High plasma aldosterone and low renin predict blood pressure increase and hypertension in middle-aged Caucasian populations.

Plasma aldosterone and renin levels have been associated with blood pressure increase and 3-4 year incidence of hypertension in a middle-aged North American community in Framingham. To confirm these findings in a different population, a nested case-control study was performed in a national sample of 1984 French non-hypertensive volunteers aged 45-64 year and followed for 5 years. Cases and controls (individuals becoming hypertensive or remaining non-hypertensive on follow-up) were individually matched on sex, diastolic and systolic pressures at baseline. Multivariable regression models show that plasma aldosterone and renin are respectively positively and negatively associated with the increase in systolic pressure (P=0.01 and 0.001) and the risk of hypertension (22% increase and 16% decrease per s.d. increment in the log, P=0.04 and 0.07). These associations are mostly observed in the lowest tertiles of dietary sodium and potassium intakes where plasma aldosterone is positively associated with the increase in systolic pressure (P=0.01 and 0.08) and the risk of hypertension (59 and 69% increase per s.d. increment in the log, P=0.02 and 0.01), whereas plasma renin is negatively associated with the increase in systolic pressure (P=0.0004 and 0.004) and the risk of hypertension (31 and 28% decrease per s.d. increment in the log, P=0.03 and 0.05). These results reinforce the hypothesis that high plasma aldosterone and low plasma renin levels precede blood pressure increase and the occurrence of hypertension in middle-aged Caucasian populations.

Cardioprotection and kallikrein-kinin system in acute myocardial ischaemia in mice.

1. Acute myocardial ischaemia and reperfusion trigger cardioprotective mechanisms that tend to limit myocardial injury. These cardioprotective mechanisms remain for a large part unknown, but can be potentiated by performing ischaemic preconditioning or by administering drugs such as angiotensin-I-converting enzyme (kininase II) inhibitors (ACEI). 2. This brief review summarizes the findings concerning the role of tissue kallikrein (TK), a major kinin-forming enzyme, kinins and kinin receptors in the cardioprotection afforded by ischaemic preconditioning (IPC) or by pharmacological postconditioning by drugs originally targeted at the renin-angiotensin system, ACEI and type 1 angiotensin-II receptor blockers (ARB) in acute myocardial ischaemia. Myocardial ischaemia was induced by left coronary occlusion and was followed after 30 min by a 3 h reperfusion period (IR), performed in vivo in mice. The role of the kallikrein-kinin system (KKS) was studied by using genetically engineered mice deficient in TK gene and their wild-type littermates, or by blocking B1 or B2 bradykinin receptors in wild-type mice using selective pharmacological antagonists. 3. Ischaemic preconditioning (three cycles: 3 min occlusion/5 min reperfusion) enhances the ability of the heart of wild-type mice to tolerate IR. Tissue kallikrein plays a major role in the cardioprotective effect afforded by IPC, which is largely reduced in TK-deficient mice. The B2 receptor is the main kinin receptor involved in the cardioprotective effect of IPC. 4. Tissue kallikrein is also required for the cardioprotective effects of pharmacological postconditioning with ACEI (ramiprilat) or ARB (losartan), which are abolished for both classes of drugs in TK-deficient mice. The B2 receptor mediates the cardioprotective effects of these drugs. Activation of angiotensin-II type 2 (AT2) receptor is involved in the cardioprotective effects of losartan, suggesting a functional coupling between AT2 receptor and TK during angiotensin-II type 1 (AT1) receptor blockade. 5. The demonstration of a cardioprotective effect of the KKS in acute myocardial ischaemia involving TK and the B2 receptor and playing a major role in IPC or pharmacological postconditioning by ACEI or ARB, suggests a potential therapeutic approach based on pharmacological activation of the B2 receptor.

Role of tissue kallikrein in the cardioprotective effects of ischemic and pharmacological preconditioning in myocardial ischemia.

Tissue kallikrein (TK), a major kinin-forming enzyme, is synthesized in the heart and arteries. We tested the hypothesis that TK plays a protective role in myocardial ischemia by performing ischemia-reperfusion (IR) injury, with and without ischemic preconditioning (IPC) or ACE inhibitor (ramiprilat) pretreatment, in vivo in littermate wild-type (WT) or TK-deficient (TK-/-) mice. IR induced similar infarcts in WT and TK-/-. IPC reduced infarct size by 65% in WT, and by 40% in TK-/- (P<0.05, TK-/- vs WT). Ramiprilat also reduced infarct size by 29% in WT, but in TK-/- its effect was completely suppressed. Pretreatment of WT with a B2, but not a B1, kinin receptor antagonist reproduced the effects of TK deficiency. However, B2 receptor-deficient mice (B2-/-) unexpectedly responded to IPC or ramiprilat like WT mice. But pretreatment of the B2-/- mice with a B1 antagonist suppressed the cardioprotective effects of IPC and ramiprilat. In B2-/-, B1 receptor gene expression was constitutively high. In WT and TK-/- mice, both B2 and B1 mRNA levels increased several fold during IR, and even more during IPC+IR. Thus TK and the B2 receptor play a critical role in the cardioprotection afforded by two experimental maneuvers of potential clinical relevance, IPC and ACE inhibition, during ischemia.

Early glomerular macrophage recruitment in streptozotocin-induced diabetic rats.

Diabetic glomerulosclerosis is defined by increased glomerular extracellular matrix (ECM) that is mainly synthesized by mesangial cells that underwent an activation mediated by cytokines and growth factors from various cellular origins. In this study, we tested whether macrophages could infiltrate the glomeruli and influence ECM synthesis in experimental diabetes. To test our hypothesis, we initially studied the dynamics of glomerular macrophage recruitment in streptozotocin-induced diabetic rats at days 1, 2, 4, 8, 15, and 30 by using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) on isolated glomeruli and immunohistochemistry and morphometry. We then assessed the role of macrophages on the basis of the pharmacological modulation of their recruitment by insulin or ACE inhibitor treatments and by X-irradiation-induced macrophage depletion at days 8 and 30. Macrophages were recruited within the glomeruli at the very early phase of hyperglycemia by using RT-PCR CD14 detection from day 2 and by using ED1 immunohistochemistry from day 8. This glomerular macrophage infiltration was associated with an increase in alpha1-chain type IV collagen mRNA. In parallel, the diabetic glomeruli became hypertrophic with an increase in the mesangial area. Macrophage recruitment was preceded by or associated with an increased glomerular expression of vascular cell adhesion molecule 1, intracellular adhesion molecule 1, and monocyte chemoattractant protein 1, which contributes to monocyte diapedesis. Glomerular interleukin-1beta mRNA synthesis was also enhanced as early as day 1 and could be involved in the increase in ECM and adhesion molecule gene expressions. Insulin treatment and irradiation-induced macrophage depletion completely prevented the glomerular macrophage recruitment and decreased alpha1-chain type IV collagen mRNA and mesangial area in diabetic rats, whereas ACE inhibitor treatment had an incomplete effect. It can be concluded that in the streptozotocin model, hyperglycemia is followed by an early macrophage recruitment that contributes to the molecular and structural events that could lead to glomerulosclerosis. Therefore, besides direct stimulation of mesangial cells by hyperglycemia, macrophages recruited in the glomeruli during the early phase of hyperglycemia could secondarily act on mesangial cells.

Inflammatory cells and myocardial fibrosis: spatial and temporal distribution in renovascular hypertensive rats.

OBJECTIVE: The fibroblasts producing collagen are co-localized with inflammatory cells in myocardial fibrosis areas of spontaneously hypertensive rats, suggesting that collagen overproduction in this model may be modulated by inflammatory cells. The present study extends these observations to the Goldblatt model of hypertension in which the renin-angiotensin system is activated. METHODS: Inflammatory cells were identified with monoclonal antibodies directed against macrophages (ED1+), T helper (CD4+) and cytotoxic lymphocytes (CD8+), and MHC class II-expressing cells (Ia+). The alkaline phosphatase-anti-alkaline phosphatase (APAAP) immuno-staining technique was used. A new computer-assisted morphometric method was utilized to quantify the inflammatory infiltrate in each cardiac compartment with polarized-light microscopy. Cells responsible for the collagen synthesis were identified by in situ hybridization. The collagen content was estimated by morphometry on left ventricle sections stained with Sirius red, and by biochemical quantification of the hydroxyproline concentration. RESULTS: Computer-assisted morphometry under polarized light was well suited to quantify inflammatory cells labeled by the APAAP technique. Inflammatory cells were co-localized with collagen-synthesizing fibroblasts. The main inflammatory cells were CD4+ lymphocytes > Ia+ > ED1+ > CD8+ cells. These cell densities were increased in hypertensive rats in all cardiac areas compared to control rats except for IA+ cells which were concentrated in microscars. Macrophage density was correlated with plasma renin activity. The inflammatory cell density which best correlated with fibrosis was macrophage density, and which best correlated with systolic blood pressure was macrophage and T helper lymphocyte densities. CONCLUSIONS: One can speculate that the correlation between macrophage density and blood pressure as well as with plasma renin activity may indicate that angiotensins and/or elevation of blood pressure could participate in the initial signalling which may mobilize inflammatory cells. These inflammatory cells could promote fibrosis by releasing mediators such as growth factors or cytokines which act upon fibroblasts.

Respective role of humoral factors and blood pressure in cardiac remodeling of DOCA hypertensive rats.

OBJECTIVES: Recent studies have shown that beside elevated arterial blood pressure, humoral factors such as angiotensin II, aldosterone, endothelin or bradykinin might play a role in the cardiac hypertrophy and fibrosis secondary to hypertension. In addition, it seems that perivascular fibrosis and interstitial fibrosis are controlled by independent mechanisms. Therefore, the goal of our study was to evaluate the respective role of the increased arterial pressure and of humoral factors on cardiac remodeling in an experimental hypertension model. METHODS: Uninephrectomized rats received DOCA, a high salt diet, and when hypertension was installed, they were treated for 6 weeks with either a long-acting calcium antagonist, mibefradil (30 mg/kg day-1), an ACE inhibitor, enalapril (3 mg/kg day-1), or a mixed ETA-ETB endothelin receptor antagonist, bosentan (100 mg/kg day-1). A group of hypertensive rats was left untreated and a sham-operated group of normotensive rats was used for control. At the end of treatment, maximal coronary blood flow was measured in isolated perfused hearts. Cardiac hypertrophy and interstitial as well as perivascular fibrosis were evaluated by quantitative morphometry. RESULTS: DOCA-salt hypertensive rats exhibited a marked cardiac hypertrophy associated with a decrease of maximal coronary blood flow and interstitial and perivascular fibrosis. The calcium antagonist nearly normalized arterial pressure and suppressed all these changes. Enalapril had no effect on arterial pressure and perivascular fibrosis but decreased subendocardial fibrosis. Bosentan had a very small effect on arterial pressure but decreased cardiac hypertrophy and both perivascular and subendocardial fibrosis. CONCLUSIONS: We conclude that in DOCA salt hypertension, humoral factors such as endothelin may play a role beside high blood pressure in cardiac remodeling. In addition, the different components of this remodeling (decrease of vascular reserve, cardiac hypertrophy and cardiac fibrosis) are controlled independently.

Evidence for in vivo carotid and femoral wall thickening in human hypertension. Groupe de Prévention Cardio-vasculaire en Médecine du Travail.

Little is known of the in vivo structural changes of large arteries in uncomplicated hypertension. Therefore, we measured the intima-media thickness and lumen diameter of common carotid and femoral arteries by a computerized ultrasonographic technique in 25 normotensive and 25 never treated hypertensive men of similar age (from 25 to 72 years). The intraobserver variability of carotid and femoral wall thicknesses was 4.3% and 5.6%, respectively. Moreover, an in vitro study of 13 human arterial segments removed at autopsy demonstrated a strong correlation (r = .989, P < .001) between computerized ultrasonic and histological intima-media thickness measurements. Compared with control subjects, hypertensive patients had similar arterial diameters but higher carotid and femoral intima-media thicknesses (P < .001) as well as higher ratios of carotid and femoral intima-media thickness to lumen (P < .001, P < .01). The carotid thickness was correlated with age in control subjects (r = .48, P < .05) but not in hypertensive patients. The femoral thickness was correlated with age both in control subjects (r = .55, P < .01) and in hypertensive patients (r = .46, P < .05). Thus, carotid and femoral arterial walls of hypertensive patients were thickened. This thickening was not due to age, although aging also thickened both vessels in control subjects and the femoral artery only in hypertensive patients. Such a wall thickening associated with a normal diameter provides direct evidence of vascular growth and represents a new target to monitor noninvasively in vivo for large artery changes in human hypertension.

Continuous versus intermittent angiotensin converting enzyme inhibition in renal hypertensive rats.

Converting enzyme inhibitors impair renal function of the kidney beyond a stenosis of the renal artery in humans and induce histological lesions in the clipped kidney of renal hypertensive rats. In two-kidney, one clip hypertensive rats, we compared the time course and magnitude of the biochemical effects of angiotensin converting enzyme inhibition on the plasma renin-angiotensin system, cardiac hypertrophy, renal lesions, and 24-hour blood pressure decrease induced by either intermittent angiotensin converting enzyme inhibition administration (benazepril PO, 10 mg/kg once a day, n = 93) or continuous administration (benazeprilat, 3 mg/kg per day via osmotic pumps, n = 92). Control rats (n = 91) received the drug vehicle intermittently or continuously. Mortality was significantly reduced by both intermittent (n = 3/93) and continuous (n = 3/92) inhibition compared with controls (n = 18/91) (P < .001). Changes in the plasma renin-angiotensin system and blood pressure were parallel. A continuous suppression of the activity of the plasma renin-angiotensin system was associated with a 24-hour decrease in blood pressure with continuous inhibition, whereas intermittent inhibition induced a similar fall in blood pressure only for the first hours after gavage.(ABSTRACT TRUNCATED AT 250 WORDS)

Left ventricular fibrosis in renovascular hypertensive rats. Effect of losartan and spironolactone.

Myocardial fibrosis resulting from arterial hypertension alters myocardial structure and function. Myocardial fibrosis is characterized by a pathological accumulation of types I and III collagens. We used an aldosterone antagonist (spironolactone) and an angiotensin II antagonist (losartan) to elucidate the respective role of these hormones and hypertension in the development of myocardial fibrosis in the Goldblatt model of two-kidney, one clip hypertension in the rat. Fibrosis was assessed by computer-assisted morphometry in the interstitial space, around coronary arteries, in microscar areas, and on left ventricular sections stained with Sirius red and by biochemical techniques. Morphometry was performed with both standard light and polarization microscopy; this latter method was used to quantify yellow-red and green collagen fibers. Concurrently, type I and type III collagen mRNAs were evaluated by a semiquantitative polymerase chain reaction method. The collagen content of the untreated two-kidney, one clip hypertensive rats increased mainly around the coronary arteries; the number and surface area of microscars also increased in chronic hypertension. Losartan treatment decreased systolic pressure and yellow-red collagen fiber content in all areas, whereas spironolactone treatment decreased green collagen fiber content without decreasing systolic pressure. mRNA levels for types I and III collagens showed profiles similar to those of yellow-red and green collagen fiber contents, respectively, suggesting that yellow-red collagen fibers are mainly type I collagen fibers and green collagen fibers are mainly type III collagen fibers. These results suggest that angiotensin II, possibly together with hypertension, and aldosterone, independently of hypertension, have a major influence on myocardial fibrosis, inducing type I and type III collagen deposits, respectively, mainly around coronary arteries.

Endothelin antagonism in end-organ damage of spontaneously hypertensive rats. Comparison with angiotensin-converting enzyme inhibition and calcium antagonism.

High blood pressure results in cardiac hypertrophy and fibrosis, increased thickness and stiffness of large artery walls, and decreased renal function. The objective of our study was to assess the role of endothelin, angiotensin II, and high blood pressure in the end-organ damage observed in spontaneously hypertensive rats (SHR). For this purpose, SHR were treated for 10 weeks with either a mixed endothelin-A and endothelin-B receptor antagonist, bosentan (100 mg/kg per day), an angiotensin-converting enzyme inhibitor, enalapril (10 mg/kg per day), or a long-acting calcium antagonist, mibefradil (20 mg/kg per day). A group of SHR was left untreated, and a group of normotensive Wistar rats was used as control. At the end of treatment, maximal coronary blood flow was measured in isolated perfused hearts. Cardiac hypertrophy and fibrosis, aortic medial thickness, and extracellular matrix content were evaluated by quantitative morphometry. Proteinuria and urea and creatinine clearances were measured, and renal histopathology was assessed. SHR exhibited cardiac hypertrophy, perivascular fibrosis, and decreased maximal coronary blood flow. Aortic medial thickness was increased, whereas elastin density was decreased. Finally, SHR showed decreased urinary excretion and decreased urea and creatinine clearances. No renal histological lesions were observed. Although bosentan did not affect blood pressure, it normalized renal function and slightly decreased left ventricular hypertrophy and fibrosis. Enalapril and mibefradil were both effective in significantly decreasing blood pressure, left ventricular hypertrophy, and aortic medial thickness and improving coronary blood flow, but in contrast to bosentan, they did not improve creatinine clearance. We conclude that in SHR, high blood pressure plays a major role in end-organ damage and that endothelin may partly mediate renal dysfunction and cardiac remodeling independently of a direct hemodynamic effect.

Glomerular capillary network of cortical nephrons is reduced in male but not in female aging rats.

The gender differences in the age-related changes of glomerular structures were determined in 10- and 30-month-old rats. In adult animals, glomerular volume, urinary space, capillary lumen area and mesangial domains of deep and superficial nephrons were larger in males than in females. Glomerular hypertrophy was evidenced with age in both males and females. This hypertrophy was greater in female (+70%) than in male (+20%) rats. Age-related hypertrophy concerned equally the urinary space and the glomerular tuft. The mesangial domain, however, increased more markedly than glomerular volume (+400%). As a result, the ratio of mesangial domain to glomerular section area was more than doubled between 10 and 30 months. In females, the age-related renal hypertrophy was associated with a constant total capillary lumen area in cortical nephrons. In contrast, the total capillary lumen area of male rats was reduced by 20% in superficial glomeruli and by 36% in deep glomeruli between 10 and 30 months. These morphological changes are in good agreement with the maintained glomerular filtration rate reported in old female rats and the decrease in renal blood flow and filtration rate reported in male rats. They suggest that the aging process does not similarly affect the vascular system of the kidney of male and female rats, although their mean blood pressure was comparable.

Structural changes and cyclic GMP content of the aorta after calcium antagonism or angiotensin converting enzyme inhibition in renovascular hypertensive rats.

OBJECTIVE: To evaluate the respective roles of elevated blood pressure and stimulation of the renin-angiotensin system in the development of structural changes in the aortae of rats with renovascular hypertension. MATERIALS AND METHODS: Renovascular hypertensive rats (two-kidney, one clip) were randomly allocated to three different groups and were treated with equihypotensive doses of an angiotensin converting enzyme (ACE) inhibitor (enalapril, 3 mg/kg per day) or of a new long-acting calcium antagonist (mibefradil, 30 mg/kg per day). A renovascular hypertensive group was left untreated. A sham-operated group of rats was used as a normotensive control group. At the end of the 5-week treatment period the rats were killed and their aortae were removed. Medial hypertrophy, elastin and collagen content and density of nuclei were evaluated using quantitative morphometry. The aortic cyclic GMP (cGMP) content was quantified by radioimmunoassay. RESULTS: Hypertension was associated with medial hypertrophy, a decreased elastin: collagen ratio, hypertrophy of the smooth muscle cells and increased cGMP content of the aorta. Mibefradil and enalapril equally prevented the morphological consequences of hypertension (i.e. medial hypertrophy and the decreased elastin:collagen ratio). The aortic cGMP content was increased by enalapril but not by mibefradil. CONCLUSION: The present results show that, even in a high-renin model (two-kidney, one clip), it is possible to prevent or suppress the vascular consequences of hypertension without interfering with the renin-angiotensin system. This suggests that the changes observed in the aorta are directly related to blood pressure or to other mechanisms independent of the renin-angiotensin system, which could be blocked by a calcium antagonist such as mibefradil.

Mibefradil prevents L-NAME-exacerbated nephrosclerosis in spontaneously hypertensive rats.

OBJECTIVE: To determine the potential renal protective effects of a novel calcium channel blocker mibefradil in chronic renal failure. METHOD: We compared the long-term effects of mibefradil with an angiotensin-converting enzyme inhibitor cilazapril on blood pressure, proteinuria, renal function and histological alterations in N-nitro-L-arginine methylester (L-NAME)-treated spontaneously hypertensive rats (SHR). Three groups of SHR were studied for 45 days: group 1 (n = 14), treated with L-NAME only (50 mg/l in the drinking water); group 2 (n = 15) L-NAME plus co-treatment with mibefradil (30 mg/kg per day); group 3 (n = 15), L-NAME plus co-treatment with cilazapril (10 mg/kg per day). RESULTS: Both mibefradil and cilazapril attenuated the increased systolic blood pressure, and prevented the development of proteinuria and the decreased creatinine clearance (Ccr) seen at day 42 in the group treated with L-NAME alone. Notably, mibefradil had similar effects to cilazapril on proteinuria and Ccr, despite a reduced antihypertensive effect All animals receiving mibefradil co-treatment remained alive throughout the experiment, whereas the mortality rate was 43% in SHR treated with L-NAME alone. Both mibefradil and cilazapril completely prevented renal structural damage as assessed by scoring glomerular, tubulo-interstitial and vascular lesions. CONCLUSIONS: Our data show that mibefradil prevented the development of hypertension and proteinuria, renal functional impairment and nephrosclerosis, and also improved animal survival. The renal protective effects of mibefradil were at least equivalent to those of an ACE inhibitor in this animal model of chronic renal failure.

Presensitization accelerates allograft arteriosclerosis.

Transplant arteriosclerosis is the major factor influencing allograft survival after the first year posttransplantation. The host's immunologic response is one of the principal effectors responsible for the constitution of this vascular wall lesion, but the effector pathway and the factors influencing the immune injury are not clear. In a rat abdominal aortic allograft model, we used a skin priming method to study the influence of sensitization on the occurrence of vascular wall lesions. Primed rats developed transplant arteriosclerosis lesions involving medial decellularization and intimal proliferation before the 21st day, whereas naive animals had the same lesions at 2 months posttransplantation. A significant difference between primed and naive rats was found for medial thickness (48.00 +/- 2.85 microm versus 79.34 +/- 2.55 microm, P<0.001) and smooth muscle cell content (160 +/- 28 cell/mm versus 466 +/- 19 cell/mm, P<0.001) at 21 days posttransplantation, and intimal hyperplasia was seen in primed animals at that time, whereas it was not observed in naive rats until the 60th day. The immune profile in naive and primed animals was different. The immune cells infiltrating the arterial wall in naive rats, were principally macrophages and CD8+ T-lymphocytes. No Ig or complement deposition was detected. IgG and complement activated fraction were present in the media of primed animals as early as the fifth day posttransplantation and CD4+ T lymphocytes were the dominant immune cell population. In conclusion, sensitization influences the immune mechanisms responsible for the development of transplant arteriosclerosis and alters the rate of its evolution.

Beneficial effects of trandolapril on experimentally induced congestive heart failure in rats.

Angiotensin-converting enzyme (ACE) inhibitors have been shown to prolong life expectancy in patients with congestive heart failure. In order to determine the relative contributions of the different factors involved in this beneficial effect, we investigated in an experimental model of postinfarction cardiac insufficiency in the rat over a 9-12-month period (1) the kinetics of the development of the hemodynamic, biologic, and morphologic alterations that accompany heart failure, and (2) the kinetics of the effects of a new, long-acting ACE inhibitor, trandolapril. Following induction of infarction, systolic blood pressure, left ventricular dP/dt, and end-diastolic pressure were immediately decreased, decreased, and increased, respectively, and these modifications persisted throughout the study. Cardiac index, on the other hand, was only initially and transiently decreased. Cardiac remodeling (left ventricular dilation, myocardial hypertrophy, and fibrosis) occurred as early as 7 days after infarction and worsened throughout the study. Plasma atrial natriuretic factor (ANF) and urinary cyclic guanosine monophosphate (cGMP) were also increased. In this model, a 1-year oral treatment with trandolapril resulted in early hemodynamic and biologic beneficial effects (reductions in pre- and afterload, increase in cardiac index, and decrease in plasma ANF), and in a delayed reversal of the infarction-induced cardiac morphologic alterations. Hence, the trandolapril-induced increase in survival rate is due initially to the drug's hemodynamic effects and over the long-term to both its hemodynamic and cardiac morphologic (limitation of remodeling) effects.

Multiple myeloma: epidemiological features in a well-defined population in Burgundy, France.

Epidemiological features of multiple myeloma were studied over a seven-year period (1980-86) in the department of Côte d'Or (population 478,000). The crude annual incidence rates were 3.7/100,000 for males and 4.0/100,000 for females. The corresponding age-standardized rates were 2.5 and 2.1. The sex ratio was 1.2. Cumulative rates were 0.3% for both sexes. Age and specific incidence were low before 50 and increased with advancing age up to 85 years in males and females. There was no significant variation in incidence over the seven-year period. The risk of multiple myeloma was slightly higher in urban than in rural areas (the variations were not significant). The period between the beginning of the symptoms and the diagnosis was often short, less than one month in 56% of the cases. When compared to other population based registries the incidence rates are similar to those reported all over the world (except for registries with a high proportion of blacks in the population). Cases have been staged according to Durie and Salmon classification: 32% of the cases were classified as Stage I. This result suggests that globally cases diagnosed in a well-defined population are less severe than those reported in hospital statistics. Survival showed significant differences: there were better rates for patients under 75 and for patients at stage I and II compared with stage III patients. Percentage and morphology of plasma cells also influenced prognosis.

Influence of acute or chronic rejection on myocardial collagen density in serial endomyocardial biopsy specimens from cardiac allografts.

BACKGROUND: The knowledge of long-term changes in the transplanted heart is still incomplete. Among these changes that could potentially have an adverse effect on long-term cardiac function, myocardial fibrosis is of great concern. The aim of this study was to investigate the possible influence of acute or chronic rejection on the development of myocardial fibrosis in cardiac allografts. METHODS: We used light microscopic computer-assisted morphometry of collagen density in 200 right ventricular endomyocardial biopsy specimens taken routinely in 21 heart transplant recipients during a mean follow-up period of 36 months (range, 12 to 84). The 21 patients were divided into two groups according to the presence of chronic rejection assessed by coronary angiography. The first group consisted of 11 patients with no chronic rejection; the second group consisted of 10 patients with chronic rejection. Both groups were divided into four subgroups according to the highest grade of acute rejection reached during the follow-up period (subgroup 1, no acute rejection or grade 1A; subgroup 2, grade 1B; subgroup 3, grades 3A or 3B; subgroup 4, grade 4). Patients of both groups were selected on the basis of similarity patterns in clinical characteristics and mean follow-up time. RESULTS: Patients with no chronic rejection had relatively little variation in serial determinations of myocardial collagen density. During the prechronic and chronic phases in patients with chronic rejection, we found no overall increase in myocardial collagen density. In both the chronic rejection and no chronic rejection groups there was no consistent relationship between myocardial collagen density and severity of acute rejection. In both groups there were occasional strikingly elevated myocardial collagen density values that were well above the other serial determinations. These elevated values of collagen density were mainly a result of scars, the sequellae of prior myocyte damage, because neither interstitial nor perivascular fibrosis could be detected. CONCLUSION: During this long-term follow-up study of endomyocardial biopsy samples, we found no significant association between either acute or chronic rejection and the later increase in myocardial collagen density.

Right ventricular late filling termination time and its relation to interstitial collagen content in early transplanted heart: a color M-mode Doppler digital analysis.

BACKGROUND: Histologic changes in cardiac allografts resulting from fibrosis or acute rejection can modify ventricular diastolic function and ventricular inflow characteristics. These abnormalities may be detected by color M-mode Doppler echocardiography which has been shown to be sensitive in assessing ventricular diastolic function. METHODS: Twelve cardiac allograft recipients were prospectively studied with serial color M-mode and single-gated Doppler echocardiography, as well as with endomyocardial biopsy, with a follow-up of approximately 10 weeks. The myocardial interstitial collagen content as evaluated by videodensitometry was compared with right and left ventricular late filling termination times measured in the absence of a severe episode of rejection. RESULTS: A positive and significant correlation was found between the collagen content and the corresponding right ventricular late filling termination time (r = 0.89, p < 0.0001), but no correlation was found with the left ventricular late filling termination time. Moreover, variations in collagen content and variations in right ventricular late filling termination time were also highly correlated (r = 0.91, p < 0.0001). In allograft recipients who had episodes of rejection of grade 3A or greater, both right and left ventricular late filling termination times were significantly increased during rejection. CONCLUSIONS: Measurements of right ventricular late filling termination time by color M-mode Doppler echocardiography performed in the absence of acute rejection can be use to monitor the evolution of interstitial collagen content in cardiac allografts. The early detection of abnormally prolonged late filling termination time could be followed by endomyocardial biopsy to confirm the histologic changes.

Respective role of humoral factors and blood pressure in aortic remodeling of DOCA hypertensive rats.

Hypertension results in increased thickness and stiffness of large artery walls. The goal of our study was to assess the respective roles of humoral factors such as Ang II, endothelin and blood pressure in these aortic modifications. For this purpose, uninephrectomized rats received DOCA and high salt diet, and when hypertension was installed, they were treated for 5 weeks with either a long-acting calcium antagonist, mibefradil (30 mg/kg/day), an ACE inhibitor, enalapril (3 mg/kg/day), or a mixed ETA and ETB endothelin receptor antagonist, bosentan (100 mg/kg/day). A group of hypertensive rats was left untreated and a sham-operated group of normotensive rats was used for control. At the end of treatment, aortic medial thickness and elastin as well as collagen were evaluated by quantitative morphometry. DOCA-salt hypertensive rats exhibited a marked increase in medial thickness associated with no change in absolute content in extracellular matrix. Elastin relative density decreased in DOCA rats. Enalapril had no effect on arterial pressure. Bosentan decreased slightly (by 12 mm Hg), but not significantly, blood pressure. None of these drugs had an effect on medial thickness suggesting that in DOCA hypertensive rats neither Ang II nor endothelin play a significant role in the remodeling of the aorta. In contrast, mibefradil almost normalized arterial pressure, prevented medial hypertrophy and increased elastin density. Further studies are required in order to assess if this effect is directly linked to the blood pressure decrease or to another mechanism related to the calcium antagonistic property of mibefradil.

Correlation between clinical and histologic patterns of degenerative mitral valve insufficiency: a histomorphometric study of 130 excised segments.

The objectives of this study were to examine quantitatively the histological changes in incompetent degenerative mitral valves obtained at surgery for mitral valve repair, and to determine whether Barlow's disease (BD) and fibroelastic deficiency (FED) can be distinguished by histology. The billowing mitral leaflet syndrome (or Barlow's disease) and FED can be distinguished on the basis of clinical patterns and gross features, but their histologic patterns have not been described. One hundred thirty patients were studied. Thirty-nine (24 males) had BD; 44 (38 males) FED; 15 (7 males) Marfan's syndrome (MS); and 32 patients (25 males) a non-determined degenerative disease. Histological changes of the resected segment of the valve were quantitatively evaluated using scores of severity. A discriminant analysis was performed. The groups defined by the computer were checked for concordance with groups defined by the surgeon. Collagen alterations were found the most severe in MS patients. BD and MS had the most myxoid infiltration. MS and FED patients had the most elastic fiber alterations. No BD in males and only one in females were misclassified by the discriminant procedure into the FED group. Overall, the percentages of correct matchings were 54% in males and 62% in females. When the age of patients and the size of ring were added to histology to determine whether this additional information provided more discrimination, the percentages of correct matchings reached 90% in males and 100% in females. BD and FED are two fairly distinct entities, which can be distinguished by quantitative histology, whereas only modest differences were found in qualitative histology.