Central artery pulse pressure in end-stage renal disease: the roles of aortic diameter, aortic stiffness and wave reflection.

In elderly subjects and patients with end-stage renal disease (ESRD), carotid pulse pressure (PP) is an independent and significant predictor of cardiovascular (CV) risk. Whereas in the elderly carotid diameter, but not carotid stiffness, is an associated CV risk factor, an opposite CV risk pattern was observed in ESRD patients that was associated with stiffness. Whether in ESRD patients arterial diameter, stiffness or both are involved in the mechanism(s) of increased carotid PP has never been investigated. Nondiabetic ESRD patients (n = 144) were compared with 57 control subjects matched for age, sex and mean blood pressure, but with higher brachial and carotid PP. Noninvasive echo-Doppler techniques and pulse wave velocity (PWV) and pulse wave analysis were used to evaluate cardiac and carotid arterial structures and functions using multiple stepwise regressions. In controls, carotid PP was associated only with stroke volume, arterial wave reflections and aortic PWV, but not aortic diameter. In ESRD patients, it was associated with wave reflections, aortic PWV, stroke volume and higher aortic diameter. In ESRD patients and controls, elevated carotid PP mainly reflected increased aortic PWV and earlier wave reflections. Aortic diameter had an impact only on ESRD patients, where it compensated for enhanced aortic stiffness and the more pronounced effect of reflected waves. This hemodynamic profile differs consistently from that in elderly subjects of the general population and selectively influences CV risk and drug treatment.

[Arterial hypertension, chronic renal insufficiency and dialysis]. / Hypertension arterielle, insuffisance renale chronique et dialyse.

The principal characteristic of hypertension in chronic kidney disease (CKD), especially at CKD stage 5. Is an increased systolic pressure, with normal or even low diastolic pressure. This isolated systolic hypertension is also characterized by ab abnormal increase in pulse pressure which is by itself an independent cardiovascular risk factor. The principal reason for these abnormalities is accelerated ageing of arterial system, principally the aorta and large central arteries. This ageing is characterized by stiffening of arteritis whose natural history is not clearly understood. One of the principal pathogenic factor associated with stiffening is extensive calcification of arterial walls, mainly the medial layer (media-calcinosis). Mineral metabolism disorders such as hyperphosphatemia, play a major role in pathophysiology of calcifications. Arterial stiffness is characterized by very steep volume-pressure relationship and for this reason is associated with hemodynamic instability. Small blood volume increase producing abnormally high pressure while small decrease in blood volume could be associated with deep hypotension.

Arterial structural and functional alterations in uraemia.

Epidemiological and clinical studies have shown that cardiovascular disease in patients with end-stage renal disease (ESRD) is frequently related to damage of large conduit arteries. Arterial disease is responsible for the high incidence of ischaemic heart disease, peripheral artery diseases, left ventricular hypertrophy and congestive heart failure. The vascular complications in ESRD are ascribed to two different but associated mechanisms, namely atherosclerosis and arteriosclerosis. Whereas the former principally affects the conduit function with ischaemic lesions being the most characteristic consequence, the latter primarily disturbs the dampening function of large arteries. Arteriosclerosis in ESRD patients is characterized by diffuse dilation and wall hypertrophy of large conduit arteries and stiffening of arterial walls. These changes represent a clinical form of an accelerated ageing process. The main clinical characteristics due to arterial stiffening are isolated increase in systolic blood pressure with normal or lower diastolic pressure resulting in an increased pulse pressure. The consequences of these alterations are: (i) an increased left ventricular afterload with development of left ventricular hypertrophy and increased myocardial oxygen demand; and (ii) altered coronary perfusion and subendocardial blood flow distribution. Epidemiological studies have identified arterial remodelling and stiffening as independent predictors of overall and cardiac mortality in ESRD patients.

Cardiovascular disease in renal failure.

Cardiovascular disease is prevalent in patients with chronic kidney disease and may account for 50% of all deaths. Left ventricular hypertrophy is the most frequent cardiac alteration in end-stage renal disease (ESRD) patients. It is due to a combination of hemodynamic and humoral factors. Volume overload and pressure overload are responsible for adaptative alterations of the heart and the vessels consider as a unique functional system. These alterations are first beneficial but their persistence leads to a detrimental process, mainly cardiac dilation and failure. Treatment of the hemodynamic overload could partially stabilize or reverse this evolution.

Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease.

To test the predictive values of and independent contributions to cardiovascular and all-cause mortality of various arterial parameters exploring characteristics of the arterial wall at different sites, we studied prospectively 110 stable end-stage renal disease patients on hemodialysis. These parameters involved carotid diameter, carotid intima-media thickness, carotid compliance, carotid distensibility, carotid incremental elastic modulus, aortic diameter, aortic pulse wave velocity, and the presence of arterial calcifications measured at the sites of the carotid artery, abdominal aorta, iliofemoral axis, and legs. The presence of calcifications was analyzed semiquantitatively as a score (0 to 4) according to the number of arterial sites with calcifications. During a follow-up of 53+/-21 months (mean+/-SD), 25 cardiovascular and 14 noncardiovascular deaths occurred. In univariate analysis, the carotid incremental elastic modulus was the most closely related to prognosis. Risk of death increased with the number of vascular sites involved by calcifications. Moreover, information (in terms of prediction) given by carotid elastic incremental modulus was additive to the presence and extent of vascular calcification-related prediction value. Adjusted hazard ratios of all-cause and cardiovascular mortality for an increase of 1 unit in calcification score were 1.9 (95% confidence interval [CI], 1.4 to 2.6) and 2.6 (95% CI, 1.5 to 4.4), respectively (P<0.001 for both). Adjusted hazard ratios of all-cause and cardiovascular mortality for a 1-SD increase in carotid incremental elastic modulus were 1.6 (95% CI, 1.2 to 2.2) and 1.7 (95% CI, 1.2 to 2.4), respectively (P<0.01 for both). The results of this study showed that the presence and extent of vascular calcifications were strong predictors of cardiovascular and all-cause mortality. Carotid incremental elastic modulus gave additional predictive value.

Arterial wave reflections and survival in end-stage renal failure.

The increased effect of arterial wave reflections on central arteries like the common carotid artery seen in end-stage renal failure (ESRF) patients favors myocardial hypertrophy and oxygen consumption and alters coronary blood flow distribution. Nevertheless, the impact of wave reflection on the outcome and end points such as mortality remains to be demonstrated. One hundred eighty ESRF patients (age, 54+/-16 years) were monitored for 52+/-36 months (mean+/-SD). Seventy deaths, including 40 cardiovascular (CV) and 30 non-CV events, occurred. At entry, patients, in addition to standard clinical and biochemical analyses, underwent aortic pulse wave velocity measurement and determination of arterial wave reflexion by applanation tonometry on the common carotid artery that was expressed as augmentation index. Cox analyses demonstrated that predictors of all-cause and CV mortality were age, aortic pulse wave velocity, low diastolic blood pressure, preexisting CV disease, and increased augmentation index, whereas the prescription of an ACE inhibitor had a favorable effect on survival. After adjustment for all confounding factors, the risk ratio for each 10% increase in augmentation index was 1.51 (95% confidence interval, 1.23 to 1.86; P<0.0001) for all-cause mortality and 1.48 (95% confidence interval, 1.16 to 1.90; P<0.0001) for CV mortality. These results provide the first direct evidence that in ESRF patients increased effect of arterial wave reflections is an independent predictor of all-cause and CV mortality.

Short and efficient syntheses of analogues of WAY-100635: new and potent 5-HT1A receptor antagonists.

Simple syntheses of four new and potent analogues of the 5-HT1A receptor ligand, WAY-100635 are described, namely the 6-(pyridinyl)-bromo-, the 6-(pyridinyl)-fluoro-, the pyrimidine- and the 5-(pyridinyl)-bromo-analogues. The first three analogues were obtained by aromatic nucleophilic substitution of the 2,6-dihalogenopyridine (activated or not as an N-oxide) or of the 2-chloropyrimidine with the corresponding amine nucleophile as a key step. The fourth analogue, the 5-(pyridinyl)-bromo-analogue, was synthesized from the 2-amino-5-bromopyridine via a progressive elongation of the skeleton. The four compounds described are all full antagonists and show good in vitro binding affinities (Ki).

New halogenated [11C]WAY analogues, [11C]6FPWAY and [11C]6BPWAY--radiosynthesis and assessment as radioligands for the study of brain 5-HT1A receptors in living monkey.

[Carbonyl-(11)C]WAY-100635 ([(11)C]WAY) is an established radioligand for the study of brain serotonin(1A) (5-HT(1A)) receptors in living animals and humans with positron emission tomography (PET). There is a recognised need to develop halogenated ligands for 5-HT(1A) receptors, either for labelling with longer-lived fluorine-18 for more widespread application with PET or with iodine-123 for application with single photon emission tomography (SPET). Here we used autoradiography and PET to assess two new halogenated analogues of WAY, namely 6BPWAY and 6FPWAY [N-(2-(1-(4-(2-methoxyphenyl)-piperazinyl)ethyl))-N-(2-(6-bromo-/fluoro-pyridinyl))cyclohexanecarboxamide] as prospective radioligands, initially using carbon-11 as the radiolabel. Labelling of 6BPWAY and 6FPWAY with carbon-11 was accomplished by acylation of the corresponding secondary amine precursors with [carbonyl-(11)C]cyclohexanecarbonyl chloride. After incubation of human brain crysections with [(11)C]6BPWAY or [(11)C]6FPWAY, the highest accumulation of radioactivity was observed in cortical areas and the hippocampal formation. Both radioligands had high nonspecific binding. There was a rapid accumulation of radioactivity in the monkey brain after intravenous injection of [(11)C]6BPWAY and [(11)C]6FPWAY. High accumulation of radioactivity was observed in the frontal and temporal cortex and the raphe nuclei, areas known to contain a high density of 5-HT(1A) receptors. The ratios of radioactivity in receptor-rich temporal cortex to that in receptor-poor cerebellum at peak equilibrium were 1.9 (at 10 min) and 3.0 at (at 20 min) for [(11)C]6BPWAY and [(11)C]6FPWAY, respectively. In pretreatment experiments with high doses of unlabelled WAY, the level of radioactivity in the frontal and temporal cortex and the raphe nuclei was reduced to the same level as in the cerebellum. Radioactive metabolites of [(11)C]6FPWAY appeared at a rate similar to those for [(11)C]WAY, with 17% of the radioactivity in plasma represented by unchanged radioligand after 40 min. Radioactive metabolites of [(11)C]6BPWAY appeared much more slowly. At 40 min after injection 45% of the radioactivity in plasma still represented unchanged radioligand. The results indicate that 6-pyridinyl radiohalogented analogues of WAY are new leads to radioligands for PET or SPET.

Impact of aortic stiffness attenuation on survival of patients in end-stage renal failure.

BACKGROUND: Aortic pulse wave velocity (PWV) is a predictor of mortality in patients with end-stage renal failure (ESRF). The PWV is partly dependent on blood pressure (BP), and a decrease in BP can attenuate the stiffness. Whether the changes in PWV in response to decreases in BP can predict mortality in ESRF patients has never been investigated. METHODS AND RESULTS: One hundred fifty ESRF patients (aged 52+/-16 years) were monitored for 51+/-38 months. From entry until the end of follow-up, the changes of PWV in response to decreased BP were measured ultrasonographically. BP was controlled by adjustment of "dry weight" and, when necessary, with ACE inhibitors, calcium antagonists, and/or beta-blockers, in combination if necessary. Fifty-nine deaths occurred, including 40 cardiovascular and 19 noncardiovascular events. Cox analyses demonstrated that independent of BP changes, the predictors of all-cause and cardiovascular mortality were as follows: absence of PWV decrease in response to BP decrease, increased left ventricular mass, age, and preexisting cardiovascular disease. Survival was positively associated with ACE inhibitor use. After adjustment for all confounding factors, the risk ratio for the absence of PWV decrease was 2.59 (95% CI 1.51 to 4.43) for all-cause mortality and 2.35 (95% CI 1.23 to 4.41) for cardiovascular mortality. The risk ratio for ACE inhibitor use was 0.19 (95% CI 0.14 to 0.43) for all-cause mortality and 0.18 (95% CI 0.06 to 0.55) for cardiovascular mortality. CONCLUSIONS: These results indicate that in ESRF patients, the insensitivity of PWV to decreased BP is an independent predictor of mortality and that use of ACE inhibitors has a favorable effect on survival that is independent of BP changes.

Different aortic reflection wave responses following long-term angiotensin-converting enzyme inhibition and beta-blocker in essential hypertension.

1. In arterial hypertension, aortic wave reflections contribute to determining central systolic and pulse pressures. The present study assessed the central pressure alterations at the level of the common carotid artery following 1 month treatment with perindopril or atenolol and investigated during the 8 h following drug intake. 2. Twenty patients suffering from permanent hypertension were included after a 4 week run-in placebo period in a double-blind, randomized cross-over study comparing the angiotensin-converting enzyme (ACE) inhibitor perindopril with the beta-blocker atenolol during a 4 week treatment period. 3. Before and during the 8 h after drug intake, serial measurements included brachial artery systolic and diastolic blood pressures (SBP and DBP, respectively; mercury sphygmomanometer), carotid artery SBP and pulse pressure (PP; applanation tonometry), aortic pulse wave velocity (Complior; Colson, Les Lilas, France) and arterial wave reflections from the aorta (applanation tonometry; Sphygmocor; PWV Medical, Sydney, NSW, Australia). 4. Both treatments decreased brachial and carotid artery SBP, DBP and PP. Heart rate and pulse wave velocity decreased following atenolol (P < 0.001). Pulse wave velocity was reduced slightly following perindopril (NS). Arterial wave reflections were significantly (P < 0.001) decreased with perindopril in comparison with atenolol, but this effect on wave reflections was not associated with a larger decrease in carotid artery PP. 5. Thus, during chronic treatment, ACE inhibition and selective beta1-adrenoceptor blockade resulted in a similar decrease in brachial and carotid artery PP, but only atenolol reduced heart rate. Aortic pulse wave velocity was reduced with both drugs, but atenolol appeared more effective in improving aortic stiffness. Arterial wave reflections were decreased only following perindopril. 6. Central pulse pressure was improved following 1 month treatment with an ACE inhibitor or beta-adrenoceptor blockade following a decrease in arterial wave reflections with perindopril and a higher decrease in regional aortic stiffness with atenolol.

Pathophysiology of anaemia: focus on the heart and blood vessels.

The amount of oxygen delivered to an organ depends on three factors: blood flow and its distribution; the oxygen-carrying capacity of the blood, i.e. haemoglobin concentration; and oxygen extraction. Non-haemodynamic and haemodynamic mechanisms operate to compensate for anaemia. Non-haemodynamic mechanisms include increased erythropoietin production to stimulate erythropoiesis, and increased oxygen extraction (displacement of the haemoglobin oxygen dissociation curve). This decreased affinity of oxygen for haemoglobin is mediated by increased 2,3-diphosphoglycerate concentrations. Increased cardiac output is the main haemodynamic factor, mediated by lower afterload, increased preload, and positive inotropic and chronotropic effects. Decreased afterload is due to vasodilatation and reduced vascular resistance as a consequence of lower blood viscosity, hypoxia-induced vasodilatation, and enhanced nitric oxide activity. Vasodilatation also involves recruitment of microvessels and, in the case of chronic anaemia, stimulation of angiogenesis. With decreased afterload, the venous return (preload) and left ventricular (LV) filling increase, leading to increased LV end-diastolic volume and maintenance of a high stroke volume and high stroke work. High stroke work is also due to enhanced LV contractility attributed to increased concentrations of catecholamines and non-catecholamine inotropic factors. In addition, heart rate is increased in anaemia, due to hypoxia-stimulated chemoreceptors and increased sympathetic activity. In the long term, these haemodynamic alterations lead to gradual development of cardiac enlargement and LV hypertrophy (LVH). The LVH is eccentric, characterized by increased LV internal dimensions and a normal ratio of wall thickness to cavity diameter, as occurs in other forms of volume overload. When anaemia-related LVH develops in an otherwise 'healthy' humoral environment, the lesions are reversible and the type of LVH is primarily physiological and is not associated with impaired diastolic function. In the absence of underlying cardiovascular disorders, severe anaemia (Haemoglobin concentration < 4-5 g/dl) leads to congestive heart failure. In the presence of heart disease, especially coronary artery disease, anaemia intensifies angina and contributes to a high incidence of cardiovascular complications. In end-stage renal disease (ESRD), LVH is influenced by many other factors, leading to intense interstitial fibrosis, to alterations in diastolic function, and usually to poor reversibility. The chronic increase in cardiac output contributes to arterial remodelling of central elastic arteries such as the aorta and common carotid artery. This remodelling consists principally of arterial enlargement and compensatory arterial intima--media thickening. In ESRD, these geometric changes are accompanied by arterial stiffening. The principal consequences of arterial alterations are increased systolic pressure and high inertia due to higher blood mass in the dilated arterial system. These alterations contribute to the development of LVH and abnormal coronary perfusion.

Radioligands for the study of brain 5-HT(1A) receptors in vivo--development of some new analogues of way.

[Carbonyl-(11)C]WAY-100635 (WAY) has proved to be a very useful radioligand for the imaging of brain 5-HT(1A) receptors in human brain in vivo with positron emission tomography (PET). WAY is now being applied widely for clinical research and drug development. However, WAY is rapidly cleared from plasma and is also rapidly metabolised. A comparable radioligand, with a higher and more sustained delivery to brain, is desirable since these properties might lead to better biomathematical modelling of acquired PET data. There are also needs for other types of 5-HT(1A) receptor radioligands, for example, ligands sensitive to elevated serotonin levels, ligands labelled with longer-lived fluorine-18 for distribution to "satellite" PET centres, and ligands labelled with iodine-123 for single photon emission computerised tomography (SPECT) imaging. Here we describe our progress toward these aims through the exploration of WAY analogues, including the development of [carbonyl-(11)C]desmethyl-WAY (DWAY) as a promising, more brain-penetrant radioligand for PET imaging of human 5-HT(1A) receptors, and (pyridinyl-6-halo)-analogues as promising leads for the development of radiohalogenated ligands.

Pathophysiology of cardiovascular disease in hemodialysis patients.

Cardiovascular disease is the principal cause of morbidity and mortality in dialysis patients. The principal alterations responsible are left ventricular hypertrophy and arterial disease characterized by an enlargement and hypertrophy of arteries and the high prevalence of atheromatous plaques. Left ventricular hypertrophy is the consequence of combined effects of chronic hemodynamic overload and nonhemodynamic biochemical and neurohumoral factors characteristic of uremia. The hemodynamic overload is due to flow and pressure overload. The flow overload is tightly related to hyperkinetic circulation caused by anemia, arteriovenous fistula, or overhydration and is characterized by an enlargement of the left ventricular cavity. The pressure overload in these patients is more tightly related to abnormal geometry and function of large conduit arteries, principally the stiffening of arterial tree. The flow overload is also in large part responsible for remodeling of arterial tree, and as the heart and vessels are a coupled interactive physiological system, cardiac and vascular alterations occur in parallel, being induced to a great extent by the same hemodynamic abnormalities. The principal clinical consequences of left ventricular hypertrophy and arterial alterations are heart failure, ischemic heart disease, and peripheral artery disease. Cardiovascular alterations are only partly reversible, and efforts should be directed toward early prevention.

Arterial stiffening and vascular calcifications in end-stage renal disease.

BACKGROUND: Epidemiological studies have identified aortic stiffness as an independent predictor of cardiovascular mortality in end-stage renal disease (ESRD) patients. In these patients, aortic pulse wave velocity (PWV) was associated with mediacalcosis, but the influence of arterial calcifications on the viscoelastic properties of large arteries was not well characterized. The purpose of the present study was to analyse the influence of arterial calcifications on arterial stiffness in stable haemodialysed patients. METHODS: We studied 120 stable ESRD patients on haemodialysis. All patients underwent B-mode ultrasonography of common carotid artery (CCA), aorta, and femoral arteries to determine CCA distensibility, the elastic incremental modulus (Einc), and the presence of vascular calcifications. All patients underwent measurement of aortic PWV and echocardiogram. The presence of calcifications was analysed semiquantitatively as a score (0 to 4) according to the number of arterial sites with calcifications. RESULTS: Our observations indicate that arterial and aortic stiffness is significantly influenced by the presence and extent of arterial calcifications. The extent of arterial calcifications is in part responsible for increased left ventricular afterload, and is inversely correlated with stroke volume. The influence of calcifications is independent of the role of ageing and blood pressure. Arterial calcifications density increases with age, duration of haemodialysis, the fibrinogen level, and the prescribed dose of calcium-based phosphate binders. CONCLUSIONS: The results of this study showed that the presence of vascular calcifications in ESRD patients was associated with increased stiffness of large capacity, elastic-type arteries, like the aorta and CCA. The extent of arterial calcifications increased with the use of calcium-based phosphate-binders.

[Cardiac anomalies in chronic renal failure]. / Anomalies cardiaques chez l'insuffisant rénal chronique.

PRINCIPAL CARDIOVASCULAR COMPLICATIONS IN END STAGE RENAL DISEASE: Cardiovascular diseases are the leading causes of morbidity and mortality in end stage renal disease patients. Very often, complications observed are left ventricular hypertrophy and various forms of arterial degenerative lesions involving coronary arteries, less frequently pericarditis and calcifying valvulopathy are diagnosed. THE REASONS ARE COMPLEX: Risk factors can be either specific of uremia per se such as anemia, overhydration, fistula or the same as in the general population. Hemodynamic alterations including tensile stress or blood flow play a major role associated to various locally or generally generated substances whose role remains currently to be determined. THEIR TREATMENTS: Treatments of cardiovascular complications are not specific in this end stage renal disease population but are more often the treatment of the etiology: reduction of fistula blood flow, increase of hemoglobin, best control of weight gain between two hemodialysis sessions or blood pressure control.

Postischemic vasodilation, endothelial activation, and cardiovascular remodeling in end-stage renal disease.

BACKGROUND: Cardiovascular complications are the major cause of death in end-stage renal disease (ESRD) patients. These complications are associated with concomitant cardiac and vascular remodeling, including left ventricular (LV) hypertrophy and hypertrophy of arterial walls. The endothelium influences the process of arterial remodeling. ESRD patients are characterized by the development of both cardiovascular remodeling and endothelial dysfunction. METHODS: Common carotid artery (CCA) intima-media thickness (IMT), CCA diameter, CCA distensibility, LV mass, and function were determined in 60 stable ESRD patients on hemodialysis and 34 age-, sex-, and blood pressure (BP)-matched controls, and their relationships with endothelial alterations were estimated by forearm postischemic vasodilation [flow debt repayment (FDR)] measured by venous plethysmography. We also evaluated the relationships between FDR and several cardiovascular risk factors or markers of inflammatory response or endothelial activation, for example, duration of dialysis, BP, smoking habits, cholesterol, parathormone (PTH), serum albumin, plasma fibrinogen, C-reactive protein (CRP), plasma homocysteine, plasminogen activator inhibitor (PAI-1), and von Willebrand factor (vWF). RESULTS: ESRD patients had increased LV mass, CCA diameter and CCA IMT, and had decreased CCA distensibility (P < 0.05). While the postischemic peak flow was comparable in controls and ESRD patients (29.2 +/- 9.1 vs. 27.9 +/- 0.2 mL/100 mL/min), FDR was lower in ESRD patients (116 +/- 31 vs. 88 +/- 32%, P < 0.001) because of the shorter duration of vasodilation (127 +/- 36 vs. 96 +/- 32 s, P < 0.001). The time to complete FDR was longer in ESRD patients (110 +/- 54 vs. 162 +/- 72 s, P < 0.001). ESRD patients had lower high-density lipoprotein cholesterol and serum albumin (P < 0.01) and higher triglycerides, fibrinogen, plasma homocysteine, vWF (P < 0.01), and PAI-1 (P < 0.05). For ESRD patients, significant negative age- and pressure-independent correlations were established between FDR and CCA diameter, duration of dialysis, and PAI-1. FDR was positively correlated with serum albumin. FDR and time to FDR were negatively correlated with CCA IMT and LV mass. CCA distensibility was positively associated with FDR (P < 0.001) and negatively with time to FDR (P < 0.001). The PAI-1 concentration was positively correlated with CCA IMT (P < 0.01) and negatively with CCA distensibility (P < 0.001). CONCLUSIONS: Our data provide the first evidence that cardiac and arterial remodeling in ESRD patients are inversely related to forearm reactive hyperemia. The diminished hyperemic response is due to the shorter duration of hyperemia and is associated with higher concentrations of serum markers of endothelial activation, suggesting that, in ESRD patients, endothelial dysfunction may be a factor influencing cardiovascular changes.

Association of hyperphosphataemia with haemodynamic disturbances in end-stage renal disease.

BACKGROUND: Because recent data demonstrated that the shortened survival and excess cardiovascular death of end-stage renal disease (ESRD) patients are predicted by hyperphosphataemia, we examined the haemodynamic alterations associated with high serum phosphorus levels in ESRD patients on haemodialysis. METHODS: Sixty-six ESRD patients were studied. Patients were separated arbitrarily into two groups, i.e. with predialysis serum phosphate <2 mmol/l ('normal' phosphate) and, serum phosphate >2 mmol/l ('high' phosphate). Cardiac and arterial function and structure were analysed by computer-assisted ultrasonography. RESULTS: Hyperphosphataemic patients were characterized by higher diastolic and mean blood pressures (P<0.05), and higher cardiac index (P<0.001) caused by an increased stroke index (P<0.05) and higher heart rate (P<0.01). The cardiac work index was significantly increased in patients with higher phosphate levels (P<0.01). Hyperphosphataemic patients tended to have a higher common carotid artery diameter (P=0.07), but similar carotid artery intima-media thickness, and lower carotid wall-to-lumen ratio (P<0.05) than patients with 'normal' serum phosphorus. As a result of lower wall-to-lumen ratio in the presence of higher mean blood pressure, the carotid tensile stress was higher in hyperphosphataemic ESRD patients (P<0.05). CONCLUSION: These findings suggest that, in stable ESRD patients, hyperphosphataemia is associated with increased BP, hyperkinetic circulation, increased cardiac work, and high arterial tensile stress. These haemodynamic abnormalities could favour the development of cardiovascular complications and contribute to high cardiovascular morbidity and mortality.

Impact of aortic stiffness on survival in end-stage renal disease.

BACKGROUND: Damage to large arteries is a major factor in the high cardiovascular morbidity and mortality of patients with end-stage renal disease (ESRD). Increased arterial stiffness and intima-media thickness, together with increased pulse pressure, are the principal arterial alterations. Whether increased aortic pulse-wave velocity (PWV), a classic marker of increased arterial stiffness, may predict all-cause and/or cardiovascular mortality has never been investigated. METHODS AND RESULTS: A cohort of 241 patients with ESRD undergoing hemodialysis was studied between April 1987 and April 1998. The mean duration of follow-up was 72+/-41 months (mean+/-SD). Mean age at entry was 51.5+/-16.3 years. Seventy-three deaths occurred, including 48 cardiovascular and 25 noncardiovascular fatal events. At entry, together with standard clinical and biochemical analyses, patients underwent echocardiography and aortic PWV measured by Doppler ultrasonography. On the basis of Cox analyses, 2 factors emerged as predictors of all-cause and cardiovascular mortality: age and aortic PWV. Hemoglobin and low diastolic pressure interfered to a smaller extent. After adjustment for all the confounding factors, an OR for PWV >12. 0 versus <9.4 m/s was 5.4 (95% CI, 2.4 to 11.9) for all-cause mortality and 5.9 (95% CI, 2.3 to 15.5) for cardiovascular mortality. For each PWV increase of 1 m/s in our study population, all-cause mortality-adjusted OR was 1.39 (95% CI, 1.19 to 1.62). CONCLUSIONS: These results provide the first direct evidence that in patients with ESRD, increased aortic stiffness determined by measurement of aortic PWV is a strong independent predictor of all-cause and mainly cardiovascular mortality.

Carotid arterial stiffness as a predictor of cardiovascular and all-cause mortality in end-stage renal disease.

Damage of large arteries is a major contributory factor to the high pulse pressure observed in patients with end-stage renal disease. Whether incremental modulus of elasticity (Einc), a classic marker of arterial stiffness, can predict cardiovascular mortality has never been investigated. A cohort of 79 patients with end-stage renal disease undergoing hemodialysis was studied between September 1995 and January 1998. Mean age at entry was 58+/-15 years. The duration of follow-up was 25+/-7 months, during which 10 cardiovascular and 8 noncardiovascular fatal events occurred. At entry, carotid Einc was calculated from measurements of diameter, thickness (echo-tracking technique), and pulse pressure (tonometry). Based on Cox analyses, 2 dominant factors emerged as predictors of all-cause and cardiovascular mortality: increased Einc and decreased diastolic blood pressure. Lipid abnormalities and the presence of previous cardiovascular events interfered to a smaller extent. After adjustment for confounding variables, the odds ratio for Einc >/=1 kPa-3 was 9.2 (95% confidence interval, 2.4 to 35.0) for all-cause mortality. These results provide the first direct evidence that in patients with end-stage renal disease undergoing hemodialysis, arterial alterations, as determined from carotid Einc, are strong independent predictors of all-cause and cardiovascular mortality.