Compliance with and effectiveness of adaptive servoventilation versus continuous positive airway pressure in the treatment of Cheyne-Stokes respiration in heart failure over a six month period.

OBJECTIVE: To compare compliance with and effectiveness of adaptive servoventilation (ASV) versus continuous positive airway pressure (CPAP) in patients with the central sleep apnoea syndrome (CSA) with Cheyne-Stokes respiration (CSR) and with congestive heart failure in terms of the apnoea-hypopnoea index (AHI), quality of life, and left ventricular ejection fraction (LVEF) over six months. METHODS: 25 patients (age 28-80 years, New York Heart Association (NYHA) class II-IV) with stable congestive heart failure and CSA-CSR were randomly assigned to either CPAP or ASV. At inclusion, both groups were comparable for NYHA class, LVEF, medical treatment, body mass index, and CSA-CSR. RESULTS: Both ASV and CPAP decreased the AHI but, noticeably, only ASV completely corrected CSA-CSR, with AHI below 10/h. At three months, compliance was comparable between ASV and CPAP; however, at six months compliance with CPAP was significantly less than with ASV. At six months, the improvement in quality of life was higher with ASV and only ASV induced a significant increase in LVEF. CONCLUSION: These results suggest that patients with CSA-CSR may receive greater benefit from treatment with ASV than with CPAP.

Tumor necrosis factor alpha and glutathione interplay in chronic heart failure.

The pro-inflammatory cytokine, tumor necrosis factor alpha (TNF alpha), in concert with neurohormones, contributes to chronic heart failure (CHF) progression. This implies that TNF a antagonism may constitute an important target for CHF therapy. However, clinical trials in CHF patients using compounds that trap TNF alpha, comprising infliximab, an antibody directed to TNF alpha, and etanercept, a soluble recombinant receptor of TNF alpha, gave disappointing results bringing back to light the dual, short-term beneficial and long-term harmful effect of TNF alpha. This review focuses on the dual, concentration- and time-related effects of TNF alpha, the yin and yang action of TNF alpha in cardiac ischemia/reperfusion and contraction. Importantly, the harmful effects of TNF a are related to glutathione deficiency, a common hallmark to several other chronic inflammatory diseases. Recently, in rat models of CHF, oral administration of the glutathione precursor, N-acetylcysteine (NAC), was shown to hinder pathways of TNF alpha harmful signalling and to rescue cardiac structure and function. These results suggest that glutathione deficiency in association with TNF alpha activation may play a role in the pathophysiology of CHF and that NAC may represent a potential therapy in CHF.

[Sleep apnoea syndrome and cardiac failure]. / Syndrome d'apnées du sommeil et insuffisance cardiaque.

Despite recent therapeutic advances, chronic cardiac failure is still associated with a significant morbidity and mortality. Sleep apnoea syndrome is common in this population, affecting almost half of these patients. However, it is rarely diagnosed and treated. There are two types of sleep apnoea syndrome, which can sometimes co-exist: the obstructive apnoea syndrome with collapse of the upper airways, and the central apnoea syndrome with cyclical Cheyne-Stokes respiration, linked with anomalies of central control. Apnoea leads to sympathetic stimulation and an increase in the left ventricular post-charge which can alter cardiac function and the prognosis. Diagnosis of sleep apnoea syndromes is now made with small ambulatory oxymeters which do not disturb sleep and which allow precise detection of episodes of desaturation. Treatment with positive pressure ventilation brings an improvement in daytime symptoms (fatigue, drowsiness) as well as an improvement in cardiac function. Screening for sleep apnoea is thus essential in patients with chronic heart failure, especially in those resistant to optimal drug treatment, in order to improve their management.

[Pathology and dental care in the context of cardiovascular conditions: myths, beliefs and realities]. / Pathologies et soins dentaires dans le cadre des affections cardiovasculaires: mythes, croyances et réalités.

The knowledge regarding the links between dental and cardiac affections are generally based on empirical concepts and lead to unjustified clinical practices. Infectious endocarditis (IE) is the principal cardiac diseases concerned with dental procedures. Although in France, the incidence of IE is stable, the incidence of oral bacteria at the origin of IE is diminishing. The risk of IE and thus the indication of antibioprophylaxis depend upon the subjacent cardiopathy and dental treatment. Antibioprophylaxis has to be very strict in patients with high or moderate risks of IE but is not necessary in low risk patients. In all cases, a good oral and dental hygiene and a regular dentist follow up are the most effective methods of preventing IE. Coronary artery disease and dental affections are associated because they present similar risk factors (i.e. smoking, excessive sugar consumption) and also because inflammation increases the risk of acute coronary syndrome. Today, dental cares are not contraindicated in patients with recent coronary syndrome if precise protocols are followed. Concerning the hemorrhagic risk during dental care in patients treated by anticoagulants and/or antithrombotics, dental cares and extractions are possible if INR or heparinemy are within the therapeutic limits and local haemostasis is meticulous. In addition, aspirin does not require to be stopped before minor dental treatments. Finally a better collaboration between dentists and cardiologists would allow an optimum management of patients with cardiac disease requiring dental cares.

[Electromechanical mapping of myocardial ischemia in coronary occlusion in the pig]. / Cartographie électromécanique du myocarde ischémique dans un modèle d'occlusion coronaire progressive chez le porc.

The NOGA-Biosense catheter-based mapping technique has been well studied experimentally in infarction model. However, chronic myocardial ischemia with this new device has not been well explored. Thus, the aim of our study was to assess electromechanical changes in a pig aneroid constricor model. To achieved this aim, ten pigs were studied 21 days after the implantation of an aneroid constrictor around the circumflex artery. Coronary reserve assess by intracoronary Doppler flow wire was reduced in the ischemic lateral area (ILA) compared with the nonischemic zone (NIZ) (1.3 +/- 0.1 in the ILA vs. 2.3 +/- 0.2 in the NSZ; p < 0.01). TM echocardiography was used to evaluate myocardial regional contractility under basal condition and after stress induced by rapid atrial pacing. In stress state, the ischemic zone showed an impaired contractility compared with basal state (wall thickening, 32.7 +/- 7.4% vs. 59.7 +/- 8.6%; p < 0.05) whereas the non ischemic zone did not (53.8 +/- 7.6% vs. 60.8 +/- 10.1%; p = ns). Constrast echography showed a decrease in contrast intensity in subendocardium of the ila compared with the niz (46.2 +/- 16.6 vs. 99.2 +/- 35.6; p = 0.03) in pacing. Ventricular mapping quantified unipolar (UV). bipolar (BV) voltage potentials and endocardial local shortening (LLS) in 9 left ventricular regions. In basal state, electrical potentials were preserved in both zones (UV: 9.1 +/- 1.8 mV in the ischemic vs 11.3 +/- 3.6 mV in the non ischemic zone; p = ns; BV: 4.2 +/- 1.1 mV in the ILA vs. 3.9 +/- 1.5 mV; p = ns). In contrast, LLS was significantly lower in the ischemic compared with non ischemic zone (6.4 +/- 5.4% vs. 17.9 +/- 3.0%, p < 0.001). In conclusion, ventricular mapping with the NOGA-Biosense system can identify the ischemic myocardium. In this pig model, the association of a preserved electrical activity and an impaired mechanical activity characterizes the ischemic myocardium. These findings could be interesting in this model in regard of the new developments of the system in particular in the field of angiogenesis.

[Aldosterone and its antagonists in heart failure]. / L'aldostérone et ses antagonistes dans l'insuffisance cardiaque.

THE ROLE OF ALDOSTERONE: Aldosterone is the key hormone in salt-water homeostasis. In heart failure, it participates in the appearance and maintenance of signs of congestion. Predominantly synthesised in the glomerular area of the cortico-adrenal glands, extra adrenal production areas have recently been identified notably in the brain, the heart and the large artery trunks. Aldosterone is activated in the cells by the intracellular mineral corticoid receptor. IN CARDIOVASCULAR-PATHOLOGIES: In chronic heart failure, patients treated with conversion enzyme inhibitor may escape from the renin-angiotensin blockade and this may lead to increased aldosterone plasma levels. This increase can induce not only vascular lesions and myocardial fibrosis but also renal and cerebral lesions. THE EFFECTS OF SPIRONOLACTONE: In patients with NYHA stage III or IV heart failure, addition of spironolactone to the treatment with conversion enzyme inhibitor, diuretic and/or digitalis leads to a reduction in morbidity and mortality, as demonstrated in the RALES study. The mechanisms by which spironolactone has a beneficial effect remain discussed. IN CLINICAL PRACTICE: The prescription of spironolactone is limited by hormonal side effects it provokes. IN THE FUTURE: Eplerenone, a new competitive aldosterone receptor antagonist that appears to be devoid of such side effects and which, at least experimentally may well have the same beneficial effects, is presently under clinical assessment.

Inflammation, cytokines and anti-inflammatory therapies in heart failure.

Both experimental and clinical studies have shown a role for inflammation in the pathogenesis of heart failure. This seems related to an imbalance between pro-inflammatory and anti-inflammatory cytokines. Certain categories in patients with dilated cardiomyopathy have shown the presence of humoral and cellular immunity activation suggesting a possible relation between myocarditis and dilated cardiomyopathy. Recent studies suggest a link between the circulating levels of cytokines (TNF alpha IL-1 et IL-6), the clinical status and prognostic. However, the mechanisms connecting heart failure and cytokine activation are unclear and the sites of cytokines production remain controversial. In the clinical setting, specific measurements of cytokines are not available. As tests of inflammation, erythrocyte sedimentation rate and C-reactive protein concentration appear to have interesting pronostic values. Current conventional therapy i.e. ACE inhibitors, type I angiotensin II antagonist and beta-blockers have shown some anti-cytokine properties. Recently, immunosuppressive therapies have shown their ability to improve symptoms and LV ejection in selected patients with dilated cardiomyopathy and clear sign of myocardium inflammation. Specific anti-cytokine therapy have been developed and showed interesting results in preliminary clinical studies. However large clinical trials testing this new therapy have been stoppel prematurely because of deterious effects.

[Future molecules in heart failure]. / Molécules du futur dans l'insuffisance cardiaque.

TODAY: The management of heart failure (HF) has considerably progressed over the last two decades. Treatment today relies on prevention and treatment of congestion (limited salt intake, diuretics, converting enzyme inhibitors) and limiting neurohormone stimulation (converting enzyme inhibitors +/- aldactone, beta-blockers). IN THE YEARS TO COME: Based on new concepts, several therapeutic strategies are interesting: blocking over vasoconstrictor systems which have not been taking into account; stimulation of vasodilator and natriuretic systems; modulation of cardiac remodelling; modulation of the immune and inflammatory systems; modification in intrinsic contractility; prevention of rhythm disorders. Among these differing strategies and molecules, it is not easy to predict those that will change the HF prognosis. In any event, their efficacy and safety remain to be demonstrated with large cohort randomised studies. THE PRINCIPLES: To reduce the number of drugs administered, two options appear particularly interesting: measurement of hormone levels (BNP) in order to adjust treatment and administration of molecules with greatest efficacy and safety profiles; limit cardiac remodelling by using new imaging techniques to detect it more precisely and select the molecule(s) exerting the required effect. To target the new molecules better, patients should be classified according to their etiology, stage and progressive profile of their disease, cardiac remodelling, expression of principle endocrine systems and pro-inflammatory cytokines, expression of inflammatory and immune systems and inherent genetic characteristics and response to treatment. This would permit the adaptation of treatment to each individual patient with heart failure.

[Quality of medical database to valorize the DRG model by ISA cost indicators]. / Qualité du recueil PMSI pour la valorisation par points ISA du modèle GHM.

BACKGROUND: The use of the French version of the DRG model is focused on cost allocation, based on the case-mix system and the use a weight called ISA (Synthetic Index of Activity) for each DRG. However, this administrative database is becoming more and more used by both researchers and health policy makers for health planning and benchmarking. In France, data abstraction and coding of medical records is done by physicians. The objective of this study was to determine the accuracy of a database of the discharge summaries used for DRGs and to compare consequences of inappropriate coding on budget estimation and risk adjustment. METHODS: Samples of discharge summaries from six cardiology units were recoded by trained physicians in data abstracting and coding. Comparison between initial and recoded diagnoses (errors on main diagnosis or on comorbidities) used by the DRG system algorithm, and the original and final case-mix were performed. The before and after abstracted data were stratified and compared by principal diagnosis (myocardial infarction or congestive heart failure) and discharge status (dead or alive). MAIN RESULTS: Comorbidities were underreported by physicians of cardiology units compared to reabstracted data (mean number of secondary diagnoses per summary: 2.1 vs. 3.6, p<0.001), especially those which had a minimal impact on the DRG classification. In spite of a 15% rate of wrong DRGs, there was no significant difference in the total amount of ISA after data reviewing. Underreporting of comorbidities is more important for medical records of dead patients at discharge but, without significant effect on rate of change in DRG and amount of ISA. CONCLUSION: Discharge summaries used in the French DRGs system consistently underestimate the presence of comorbid conditions, which has direct implications for policy-makers comparing performance between hospital units. Both clinical practitioners and policy makers should be aware of this bias when assessing patient's quality of care or performing health planning through discharge summaries.

[Left ventricular functional imagery by magnetic resonance. Applications and developments]. / Imagerie fonctionnelle du ventricule gauche par résonance magnétique. Applications et développements.

Technical developments have considerably reduced the acquisition time and have improved the quality of magnetic resonance imaging. The recent recommendations of the European Society of Cardiology place MRI in the front line of investigations for the diagnosis and evaluation of congenital heart disease, cardiac tumours and pathology of the pericardium and great vessels. With the possibility of obtaining oblique planes in all 3 dimensions, MRI is the reference for the measurement of left ventricular mass, volumes, and ejection fraction, with the major advantage of not depending on hypotheses of left ventricular geometry. In addition to these known applications, the development of functional cardiac MRI has led to significant advances in the study of regional myocardial function and perfusion. The aim of this article is to discuss present indications and the potential developments of functional cardiac MRI, focusing on the quantitative evaluation of myocardial function and perfusion.

Myocardial stunning in exercise-induced ischemia in dogs: lack of late preconditioning.

Late preconditioning (PC) against myocardial stunning develops after coronary artery occlusion (CAO) at rest and subsequent reperfusion. We investigated whether late PC occurs after exercise-induced ischemia (high-flow ischemia) in dogs. A circumflex coronary artery stenosis (by using occluders) was set up before the onset of treadmill exercise in nine chronically instrumented dogs to suppress exercise-induced increase in mean coronary blood flow velocity (CBFV, Doppler) without simultaneously affecting left ventricular (LV) wall thickening (Wth) at rest. Two similar exercises were performed 24 h apart. On day 1, LV Wth was reduced by 84 +/- 5% (P < 0.01), and exercise-induced increases in transmural myocardial blood flow (MBF, fluorescent microspheres) in the ischemic zone were blunted. LV Wth was depressed throughout the first 10 h and returned to its baseline value after 24 h. On day 2, changes in LV Wth and MBF were similar as was the time course for LV Wth recovery, indicating lack of late PC. Also, CBFV responses to acetylcholine, nitroglycerin, and reactive hyperemia (20-s CAO) were not significantly different on days 1 and 2. Similar results were obtained in a subgroup of four additional dogs with more severe stenosis during exercise. Late PC against myocardial stunning was confirmed to occur in a model of 10-min CAO followed by coronary artery reperfusion (CAR) in another four dogs. Thus in contrast with CAO at rest followed by CAR, severe myocardial ischemia in coronary flow-limited exercising dogs does not induce late PC against myocardial stunning.

[Hospital mortality in cardiology. Analysis of deaths occurring in the Federation of Cardiology of a university hospital center]. / Mortalité hospitalière en cardiologie. Analyse des décès survenus au sein de la fédération de cardiologie d'un centre hospitalo-universitaire.

The aim of this study was to examine the nature of cardiovascular deaths occurring in a University Hospital. All the hospital files of 1999 of the Federation of Cardiology of Henri Mondor Hospital, Creteil, of patients who died in the department or after transfer to the intensive care unit or cardiac surgery department, were analysed. Myocardial ischaemia was the leading cause of death, occurring either in the acute phase of transmural infarction or in patients with chronic cardiac failure. Deaths occurring during acute myocardial infarction were associated with late treatment and/or non-reperfusion of the culprit artery. The delay of diagnosis seemed to be secondary to late consultation or difficulty in diagnosis. This resulted in severe left ventricular dysfunction and, in a quarter of cases, mechanical complications. They led to the early death of the patients (2.9 +/- 3.5 days after admission). Campaigns of patient information and education of doctors who see these patients would seem to be the most appropriate approach to reduce the delay before hospital admission in order to reduce mortality related to myocardial infarction. Cardiac failure is a common cause of death in cardiology departments. The deaths of patients occurred after a long follow-up and several days after hospital admission (11 +/- 10 days). Optimisation of the treatment of cardiac failure, the investigation of ischaemic heart disease, the search for new therapeutic strategies of acute cardiac failure and information of patients about their disease, seem to be the principal measures to take to improve the poor prognosis of this disease.

Stimulation of bradykinin B(1) receptors induces vasodilation in conductance and resistance coronary vessels in conscious dogs: comparison with B(2) receptor stimulation.

BACKGROUND: Constitutive bradykinin B(1) receptors have been identified in dogs; however, their physiological implications involving the coronary circulation remain to be determined. This study examined, in conscious dogs, the coronary response to des-Arg(9)-bradykinin (a B(1) receptor agonist) and the mechanisms involved. METHODS AND RESULTS: Eleven dogs were instrumented with a left ventricular micromanometer, a circumflex coronary catheter, a cuff occluder, a Doppler flow probe, and ultrasonic crystals to measure coronary blood flow velocity (CBFv) and coronary diameter (CD). Intracoronary des-Arg(9)-bradykinin (3 to 100 ng/kg) and bradykinin (0.1 to 10 ng/kg) did not modify systemic hemodynamics but dose-dependently increased CBFv and CD. Des-Arg(9)-bradykinin was less potent than bradykinin. Hoe 140 (a B(2) antagonist, 10 microg/kg) abolished the effects of bradykinin but did not influence the effects of des-Arg(9)-bradykinin. When CBFv increase was prevented by the cuff occluder, CD responses to bradykinin and des-Arg(9)-bradykinin were maintained. Intracoronary lisinopril (0. 75 mg) increased the CD response to bradykinin, with only minimal effect on CBFv, and extended the duration of the effect. Lisinopril did not alter des-Arg(9)-bradykinin responses. Intracoronary N(omega)-nitro-L-arginine (2 mg/kg) decreased the CD effect of bradykinin and prevented the CBFv and CD effects of des-Arg(9)-bradykinin. The relaxing effect of des-Arg(9)-bradykinin on isolated coronary rings was prevented by des-Arg(9), [Leu(8)]-bradykinin. CONCLUSIONS: In the conscious dog, B(1) receptors are present in coronary vessels, and their stimulation produces vasodilation in conductance and resistance vessels, which is mediated essentially by NO but not modulated by angiotensin-converting enzyme. However, the coronary vasodilation induced by B(1) receptor stimulation is not as great as that produced by B(2) receptor stimulation.

Beneficial effects of the T- and L-type calcium channel antagonist, mibefradil, against exercise-induced myocardial stunning in dogs.

Abnormalities in calcium homeostasis such as calcium overload have been shown to participate in the pathogenesis of myocardial stunning. The goal of this study was to investigate the effects of mibefradil, a mixed T- and L-type calcium channels antagonist on exercise-induced ischemia (i.e., high-flow ischemia). Nine dogs were permanently instrumented to measure left ventricular wall thickening (Wth) and coronary blood flow (Doppler). Infusion of saline or mibefradil (30 and 40 microg/kg/min, i.v., for 20 min) was started 10 min before exercise (10 min, 14 km/h; slope, 13%) and stopped at its end. Circumflex coronary artery stenosis (pneumatic occluders) was set up 5 min before exercise to suppress exercise-induced increase in mean coronary blood flow without simultaneously affecting Wth at rest. Mibefradil (30 microg/kg/min) was also administered at the beginning of the recovery period in a subset of four dogs. During exercise with saline, Wth was dramatically reduced (-77 +/- 7%; p < 0.05) and recovered only after 24 h. Mibefradil at both doses significantly limited tachycardia during exercise (211 +/- 7 and 210 +/- 5 beats/min vs. 240 +/- 8 beats/min for mibefradil, 30 microg/kg/min, mibefradil, 40 microg/kg/min, and saline, respectively) but exerted no negative inotropic effects. Mibefradil at both doses significantly reduced the intensity of myocardial stunning and the time to recovery in Wth (3 h). Administration of mibefradil at the beginning of the recovery period did not protect against myocardial stunning. Administration of a mixed T- and L-type calcium channel antagonists before ischemia confers cardioprotection against exercise-induced myocardial stunning. This may potentially be related to the limitation of exercise-induced tachycardia and/or the prevention of calcium overload.

[Role of nitric oxide in heart failure]. / Rôle du monoxyde d'azote dans l'insuffisance cardiaque.

The benefit effects of nitric oxide (NO) donors in acute heart failure have led to the development of vasodilators as treatment of chronic heart failure. However, the mechanisms involved in the effects of NO are complex and still discussed. In chronic heart failure, the eNOS downregulation in vascular endothelium explains the alteration of endothelial function. In addition, in the myocardium, cytokines induce the expression of inducible nitric oxide synthase (iNOS) which increase NO production by myocytes and surrounding cells. This excess of NO production, associated with anion superoxide synthesis, limits the inotropic properties of catecholamines and exert proapoptotic effects. The role of NO donors in heart failure treatment is still controversial but by reducing preload they improve patient's symptoms. Beside blockade of the renin-angiotensin system, the angiotensin converting enzyme inhibitors act via the inhibition of bradykinin degradation which increase NO levels. Finally, vascular endothelial NO expression is improved by exercise training and participates in the improvement of exercise capacity in patients with chronic heart failure involved in cardiac readaptation program.

Coronary microcirculation and cardiovascular pathology.

The recent arrival of new techniques for exploring the coronary microcirculation has facilitated assessment of both the incidence and consequences of disorders of this network in a large number of cardiovascular diseases. The microcirculation is affected in numerous cardiomyopathies in the presence of different cardiovascular risk factors and also following cardiac transplantation. Dysfunction of the microcirculation may correspond to a reduction in the surface of the maximum section of coronary arterioles, which involves multiple mechanisms, although this phenomenon does not appear to play a role in ischaemic heart disease. Reduced coronary flow is most frequently related to vascular rarefaction of multifactorial origin, including greater or lesser degrees of intimal proliferation, perivascular fibrosis, hypertrophy of the media and extrinsic compression.

Increased bradykinin levels accompany the hemodynamic response to acute inhibition of angiotensin-converting enzyme in dogs with heart failure.

To determine the short-term effects of angiotensin-converting enzyme (ACE) inhibition on hemodynamics and circulating levels of norepinephrine, angiotensin, and bradykinin, responses to enalaprilat and perindoprilat were examined at doses of 0.03, 0.3, and 1 mg/kg in permanently instrumented conscious dogs with pacing-induced heart failure (right ventricular pacing, 240-250 beats/min, 3 weeks). All doses of the two inhibitors produced similar decrease in mean aortic pressure and increase in cardiac output. Neither inhibitor affected plasma norepinephrine level. Both compounds induced a similar 60-80% decrease in blood angiotensin II level, a similar two- to eightfold increase in blood angiotensin I level, and a 80-95% decrease in the angiotensin II/angiotensin I ratio. There were also a fourfold to 10-fold increase in blood bradykinin-(1-9) level, a twofold increase in blood bradykinin-(1-7) level, and a 70-85% decrease in bradykinin-(1-7)/bradykinin-(1-9) ratio. In addition, the changes in total peripheral resistance induced by the two ACE inhibitors were weakly but significantly correlated with the changes in blood angiotensin II or blood bradykinin-(1-9). Thus whatever the specificity of enalaprilat and perindoprilat, both inhibitors produced similar acute hemodynamic effects in dogs with heart failure, which was associated with marked decrease in circulating angiotensin II level and increase in bradykinin-(1-9) level. This study, which measures for the first time in heart failure the blood bradykinin level after ACE inhibitors, indicates, in concert with angiotensin II reduction, a role for increased bradykinin-(1-9) level in mediating short-term hemodynamic effects of ACE inhibition in this model of heart failure.

Coronary microcirculation and cardiovascular pathology.

The recent arrival of new techniques for exploring the coronary microcirculation has facilitated assessment of both the incidence and consequences of disorders of this network in a large number of cardiovascular diseases. The microcirculation is affected in numerous cardiomyopathies in the presence of different cardiovascular risk factors and also following cardiac transplantation. Dysfunction of the microcirculation may correspond to a reduction in the surface of the maximum section of coronary arterioles, which involves multiple mechanisms, although this phenomenon does not appear to play a role in ischaemic heart disease. Reduced coronary flow is most frequently related to vascular rarefaction of multifactorial origin, including greater or lesser degrees of intimal proliferation, perivascular fibrosis, hypertrophy of the media and extrinsic compression.