flow rather than as a boost to late systolic pressure. Reduction in wave reflection through use of vasodilatory agents is a logical strategy in treatment of systolic hypertension. That type of therapy is equally logical in treatment

Animals

Pressure wave propagation in a multibranched model of the human upper limb.

The influence of the large arteries and the peripheral load on pressure wave propagation in the human upper limb was investigated in an anatomically realistic multibranched model based on linear transmission theory. To mimic vascular changes seen in life, the viscoelastic properties of large arteries and the peripheral load properties (represented as modified windkessels) were altered as follows: Young's modulus (from 10.9 x 10(6) to 15.3 x 10(6) dyn/cm2) and phase (from 0 to 15 degrees) of the complex elastance, windkessel time constant (from 0 to 0.6 s), and peripheral reflection coefficient (from 0 to 0.95). The relationship between the central aortic and peripheral radial pressure waveforms was analyzed in the time and the frequency domain. Results indicate that the large arterial properties have less influence (peak systolic pressure changed by 3% and peak of transfer function changed by 29%) than the properties of the peripheral load (systolic pressure changed by 14% and peak of transfer function changed by 74%) on the pressure wave propagation in the upper limb.

Arm

Functional origin of reflected pressure waves in a multibranched model of the human arterial system.

The effects of wave travel and wave reflection were simulated in a mathematical model of the whole arterial tree consisting of 142 uniform transmission line segments. The arterial model was partitioned into three separate segments: upper limbs, trunk, and lower limbs. Aging was simulated by increasing average pulse wave velocities of these segments (10.9-12.9, 8.0-11.7, and 9.0-11.3 m/s for upper limbs, trunk, and lower limbs, respectively). Reflection coefficients at the terminal elements were altered to simulate vasodilation (0.0) and vasoconstriction (0.95). The impedance patterns and spatial distribution of pressure waveforms generated by the model simulating aging and vasoconstriction were similar to in vivo measurements by other investigators. Reflected pressure waves from each segment reached the ascending aorta and contributed differently to the late systolic peak on the aortic pressure wave. Aging does not alter the origin of these reflected pressure waves in the trunk. Aortic impedance and pressure wave changes induced by simulation of dilation of splanchnic bed were similar to those observed experimentally with nitroglycerin.

Aorta