Phosphate control and 25-hydroxycholecalciferol administration in preventing experimental renal osteodystrophy in the dog.

Previous studies from this laboratory demonstrated that secondary hyperparathyroidism in dogs with chronic renal disease may occur, at least in part, as a consequence of the need for progressive adaptation in renal phosphorus (P) excretion that occurs as glomerular filtration rate falls. However, the studies were of relatively short duration. Moreover, no information emerged regarding a potential role of calcium malabsorption in the pathogenesis of secondary hyperparathyroidism. The short duration of the protocol did not lend itself to the study of the effect of P control or the administration of vitamin D in the pathogenesis of renal osteodystrophy. In the present studies, 14 dogs with experimental chronic renal disease were studied serially for a period of 2 yr. Each animal was studied first with two normal kidneys on an intake of P of 1,200 mg/day. Then, renal insufficiency was produced by 5/6 nephrectomy. The dogs then were divided into three groups. In group I, 1,200 mg/day P intake was administered for the full 2 yr. In group II, P intake was reduced from the initial 1,200 mg/day, in proportion to the measured fall in glomerular filtration rate, in an effort to obviate the renal adaptation in P excretion. In group III, "proportional reduction" of P intake also was employed; but in addition, 20 mug of 25(OH)D(3) were administered orally three times a week. In group I, parathyroid hormone (PTH) levels rose throughout the 2-yr period reaching a final concentration of 557+/-70 U (normal 10-60). In group II, values for PTH remained normal throughout the 1st yr, increased modestly between the 12th and the 18th mo, but then did not rise after the 18th mo. In group III, no elevation of PTH levels was observed at any time; however, these animals were hypercalcemic. Histomorphologic analyses of the ribs of these dogs were performed serially throughout the 2-yr period. A linear relationship was obtained between the osteoclastic resorption surface and the concentration of circulating immunoreactive PTH. The osteoid volume was greater in group I animals when compared to those in group II. None of the morphologic abnormalities associated with renal osteodystrophy were observed in the animals in the third group.

Anemia and secondary hyperparathyroidism.

Anemia has been recognized recently as a possible complication of primary hyperparathyroidism. If the hyperparathyroid state can induce anemia in patients with normal kidney function, the extremely high levels of circulating parathyroid hormone usually observed in hyperparathyroidism secondary to chronic renal failure may have an unfavorable influence on the anemia of uremic patients. We investigated the influence of subtotal parathyroidectomy on the severity of the anemia of 18 uremic subjects undergoing long-term hemodialysis therapy. Subtotal parathyroidectomy resulted in a significant increase of mean hematocrit value. RBC count, and hemoglobin level. Serial bone biopsies suggested a relationship between the amount of marrow fibrosis and the improvement of anemia after surgery, but the precise mechanism of this phenomenon is still unknown.

Vitamin D metabolites and bone mineralization in man.

A comparison was made of the biochemical and osseous effects of 25-hydroxyvitamin D3 [25(OH)D3], 1 alpha-25-hydroxyvitamin D3 [1 alpha, 25(OH)2D3], and 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] in adult vitamin D-deficient man. Administration of 50 micrograms/d of 25(OH)D3 for 8 weeks led to a return of the mineralization front to normal associated with a return of TmPO4/GFR to normal, an increase in serum phosphate and calcium concentrations, a fall in serum IPTH, and a rise in serum alkaline phosphatase activity. Giving 2.5 micrograms/d of 1 alpha,25(OH)2D3 did not produce these effects. Administration of 1 alpha, 25 (OH)2D3 caused an increase in intestinal calcium absorption, and a rise in serum calcium associated with a fall in serum immunoreactive parathormone (IPTH) concentrations but no sustained rise in either alkaline phosphatase, serum phosphate concentration, nor in TmPO4/GFR. Its administration caused an increase in the extent of the osteoclastic bone resorption surface but the extent of the mineralization front remained subnormal. Administration of 20 micrograms/d of 24,25(OH)2D3 caused a fall in urinary calcium excretion and in serum IPTH, and a rise in serum alkaline phosphatase, but no change in TmPO4/GFR or serum phosphate, and only a slight increase in the extent of the mineralization front. Combined treatment with 1 alpha, 25(OH)2D3 and 24,25(OH)2D3 led to a return of the mineralization front of normal even though both TmPO4/GFR and serum phosphate concentration remained low. It is concluded that 1alpha,25(OH)2D3 is not the sole biologically active metabolite of vitamin D in man. It is apparent that either 25(OH)D3 or some as yet unidentified metabolite of 25(OH)D3 stimulates the renal tubular reabsorption of calcium and phosphate, and that the subsequent rise in serum phosphate concentrations along with the direct actions of 1 alpha-25(OH)2D3, 24,25(OH)2D3, and possibly 25(OH)D3 on bone cells all participate in the restoration of normal bone formation and bone mineralization in vitamin D-deficient man.

The effect of 1alpha(OH)D3 and 1alpha,25(OH)2D3 on the bone in patients with renal osteodystrophy.

Six patients with chronic renal disease and variable degrees of renal osteodystrophy were treated for three weeks with either 1alpha,25-dihydroxyvitamin D3 (1alpha25(OH)D3) or 1alpha,hydroxyvitamin D3 (1alpha(OH)D3) and both the biochemical and osseous responses measured. The most consistent changes seen were an increase in serum calcium concentration to normal, a decrease in immunoreactive parathyroid hormone toward normal, an increase in the extent of the calcification front and a decrease in the extent of fibrous dysplasia in the marrow cavity. Two important parameters which did not change significantly were serum alkaline phosphatase activity and the osteoid volume. These data, in conjunction with that from previous studies, indicate that therapy with 1alpha,25(OH)2D3 or 1alpha(OH)D3 does not heal the osteomalacia of renal osteodystrophy, but that it does suppress the secondary hyperparathyroidism, and ameliorate the osteitis fibrosa seen in patients with chronic renal disease. They raise the likelihood that additional factors, such as metabolites of vitamin D other than 1alpha,25(OH)2D3, play a role in regulating bone formation and/or mineralization.

Effect of atrioventricular synchronous pacing on cardiac output determined by CO2 rebreathing at constant submaximal exercise.

This study compared cardiac output assessed by a noninvasive CO2 rebreathing method at identical submaximal exercise and heart rate response in patients undergoing DDD or VVI pacing. Our results did not show any hemodynamic superiority of AV synchronous pacing.

Pharmacological studies on retinoic acid in Wistar and in atrichos rats.

Retinoic acid produces some changes in the skin which could be interpreted as a mechanism of action: release of acid hydrolases and phosphatases, inflammatory reactions, increase in lipid synthesis and transport as an energy dependent phenomenon, increase in the lipid flux perhaps as a lipoprotein complex, since there is a rise in nucleic acid synthesis. Stimulation of bone remodeling is observed only when high dosage of retinoic acid is given orally.

[Role of electric stimulation in apnea syndromes]. / Place de la stimulation électrique dans les syndromes apnéiques.

The sleep apnoea syndrome is the best known apnoeic syndrome. It is observed in 4% of men and 2% of women. Nasal ventilation with continuous positive pressure is the best treatment for most patients. To date, electrical stimulation has a limited role in its treatment as it is used only when the apnoea requires ventilation by tracheotomy. This electrogenic ventilation requires so-called diaphragmatic stimulators. Although severe bradycardia may occur during sleep apnoea, there is usually no indication for cardiac pacing. However, recent publications have reported an anti-apnoeic effect of permanent atrial pacing. The modes of action remain unclear but these results support other recently reported data concerning the value of pacing in cardiac failure, the high incidence of sleep apnoea in cardiac failure patients and the possibility of diagnosing and monitoring apnoea by minute ventilation sensors. Therefore, there appears to be a field of research for cardiac pacing in apnoea syndromes. The authors review the principal reported data on the indications and possibilities of extra-cardiac and cardiac stimulation in apnoeic syndromes.

[Mechanisms of ventricular tachycardia]. / Mécanismes des tachycardies ventriculaires.

There are three fundamental mechanisms of ventricular tachycardia (VT) reentry, abnormal automaticity and triggered activity (TA) related to early or late after potentials. Reentry is certainly the mechanism of branch to branch and post-infarction VT. Early TA is responsible for Torsades de Pointes. Late TA is possibly the cause of certain verapamil-responsive VT but calcium-dependent reentry cannot be excluded. Abnormal automaticity or late TA may also play a role in catecholamine-induced VT. The development of drugs specific for the mechanism confronted with the results of programmed stimulation and mapping should improve the understanding of the mechanism of VT in each individual patient and allow more effective and better tolerated antiarrhythmic therapy.

[Normal blood pressure profiles during exercise according to age, sex and protocols]. / Profils tensionnels normaux à l'effort selon l'âge, le sexe et les protocoles.

Systolic and diastolic blood pressure profiles of 2,808 healthy subjects are reported according to age, sex and exercise protocols. The rates of increase of systolic pressures are expressed with respect to the heart rate and decrease with age. For a given sub-maximal effort the systolic blood pressure is lower in males and in the younger age groups: the diastolic blood pressure only increases significantly on exercise after 50 years of age. These variations according to age and sex were confirmed on treadmill exercise but the peak pressure values were lower. These quantitative results differ from those of previously reported studies and suggest that the diagnostic criteria of hypertension of effort should be redefined.

[The exercise-recovery loop and exercise slope of ST segment changes/heart rate in the diagnosis of coronary disease and restenosis after angioplasty]. / Apport de la boucle effort-récupération et de la pente d'effort des variations du segment ST selon la fréquence cardiaque au diagnostic de maladie coronaire et de la resténose après angioplastie.

This study addresses the diagnostic value of two new criteria of exercise stress testing for primary coronary artery disease and restenosis after angioplasty: the slope of the linear relation between ST segment changes and heart rate during exercise; the exercise-recovery loop (clockwise direction in normal subjects and anticlockwise direction in coronary patients). These two criteria were compared with the standard diagnostic criteria (horizontal or descending ST segment depression greater than 1 mm or ascending ST segment depression greater than 2 mm) in 125 patients with suspected coronary artery disease who underwent computerised exercise stress testing and coronary angiography (30 single, 31 double and 30 triple vessel disease; 34 without significant stenosis) and in 24 patients with single vessel disease who underwent successful angioplasty and who performed exercise stress testing before, immediately after and 6 months after angioplasty before routine control coronary angiography. The sensitivity (Se), specificity (Sp), positive predictive value (PPV) of the exercise-recovery loop for the diagnosis of coronary disease were 81 %, 82 %, 89 %, respectively, versus 69 %, 71 % and 88 % for the standard criteria. The detection of restenosis by these criteria also appeared to be better (71 %, 91% and 91 % versus 46 %, 63 % and 60 %, respectively). However, for the classical threshold value of 2.4 mv/beat/min, the ST/HR criteria seemed to be less useful (Se : 80 %, Sp : 26 %).

[Segmental rehabilitation in cardiac failure: short and long-term results]. / Réadaptation segmentaire chez les insuffisants cardiaques: résultats à court et à long terme.

Many patients with chronic cardiac failure may benefit from exercise rehabilitation. However, the usual protocols, which may lead to haemodynamic disturbances or induce arrhythmias, are rarely applicable in the most severe cases. Therefore, the authors developed a protocol of segmental rehabilitation where the same muscle groups as in global readaptation are involved, but successively and not simultaneously. This study included 25 patients in the NYHA class III. Many parameters were analysed before and after forty sessions. Although the resting isotopic ejection fraction (0.26 +/- 0.1 vs 0.27 +/- 0.11; p = NS), oxygen consumption at the ventilatory threshold (14.3 +/- 3.5 vs 18.3 +/- 5.2 ml/kg/min; p = NS) or at peak effort (17.4 +/- 4.7 versus 18.3 +/- 5.2 ml/kg/min, p = NS) were unchanged, three other parameters were significantly improved: the duration of exercise (9.2 +/- 2.4 vs 10.4 +/- 3.4 min; p < 0.02) maximum work load (3 046 +/- 1 510 vs 3 992 +/- 2 482; p < 0.01) and muscular force (151 +/- 35 versus 220 +/- 41 kg; p < 0.0001). In addition, after a follow-up period of 43 +/- 18 months, a close inverse relationship was observed between the gains obtained in terms of duration of exercise and maximum work load and the number of hospital readmissions. Similarly, the 10 patients having undergone rehabilitation with this protocol had 11.7 times fewer hospital readmissions than the other 15. Segmental rehabilitation would therefore seem to be a safe technique for patients with severe cardiac for significantly increasing exercise capacity and lowering the number of readmissions to hospital.

[Doppler study of phasic variations of blood flow velocity in the anterior interventricular artery]. / Etude Doppler des variations phasiques des vitesses du sang dans l'artère interventriculaire antérieure.

Studies of changes in coronary blood flow during cardiac cycles may be a useful adjuvant to the measurement of coronary flow reserve to evaluate the hydraulic severity of coronary arterial stenoses. We used intracoronary pulsed Doppler velocimetry to measure phasic variations of blood flow in the anterior interventricular artery of 12 patients with angiographically identified stenosis of that vessel. The Doppler signal was obtained by means of a 20 MHz emission from a source placed at the tip of a catheter selectively positioned at the ostium of the anterior interventricular artery, upstream of the stenosis. The increase in severity of stenosis was paralleled by a relative decrease of diastolic blood flow velocity in relation to systolic blood flow velocity. The diastolic/systolic maximum velocities ratio was greater than 1 in 6 patients with a less than 70 p. 100 stenosis (group A) and inferior to 1 in 6 other patients with a 70 p. 100 or more stenosis (group B). In 5 patients of group B this ratio was reversed to normal after percutaneous transluminal angiography. Thus, measurement of intracoronary blood flow velocity may be helpful to evaluate the severity of stenosis, notably in the anterior interventricular artery where angiographic evaluation is difficult.

[Antihypertensive treatment and remission of left ventricular hypertrophy. Critical study]. / Traitement antihypertenseur et régression de l'hypertrophie ventriculaire gauche. Etude critique.

Left ventricular hypertrophy which is the adaptive mechanism of the heart to hypertension may become a cardiovascular risk factor independent of the hypertension which induced it: the regression of left ventricular hypertrophy therefore constitutes one of the medium-term objectives of antihypertensive therapy. Some antihypertensive drugs make the left ventricular hypertrophy regress early and permanently: methyldopa, betablockers, converting enzyme inhibitors, calcium antagonists. The reduction of myocardial mass is slight or debatable with diuretics and absent or inconstant with vasodilator therapy. The regression of left ventricular hypertrophy in hypertension raises several problems: the reliability of methods of measurement; inter-individual and inter-drug variations; the beneficial nature of this regression; the preventive effect of regression of left ventricular hypertrophy on cardiovascular complications. In the light of recent trials, early treatment of hypertension may prevent the development of left ventricular hypertrophy.

Flecainide-induced Increase in QRS Duration and Proarrhythmia during Exercise.

In patients taking flecainide, exercise-induced arrhythmias are believed to be related to QRS widening at rest and during exercise. Our aim was to determine, retrospectively, predictive factors of flecainide-induced (a) QRS widening at rest and during exercise, and (b) proarrhythmia (PA) during exercise. Flecainide was administered to 119 patients for atrial and/or ventricular arrhythmias who performed a maximal treadmill test. A total of 63 patients had a normal heart (defined by the absence of structural heart disease and an ejection fraction ≥ 55% by echocardiography and/or cardiac catheterisation), 26 had coronaropathy, 18 valvulopathy and 3 had both, and 7 had dilated and 2 hypertrophic cardiomyopathy. The mean dosage of flecainide was 190 or 200 ± 10 mg/day. Previous myocardial infarction (MI) was a predictive variable of flecainide-induced QRS widening at rest (p = 0.04). During exercise, the risk factors of QRS widening were previous MI (p = 0.008), angina without previous MI (p = 0.009), structural heart disease (p = 0.001) and a bundle branch block at rest (p = 0.01). PA on exercise occurred in 7 patients. Structural heart disease (p = 0.04) and an impaired left ventricular ejection fraction (LVEF) [p = 0.02] were predictive variables of PA. All patients with left ventricular dysfunction and PA had a QRS widening with flecainide at rest ≥ 25%. The risk factors of QRS widening at rest and during exercise with flecainide were distinct from those of PA on exercise. In patients with an impaired LVEF, a flecainide-induced QRS widening of 25% at rest was the threshold value beyond which there was a high risk of PA during exercise. This study was retrospective and not a double-blind trial, therefore the results need to be corroborated in a prospectively designed trial.

[Sleep apnea and cardiac pacing: mechanisms of action and perspectives]. / Apnées du sommeil et stimulation cardiaque: mécanismes d'action et perspectives.

In an adult population, the prevalence of sleep apnea is 4% for men and 2% for women. Generally, nasal positive pressure ventilation is the best therapeutic option. To date, and in spite of the possible presence of marked brady-arrhythmias during sleep apnea, there is no recognised indication for Pacemaker implantation. However, recent data show the potential benefit of permanent cardiac stimulation in these patients. Increasing heart rate (using atrial pacing) improves cardiac output, and reduces pulmonary congestion and pulmonary vagal afferent nerves are no longer stimulated. The incidence of central sleep apnea is thereby reduced. Excessive nocturnal vagal tone increases snoring and sleep apnea, because of excessive relaxation of the oropharyngeal muscles. In patients with bradycardia, atrial stimulation may oppose increased vagal tone, by stimulating the sympathetic system or maintaining it at a minimal level. It is therefore possible that cardiac stimulation will become part of the treatment of sleep apnea in patients with documented bradycardia and/or heart failure.

[Flecainide acetate]. / L'acétate de flécaïnide.

Flecainide acetate is a powerful antiarrhythmic initially used to treat ventricular arrhythmias. Despite an excess mortality in this indication and in the presence of heart disease, flecainide remains a good antiarrhythmic for supraventricular tachycardias in a healthy heart.

[Acute myocardial infarction management in a hospital center with emergency ambulance service and intensive care unit, without cardiac catheterization laboratory]. / Prise en charge de l'infarctus aigu du myocarde dans un centre hospitalier équipé de services SMUR et réanimation médicale, sans salle de cathétérisme cardiaque.

OBJECTIVES: We report our experience about acute myocardial infarction management in a small hospital with no possibility of coronarography. MATERIALS AND METHODS: In 1998, 60 patients were hospitalized for acute myocardial infarction < 10 days. We studied characteristics of patients, the management of myocardial infarction, the mortality. RESULTS: Our population consisted of 83% of men and 17% of women with a mean age of 63.5 and 74 years respectively. An out-hospital doctor was first warned by 60% of patients. For hospitalization, the emergency ambulance service (SMUR) was used in 45% of cases, out-hospital doctors using these means of transport in 36% of cases. The global time of intervention was 18h30. The mean time for patients managed in the first sixth hours was 2h10. A thrombolysis was applied for 35% of patients (15% in prehospital that is to say 32% of "SMUR patients", and 20% in hospital). A transfer to the neighbouring university hospital for primary or rescue coronary angioplasty was decide for 41% of patients. A total of 77% of our patients underwent a coronarography. The global mortality at 10 days was 13.3% (< 75 years: 10.6%; > 75 years: 23%). CONCLUSIONS: A low volume centre and with no possibility of coronarography can manage the acute phase of myocardial infarction with results closed to those of the literature.

[An evaluation of the therapeutic trials aimed at regression of ventricular hypertrophy in arterial hypertension]. / Bilan des essais thérapeutiques visant à faire régresser l'hypertrophie ventriculaire gauche dans l'hypertension artérielle.

Left ventricular hypertrophy (LVH) which is a mechanism of adaptation of the heart to hypertension (HT) may become a cardiovascular risk factor independent of the HT which has caused it. Causing the regression of LVH is thus one of the mid-term aims of antihypertensive therapy. Certain antihypertensive drugs are capable of producing an early and durable regression of LVH: methyldopa, beta-blockers, ACEI, calcium blockers. The effect of mass reduction is moderate or doubtful with diuretics, while it is nil or inconstant with vasodilators. The regression of LVH in HT raises various problems: 1) reliability of the measurement technique, 2) inter-individual and inter-drug variations, 3) favourable nature of regression, 4) preventive effect of regression against cardiovascular complications. Finally, in the light of recent studies it appears that early treatment of HT may prevent the onset of LVH.

[Secondary prevention of atherosclerosis: effects on coronary plaques and on myocardial ischemia]. / Prévention secondaire de l'athérosclérose: effets sur les plaques coronaires et sur l'ischémie myocardique.

The coronary atherosclerotic plaque progresses in successive stages, determined by phenomena such as spasm, thrombosis and inflammation. Studies of regression are hindered by methodological problems involving the variability of angiographic results over intervals of several years. Longitudinal clinical studies are probably more useful. For long-term clinical outcome, it appears that stabilisation of young plaques is more important than regression of older plaques. To this end, cessation of smoking seems the most effective means; progressive plaques are most often seen early in the disease, in patients under 60 years of age, of whom more than 70% are smokers. The inevitable lack of studies as rigorous as those dealing with hyperlipidaemia reduction should not be used as a pretext for scruples leading to ignoring the results of clinical practice. Prevention by diet is no doubt essential, but prospective studies are still rare and biases are numerous. The same is true for physical exercise.