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Biomedical subjects

Michael P Frenneaux

Publications and source records attributed to Michael P Frenneaux.

At least 19 recordsLinked to original sources
PubMed2007

Mechanisms of reduction of mitral regurgitation by cardiac resynchronization therapy.

OBJECTIVES: We sought to investigate the effects of improved left ventricular (LV) synchrony on secondary mitral regurgitation in patients receiving cardiac resynchronization therapy for severe heart failure. METHODS: A total of 22 patients, aged 63 +/- 8 years, were studied during sinus rhythm (unpaced), during LV pacing, and during biventricular pacing. Echocardiography was used to assess LV shape, mitral valve morphology and function, and global systolic and diastolic function. Mechanical ventricular synchrony was calculated from regional systolic timings and velocities, using tissue Doppler. RESULTS: Synchronicity index of LV longitudinal function improved from 36 +/- 19 to 14 +/- 8 milliseconds with LV pacing, and from 31 +/- 17 to 12 +/- 7 milliseconds with biventricular pacing (both P < .01). Heterogeneity of myocardial velocities decreased and mean systolic longitudinal velocity increased. Long-axis and short-axis systolic dimensions decreased, and the LV became less spherical. Apical displacement of coaptation from the plane of the mitral annulus, and annular diameter, were reduced. The severity of mitral regurgitation decreased: vena contracta diameter decreased from 5.3 +/- 1.7 to 4.1 +/- 1.5 mm with LV pacing, and from 5.2 +/- 1.7 to 4.0 +/- 1.7 mm with biventricular pacing (both P < .05), correlating with the increase in mean systolic longitudinal velocity (r = -0.49 for LV pacing and r = -0.67 for biventricular pacing, both P < .05). CONCLUSIONS: Cardiac resynchronization reduces mitral regurgitation by improving LV mechanical synchrony, which leads to an increase in LV longitudinal function and a reduction in subvalvar traction.

Analysis of Variance↗
PubMed2007

Human arterial responses to isometric exercise: the role of the muscle metaboreflex.

The effects of exercise on the distensibility of large and medium-sized arteries are poorly understood, but can be attributed to a combination of local vasodilator effects of exercise opposed by sympathetic vasoconstrictor tone. We sought to examine this relationship at the conduit artery level, with particular reference to the role of the sympatho-excitatory muscle metaboreflex. The effect of maintained muscle metaboreflex activation on a previously passive or exercised limb femoral artery was investigated. A total of ten healthy volunteers performed 2 min of isometric ankle plantar-flexion at 40% MVC (maximal voluntary force), in conjunction with 2 min of either non-ischaemic isometric HG (handgrip; control condition) or IHG (ischaemic HG) at 40% MVC. IHG was followed by 2 min of PECO (post-exercise circulatory occlusion) to maintain muscle metaboreflex activation. FTPWV [femoral-tibial PWV (pulse wave velocity)] was measured in the exercised or contralateral limb at baseline and immediately following calf exercise. BP (blood pressure) and HR (heart rate) were measured continuously throughout. In the HG condition, BP and HR returned promptly to baseline post-exercise, whereas exercised leg FTPWV was decreased (less stiff) by 0.6 m/s (P<0.05) and the non-exercised leg PWV was not changed from baseline. PECO caused a sustained increase in BP, but not HR, in the IHG condition. Contralateral leg PWV increased (stiffened) during PECO by 0.9 m/s (P<0.05), whereas exercised limb FTPWV was not changed from baseline. In conclusion, muscle metaboreflex activation causes a systemic stiffening of the arterial tree, which can overcome local exercise-induced decreases in arterial PWV.

Adult↗
PubMed2006

Chronic oral ascorbic acid therapy worsens skeletal muscle metabolism in patients with chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) is associated with abnormalities of skeletal muscle metabolism. This may be due to impaired oxygen delivery as a result of endothelial dysfunction. AIMS: We postulated that ascorbic acid would improve oxygen delivery to exercising muscle and improve skeletal muscle metabolism. METHODS: We studied skeletal muscle metabolism using (31)P magnetic resonance spectroscopy in 39 CHF patients. Endothelial function was assessed by changes in pulse wave velocity. Subjects were randomised to receive 4 g ascorbic acid daily for 4 weeks in a placebo-controlled double-blind study. RESULTS: Ascorbic acid significantly increased phosphocreatine utilization during exercise. In addition, glycolytic ATP synthesis increased in the ascorbic acid group (change in rate of ATP synthesis at 1 min -0.21+/-0.76 with placebo, 2.06+/-0.60 following ascorbic acid; p<0.05). Phosphocreatine and ADP recovery after exercise were not changed. The fall in pulse wave velocity during reactive hyperaemia was increased by ascorbic acid from -6.3+/-2.6% to -12.1+/-2.0% (p<0.05). CONCLUSIONS: These findings suggest that ascorbic acid increased both phosphocreatine utilization and glycolytic ATP synthesis during exercise in patients with CHF implying worsened skeletal muscle metabolism despite improvements in endothelial function.

Adenosine Triphosphate↗
PubMed2006

Metyrapone improves endothelial dysfunction in patients with treated depression.

OBJECTIVES: This study sought to examine the effect of metyrapone on endothelial dysfunction in patients with treated recurrent major depression. BACKGROUND: Depression is an independent risk factor for the development of coronary heart disease, and patients with depression have endothelial dysfunction, an atherogenic abnormality. This abnormality may be attributable to abnormal hypothalamic-pituitary-adrenal (HPA) axis function, a feature of depression, resulting in increased exposure to cortisol. Cortisol administration produces endothelial dysfunction in healthy subjects. METHODS: We measured endothelial function using flow-mediated dilation (FMD) of the brachial artery in 30 patients with depression and in 36 matched control subjects. Patients were randomized (double blind) to metyrapone (an inhibitor of cortisol synthesis) or placebo, and FMD was remeasured 6 h later. RESULTS: At baseline, FMD was impaired in patients versus control subjects (mean [standard error]), -1.27% [0.91%] vs. 4.37% [0.59%] (p < 0.001). The FMD was similar in the placebo and the metyrapone patient groups at baseline (0.17% [1.04%] vs. -2.72% [1.30%], p = 0.11). Metyrapone significantly reduced plasma cortisol levels. There was a significant improvement in FMD in the metyrapone group from -2.72% [1.30%] to 3.82% [0.99%] (p < 0.001), whereas the change in the placebo group, from 0.17% [1.04%] to 1.15% [1.14%], was not significant. Analysis of covariation showed that the effect of metyrapone was significant (p = 0.034). CONCLUSIONS: Inhibition of cortisol production by metyrapone ameliorates the endothelial dysfunction seen in depression, suggesting that the mechanism of the endothelial dysfunction may involve cortisol.

Adult↗
PubMed2006

Integration of the metabolic and cardiovascular effects of exercise.

Most of the essays in this volume have adopted a reductionist approach and have focused on the biochemistry either in skeletal muscle or in the vascular wall. There is however a complex interaction between the biochemistry in the endothelium of the microvascular wall, the vascular smooth muscle and the skeletal muscle fibres involving signalling pathways in the three tissues and an intense exchange of signal molecules between them. In the present essay an integrative overview is given of this complex metabolic interaction and the impairments in it that lead to type 2 diabetes and cardiovascular disease.A reduced nitric oxide production by the (micro)vascular endothelium is identified as the key event and is reversible by regular exercise and a reduced calorie intake. The chapter also contains a description of the complex metabolic network controlled by the inducible transcription factor nuclear factor-kappaB, that is activated in more advanced stages of the chronic diseases, and either leads to repair of the microvascular wall or to irreversible damage and the severe complications of end stage cardiovascular disease and type 2 diabetes.

Atherosclerosis↗
PubMed2006

Haemodynamics of cardiac arrest and resuscitation.

PURPOSE OF REVIEW: This review will summarize the available data regarding the haemodynamic changes occurring following cardiac arrest in humans and animal models. RECENT FINDINGS: Following cardiac arrest due to ventricular fibrillation without cardiopulmonary resuscitation, blood flow exponentially falls but continues for approximately 5 min until the pressure gradient between the aorta and the right heart is completely dissipated. During cardiopulmonary resuscitation forward flow occurs into the aorta during the compression phase. Coronary blood flow is retrograde during the compression phase and antegrade during the decompression phase. Carotid blood flow takes over a minute to reach plateau levels following the initiation of chest compressions, and even brief interruptions of compressions result in a dramatic reduction in carotid blood flow which takes a minute or so to recover to plateau levels when compressions are reinstituted. Coronary perfusion pressure during the release phase of cardiopulmonary resuscitation has been shown to be a powerful predictor of the likelihood of recovery of spontaneous circulation following restoration of electrical activity. SUMMARY: Recent studies have provided important insights into the haemodynamics of cardiac arrest and of cardiopulmonary resuscitation which may inform more effective strategies for the management of cardiac arrest in the future.

Animals↗
PubMed2005

Conjugated linoleic acid impairs endothelial function.

OBJECTIVE: To determine the effect of dietary supplementation with conjugated linoleic acid (CLA) on body mass index (BMI), body fat distribution, endothelial function, and markers of cardiovascular risk. METHODS AND RESULTS: Forty healthy volunteers with BMI >27 kg/m2 were randomized to receive a CLA isomeric mixture or olive oil in a 12-week double-blind study. Subcutaneous body fat and abdominal/hepatic fat content were assessed using skin-fold thicknesses and computed tomography scanning, respectively. Endothelial function was assessed by brachial artery flow-mediated dilatation (FMD). Plasma isoprostanes were measured as an index of oxidative stress. CLA supplementation did not result in a significant change in BMI index or total body fat. There was a significant decrease in limb (-7.8 mm, P<0.001), but not torso skin-fold thicknesses or abdominal or liver fat content. Brachial artery FMD declined (-1.3%, P=0.013), and plasma F2-isoprostanes increased (+91 pg/mL, P=0.042). CONCLUSIONS: A CLA isomeric mixture had at most modest effects on adiposity and worsened endothelial function. On the basis of these results, the use of the isomeric mixture of CLA as an aid to weight loss cannot be recommended.

Adult↗
PubMed2005

Reversal of inappropriate peripheral vascular responses in hypertrophic cardiomyopathy.

OBJECTIVES: We assessed the frequency of abnormal forearm vasodilator responses during lower body negative pressure (LBNP) in 21 non-obstructive hypertrophic cardiomyopathy (HCM) patients (31 +/- 8 [20 to 43] years) with abnormal blood pressure response (ABPR) to exercise and the effects of three drugs used to treat vasovagal syncope (propranolol, clonidine, and paroxetine) in a double-blind crossover study. BACKGROUND: Some HCM patients have an ABPR to exercise, which may be due to paradoxical peripheral vasodilatation. A similar proportion has paradoxical forearm vasodilatation during central volume unloading using LBNP. These abnormal reflexes may be caused by left ventricular mechanoreceptor activation. Similar mechanisms may also contribute to some cases of vasovagal syncope. METHODS: Blood pressure changes were assessed during exercise, and forearm vascular responses and baroreceptor sensitivity were assessed during LBNP using plethysmography. RESULTS: Nine (43%) patients (group A) had paradoxical vasodilator responses (forearm vascular resistance [FVR] fell by 7.5 +/- 4.6 U), and 12 (57%) patients (group B) had normal vasoconstrictor responses during LBNP (FVR increased by 7.7 +/- 4.9 U). Paroxetine augmented systolic blood pressure (SBP) during exercise in group A (21 +/- 6 mm Hg vs. 14 +/- 11 mm Hg at baseline, p = 0.02); no effect was detected in group B. Paroxetine reversed paradoxical vascular responses during LBNP in seven (78%) patients from group A. Propranolol and clonidine had no significant effect on SBP during exercise but reversed paradoxical vascular responses in some patients from group A (n = 5 and n = 3). CONCLUSIONS: Paradoxical vasodilatation during LBNP occurs in 40% of patients with ABPR during exercise and is reversed by propranolol, clonidine, and paroxetine. Paroxetine also improved SBP response to exercise.

Adrenergic beta-Antagonists↗
PubMed2005

Inhibition of cortisol production with metyrapone prevents mental stress-induced endothelial dysfunction and baroreflex impairment.

OBJECTIVES: This study was designed to investigate the role of cortisol in stress-induced endothelial dysfunction and impaired baroreflex sensitivity (BRS) by blocking cortisol production with metyrapone before subjecting healthy volunteers to mental stress. BACKGROUND: Mental stress raises cortisol levels and is associated with increased coronary heart disease (CHD) morbidity and mortality, especially from sudden cardiac death. It also causes endothelial dysfunction and impaired BRS. METHODS: We measured brachial artery flow-mediated dilation (FMD), a measure of endothelial function, and BRS in 36 subjects without CHD risk factors who were then randomized in a double-blind fashion to oral metyrapone 750 mg x 2 or placebo. Five hours later we subjected subjects to mental stress and then remeasured endothelial function and BRS. RESULTS: Prestress cortisol levels were significantly higher in the placebo group at 270.5 (30.9) nmol/l versus 89.1 (11.8) nmol/l (p = 0.01), and the increase with stress was higher at 57.9 (17.9) nmol/l versus 11.2 (2.2) nmol/l (p < 0.001). In the placebo group, compared to baseline, FMD and BRS fell significantly from 4.5% (0.7%) to 1.4% (1.1%) (p = 0.02) and 21.4 (2.3) ms/mmHg to 16.3 (1.5) ms/mmHg (p = 0.04), respectively. In the metyrapone group, FMD and BRS were unchanged from baseline: 4.3% (0.9%) versus 5.1% (0.8%) (p = 0.48) and 26.4 (2.9) ms/mmHg versus 24.9 (2.6) ms/mmHg (p = 0.62), respectively. Analysis of covariation showed a significant effect of metyrapone on change in both FMD (p = 0.009) and BRS (p = 0.024). CONCLUSIONS: Stress-related endothelial dysfunction and BRS impairment can be prevented by blocking cortisol production with metyrapone, demonstrating a direct or facilitative role for cortisol in these phenomena and suggesting mechanisms by which stress contributes to CHD and sudden cardiac death.

Adult↗
PubMed2005

Detection of human red blood cell-bound nitric oxide.

Major disparities in reported levels of basal human nitric oxide metabolites have resulted in a recent literature focusing almost exclusively on methods. We chose to analyze triiodide chemiluminescence, drawn by the prospect of identifying why the most commonly employed assay in nitric oxide biology typically yielded lower metabolite values, compared with several other techniques. We found that the sensitivity of triiodide was greatly affected by the auto-capture of nitric oxide by deoxygenated cell-free heme in the reaction chamber. Potential contaminants and signal losses were also associated with standard sample purification procedures and the chemistry involved in nitrite removal. To inhibit heme nitric oxide auto-capture, we added potassium ferricyanide to the triiodide reagent, reasoning this would provide a more complete detection of any liberated nitric oxide. From human venous blood samples, we established nitric oxide levels ranging from 0.000178 to 0.00024 mol nitric oxide/mol hemoglobin. We went on to find significantly elevated nitric oxide levels in venous blood taken from diabetic patients in comparison to healthy controls (p < 0.0001). We concluded that the lack of signals reported of late by several groups using triiodide chemiluminescence for the detection of hemoglobin-bound nitric oxide may not represent levels on the border of assay sensitivity but rather underestimated values because of methodological limitations. We therefore stress the need for assay systems to be developed that differentiate between individual nitric oxide metabolite species and overcome the limitations we outline, allowing accurate conclusions to be drawn regarding physiological nitric oxide metabolite levels.

Diabetes Mellitus↗
PubMed2005

Reduced myocardial velocities of left ventricular long-axis contraction identify both systolic and diastolic heart failure-a comparison with brain natriuretic peptide.

BACKGROUND: Echocardiographic diagnosis of radial fractional shortening or global ejection fraction fails to diagnose all patients with heart failure; about 40%, with apparently normal global systolic function, will have elevated brain natriuretic peptide (BNP) concentrations and "pure" diastolic dysfunction. Screening methods do not include assessment of left ventricular (LV) longitudinal function, however, which is a more sensitive marker of subclinical disease. AIMS: We investigated the diagnostic potential of assessment of LV longitudinal function in suspected heart failure, in a comparison against BNP. METHODS: Fifty consecutive subjects (aged 65+/-12 years; 30 men) referred to a heart failure clinic with unexplained breathlessness were examined by echocardiography and had plasma BNP measured by fluorescence immunoassay. RESULTS: Global systolic function (ejection fraction) correlated moderately with log-transformed BNP (r=-0.54), as did global diastolic function (r=0.55 for estimated LV filling pressure, and r=-0.51 for transmitral flow propagation velocity), and radial systolic function (r=-0.60) (all p<0.001). The echocardiographic parameter that correlated best with BNP, however, was LV longitudinal systolic function (r=-0.78, p<0.001). By stepwise multiple regression analysis, BNP was predicted by longitudinal systolic velocity, in association with LV mass index and radial systolic velocity (r=0.81, r(2)=0.66, p<0.0001). The sensitivity and specificity of a longitudinal systolic velocity of </=5.5 cm/s (mean of 4 basal segments) to diagnose heart failure (defined as an elevated BNP) were 94% and 85%, respectively; the negative predictive value was 97%. CONCLUSION: Non-invasive diagnosis or exclusion of suspected heart failure, whether systolic or diastolic, can be performed accurately by echocardiographic measurement of LV longitudinal systolic function.

Aged↗
PubMed2005

Platelet nitrate responsiveness in fasting and postprandial type 2 diabetes.

Vascular responsiveness to exogenous nitrates in type 2 diabetes (T2DM) is attenuated in brachial and coronary vessels. We determined platelet responsiveness to nitric oxide (NO) in T2DM and control subjects. We examined whether the postprandial (PP) state affected platelet sensitivity to NO donors in T2DM patients and the extent of correlation between this and measures of oxidative stress, compared to changes in endothelial function. Twelve T2DM subjects were studied fasting and four hours after a test meal and compared with 15 healthy controls. We assessed the inhibitory effects of NO donors on adenosine 5'-diphosphate (ADP)-induced platelet aggregation. Oxidative stress was assessed by lipid-derived free radicals, ex vivo by electron paramagnetic resonance spectroscopy and markers of lipid peroxidation. Endothelial function was assessed by flow-mediated vasodilatation (FMD) of the brachial artery. Results are expressed as (mean +/- SEM). Fasting platelet aggregation was increased in diabetics versus controls (14.86 +/- 1.1 Ohms vs. 10.76 +/- 1.1 Ohms, p < 0.05). Sodium nitroprusside (SNP) and glyceryl trinitrate (GTN) inhibited ADP-induced aggregation by 73.1 +/- 5.9% and 50.3 +/- 7.7% in healthy controls compared to 15.4 +/- 7% and 19.5 +/- 8.2% in T2DM (p < 0.05). Fasting and postprandial inhibition of platelet aggregation with NO donors in T2DM was similar. T2DM patients had higher levels of oxidative stress in the fasting state and postprandially. There were no PP correlations with platelet NO resistance. In conclusion, there is platelet hyporesponsiveness to NO donors (SNP/GTN) in T2DM compared to controls, with increased ADP-induced platelet aggregation. Platelet abnormalities were associated with increased oxidative stress.

Adenosine Diphosphate↗
PubMed2004

Comparison of left ventricular-biventricular pacing on ventricular synchrony, mitral regurgitation, and global left ventricular function in patients with severe chronic heart failure.

We compared the effects of left ventricular and biventricular pacing in 16 patients (15 men and 1 woman; aged 64 +/- 8 years) with severe heart failure by conventional and tissue Doppler echocardiography. Intraventricular synchrony, regional and global systolic function, diastolic function and filling time, and the severity of secondary mitral regurgitation were similar between left ventricular and biventricular pacing.

Aged↗
PubMed2004

Electrical and mechanical components of dyssynchrony in heart failure patients with normal QRS duration and left bundle-branch block: impact of left and biventricular pacing.

BACKGROUND: Resynchronization pacing is an effective symptomatic treatment for heart failure patients with prolongation of the QRS duration (QRSd). Dyssynchronous contraction of the left ventricle is also observed with normal QRSd. We set out to determine how electrical activation of the left ventricular (LV) free wall differed between patients with left bundle-branch block (LBBB) and normal QRSd and if synchrony improved during pacing in patients with normal QRSd. METHODS AND RESULTS: Twenty-two patients were implanted with resynchronization pacemakers, 13 with LBBB (mean QRS, 171 ms) and 9 with normal QRSd <120 ms (mean, 100 ms). LV lead electrograms and surface ECGs in sinus rhythm (unpaced) were recorded. Conventional and tissue Doppler echocardiography were performed without pacing, with LV and biventricular pacing at optimal atrioventricular delay. Lead electrograms from the LV free wall were later in the LBBB patients in absolute terms (155 ms [SD 23] versus 65.5 ms [SD 25]; P=0.05) and also relative to the surface QRS (90.5% [SD 8] versus 65.5% [SD 24]). Improved synchrony of the left and right ventricles (interventricular synchrony) and of the LV myocardial segments (intraventricular synchrony) was observed for patients with LBBB and normal QRSd. Baseline LV synchrony correlated with timing of LV free-wall electrical activation. Improved intraventricular synchrony during pacing also correlated with LV free-wall electrical activation time. CONCLUSIONS: Resynchronization of systole can be achieved for patients with normal QRSd and LBBB during biventricular and LV pacing. The timing of LV free-wall electrical activation correlated with the improvement in synchrony.

Aged↗
PubMed2004

Effects of exogenous and endogenous natriuretic peptides on forearm vascular function in chronic heart failure.

OBJECTIVE: Natriuretic peptides (NPs) reduce central venous pressure in patients with chronic heart failure (cHF) despite attenuation of arterial, renal, and humoral effects. This suggests a preserved venodilator response. This study had 4 aims: to compare the venodilator effects of human NPs in patients with cHF; to assess the contribution of basal ANP and BNP levels to regulation of forearm vascular volume (FVV); to test the hypothesis that venous ANP responsiveness is preserved in cHF; and to assess the involvement of endothelial nitric oxide-synthase (eNOS) in NP-induced vascular effects. METHODS AND RESULTS: Venous and arterial forearm vascular responses to incremental intra-arterial doses of ANP, Urodilatin, BNP, CNP, or the ANP receptor antagonist A71915 were studied in 53 patients and 11 controls. ANP receptor antagonism reduced FVV by 4.4%+/-1.2% (P<0.05). The forearm blood flow (FBF) response to ANP was significantly blunted in patients versus controls (P<0.01), whereas FVV increased similarly in both groups (maximum 14.7% and 13.4%, both P<0.001). The eNOS blockade reduced ANP-induced FBF changes in controls but not in patients (P<0.05), whereas similar reductions in FVV changes were seen in groups (both P<0.001). CONCLUSIONS: In cHF venous, but not arterial, ANP responsiveness is preserved. Arterial endothelial dysfunction may contribute to NP resistance.

Adult↗
PubMed2004

Vasorelaxation by red blood cells and impairment in diabetes: reduced nitric oxide and oxygen delivery by glycated hemoglobin.

Vascular dysfunction in diabetes is attributed to lack of bioavailable nitric oxide (NO) and is postulated as a primary cause of small vessel complications as a result of poor glycemic control. Although it has been proposed that NO is bound by red blood cells (RBCs) and can induce relaxation of blood vessels distal to its site of production in the normal circulation, the effect of RBC glycation on NO binding and relaxation of hypoxic vessels is unknown. We confirm RBC-induced vessel relaxation is inversely related to tissue oxygenation and is proportional to RBC S-nitrosohemoglobin (HbSNO) content (but not nitrosylhemoglobin content). We show more total NO bound inside highly glycated RBCs (0.0134 versus 0.0119 NO/Hb, respectively; P<0.05) although proportionally less HbSNO (0.0053 versus 0.0088 NO/Hb, respectively; P<0.05). We also show glycosylation impairs the vasodilator function of RBCs within a physiological range of tissue oxygenation. These findings may represent an important contribution to reduced NO bioavailability in the microvasculature in diabetes.

Animals↗