Pamela W. Anderson

Design and Methods of the Raloxifene Use for The Heart (RUTH) Study

Raloxifene is a selective estrogen receptor modulator that lowers total and low-density lipoprotein (LDL) cholesterol, reduces the risk of vertebral fracture, and is associated with a reduced incidence of invasive breast cancer in postmenopausal women with osteoporosis. The Raloxifene Use for The Heart (RUTH) trial is designed to determine whether raloxifene 60 mg/day compared with placebo: (1) lowers the risk of the coronary events (coronary death, nonfatal myocardial infarction [MI], or hospitalized acute coronary syndromes other than MI); and (2) reduces the risk of invasive breast cancer in women at risk for a major coronary event. RUTH is a double-blind, placebo-controlled, randomized clinical trial of 10,101 postmenopausal women aged > or =55 years from 26 countries. Women are eligible for randomization if they are postmenopausal and have documented coronary heart disease (CHD), peripheral arterial disease, or multiple risk factors for CHD. Use of estrogen within the previous 6 months is an exclusion factor. The study will be terminated after a minimum of 1,670 participants experience a primary coronary end point. Secondary end points include cardiovascular death, myocardial revascularization, noncoronary arterial revascularization, stroke, all-cause hospitalization, all-cause mortality, all breast cancers, clinical fractures, and venous thromboembolic events, in addition to the individual components of the composite primary coronary end point. RUTH will provide important information about the risk-benefit ratio of raloxifene in preventing acute coronary events and invasive breast cancer, as well as information about the natural history of CHD in women at risk of major coronary events.

Hypertension, the endothelial cell, and the vascular complications of diabetes mellitus.

Hypertension is a major factor that contributes to the development of the vascular complications of diabetes mellitus, which primarily include atherosclerosis, nephropathy, and retinopathy. The mechanism of the pathophysiological effects of hypertension lies at the cellular level in the blood vessel wall, which intimately involves the function and interaction of the endothelial and vascular smooth muscle cells. Both hypertension and diabetes mellitus alter endothelial cell structure and function. In large and medium size vessels and in the kidney, endothelial dysfunction leads to enhanced growth and vasoconstriction of vascular smooth muscle cells and mesangial cells, respectively. These changes in the cells of smooth muscle lineage play a key role in the development of both atherosclerosis and glomerulosclerosis. In diabetic retinopathy, damage and altered growth of retinal capillary endothelial cells is the major pathophysiological insult leading to proliferative lesions of the retina. Thus, the endothelium emerges as a key target organ of damage in diabetes mellitus; this damage is enhanced in the presence of hypertension. An overall approach to the understanding and treatment of diabetes mellitus and its complications will be to elucidate the mechanisms of vascular disease and endothelial cell dysfunction that occur in the setting of hypertension and diabetes.

Angiotensin II causes mesangial cell hypertrophy.

Angiotensin II, a potent vasoconstrictor and known growth factor for vascular smooth muscle cells, has been implicated in the development of glomerulosclerosis. Because mesangial cell growth plays a critical role in the glomerulosclerotic process, the objective of this study was to determine the direct effect of long-term (48-hour) angiotensin II treatment on the growth of cultured murine mesangial cells. Subconfluent, quiescent adult murine mesangial cells were treated for 48 hours with media containing angiotensin II with and without its specific inhibitor losartan. In comparison to cells treated with serum-free medium, cells treated with serum plus insulin demonstrated a significant increase in cell number (1.93 +/- 0.1 times control, p < 0.05), [3H]thymidine incorporation per 10(5) cells (2.29 +/- 0.12 times control, p < 0.05), [3H]leucine incorporation per 10(5) cells (1.81 +/- 0.18 times control, p < 0.05), and total protein content per 10(5) cells (1.65 +/- 0.07 times control, p < 0.05). In contrast, cells treated with angiotensin II (10(-6) M) had no significant increase in cell number (0.84 +/- 0.01 times control) or [3H]thymidine incorporation per 10(5) cells (1.23 +/- 0.12 times control) but demonstrated a significant increase in [3H]leucine incorporation per 10(5) cells (1.61 +/- 0.09 times control) and total protein content per 10(5) cells (1.38 +/- 0.04 times control). Pretreatment with losartan blocked 56% of the angiotensin II-induced increase in [3H]leucine incorporation and 84% of the angiotensin II-induced increase in total protein content.(ABSTRACT TRUNCATED AT 250 WORDS)

Human decidua is a major source of renin.

Plasma prorenin levels are elevated in normal pregnant women. Current evidence suggests renin production by tissues of the uteroplacental unit contribute to this elevation. The purpose of this investigation was to define the source of renin biosynthesis within the human uteroplacental unit and to characterize the renin produced. RNA extraction and Northern blot analysis consistently demonstrated renin mRNA expression in uterine lining both in the pregnant (decidua) and nonpregnant states (endometrium) and in fetal chorion laeve, which is inseparable from the decidua. In contrast, renin mRNA expression was not detected in basal plate and intertwin chorion (which is separate from decidua), amnion, myometrium, or placental villi. The total renin content in decidual homogenates was two- to threefold greater than in endometrial homogenates, and cultured human decidual cells produced significantly more total renin than cultured human endometrial cells, suggesting that pregnancy enhanced renin production by the cells lining the uterus. Immunoblot analysis and [3H]leucine incorporation identified 47,000-mol wt prorenin as the major form of renin produced by cultured human decidual cells. These studies indicate that maternal decidua is the major source of prorenin in the uteroplacental unit.

Baseline characteristics of participants in the Raloxifene Use for The Heart (RUTH) trial

The Raloxifene Use for The Heart (RUTH) trial is a randomized, placebo-controlled, double-blind trial designed to determine whether raloxifene 60 mg/day compared with placebo lowers the risk of coronary events (coronary death, nonfatal myocardial infarction [MI], or hospitalized acute coronary syndromes other than MI) and reduces the risk of invasive breast cancer in women at risk for a major coronary event. Raloxifene is a selective estrogen receptor modulator that improves cardiovascular risk factors, reduces the risk of vertebral fracture, and is associated with a reduced incidence of invasive breast cancer in postmenopausal women with osteoporosis. Between June 1998 and August 2000, 10,101 women were enrolled at 187 sites in 26 countries. Approximately half of the women had documented coronary heart disease (CHD) (n = 5,031); the remainder had multiple CHD risk factors that increased their risk for a CHD event (n = 5,070). The mean age of participants was 68 years (39% were >70 years old), and did not differ between those with documented CHD and those at increased CHD risk. Most women were Caucasian (84%); 60% had a body mass index >/=27 kg/m(2), 46% had diabetes mellitus, 78% had systemic hypertension, and 14% had low-density lipoprotein cholesterol >160 mg/dl. Compared with women at increased CHD risk, women with documented CHD had higher cardiovascular risk scores, a higher prevalence of abnormal electrocardiograms, greater use of cardiovascular medications, were more likely to have had cardiac rehabilitation, and were more likely to have previously used estrogen or oral contraceptives, but had a slightly lower prevalence of CHD risk factors such as smoking, obesity, diabetes mellitus, and systemic hypertension, and had lower serum levels of total and low-density lipoprotein cholesterol. The RUTH cohort is the largest group of postmenopausal women at increased risk of CHD events ever assembled in a clinical trial, and is the first trial designed to determine the effect of a selective estrogen receptor modulator on the risk of CHD events.

A novel potential therapy for diabetic nephropathy and vascular complications: protein kinase C β inhibition

Diabetic nephropathy is one of the most common microvascular complications of diabetes mellitus and the leading cause of end-stage renal disease in developed countries. Current treatment includes glycemic control, blood pressure control (with special emphasis on agents targeting the renin-angiotensin system), a low-protein (0.6 to 0.8 g/kg) diet, and the use of hypolipidemic agents. Although these therapeutic options may slow progression, the burden of disease remains large, and additional therapeutic agents are urgently needed. Ruboxistaurin (LY333531) mesylate is a bisindolylmaleimide that shows a high degree of specificity within the protein kinase C (PKC) gene family for inhibiting PKC beta isoforms. In animal models of diabetes, including the streptozotocin (STZ) rat, Lepr(db)/Lepr(db) mouse, and STZ-Ren 2 rat models, ruboxistaurin normalized glomerular hyperfiltration, decreased urinary albumin excretion, and reduced glomerular transforming growth factor-beta1 and extracellular matrix protein production. As a result, improvements were noted in mesangial expansion, glomerulosclerosis, tubulointerstitial fibrosis, and renal function. Other studies using less specific probes of PKC activity also have shown an important role for PKC in the development of diabetic nephropathy and a close relationship to pathways believed to be important in its pathogenesis. Inhibition of PKC beta, a common signaling molecule in diabetes-related renal and vascular injury, holds promise as a novel strategy to improve microvascular and macrovascular outcomes in diabetes. Such therapies are needed to reduce the occurrence of devastating diabetic complications.

How the diabetic eye loses vision

The objective is to review the most common causes of vision loss in patients with diabetes with the goal of better managing patients with diabetic eye disease. In this review, the causes of vision loss, and the clinical evaluation and management of diabetic retinopathy (DR) and diabetic macular edema (DME) are outlined. Patients with diabetes mellitus have an increased risk of vision loss and blindness. In patients with diabetes, the primary mechanism responsible for vision loss is centrally involved DME or clinically significant macular edema (CSME), defined as vascular leakage resulting in fluid accumulation that affects the center of the macula. DR and DME are thought to result from the effects of excessive blood glucose on the vessels that produces microvascular damage. The progression of DR can be slowed by intensive glycemic and blood pressure control. Severe visual loss from proliferative DR and moderate visual loss from DME can be reduced by laser photocoagulation. DR and DME are diagnosed on dilated retinal examination and confirmed with diagnostic testing. Many experts and associations recommend that patients with diabetes have an yearly, thorough, dilated eye exam. This manuscript describes the case history of a patient with diabetes and vision loss.

Post hoc analysis of data from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial on the effects of three years of raloxifene treatment on glycemic control and cardiovascular disease risk factors in women with and without type 2 diabetes.

BACKGROUND The long-term effects of the selective estrogen-receptor modulator raloxifene hydrochloride on glycemic control and markers of cardiovascular disease risk in postmenopausal women with type 2 diabetes mellitus are unknown. OBJECTIVE The aim of this analysis was to compare the effects of 3-year treatment with raloxifene 60 mg/d versus placebo on glycemic control and markers of cardiovascular disease risk in osteoporotic postmenopausal women with and without type 2 diabetes. METHODS In this analysis, we included women from the Multiple Outcomes of Raloxifene Evaluation trial (a multicenter, double-masked trial) who were randomized to receive raloxifene 60 mg/d (n = 2557) or placebo (n = 2576). Baseline and 36-month fasting plasma glucose (FPG) and total cholesterol (TC) were measured for all participants. Glycated hemoglobin (HbA1c), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), apolipoprotein (apo) A-I, apo B, and fibrinogen were assessed in approximately 1800 participants from selected larger sites. RESULTS At baseline, 202 of all 5133 women (3.9%) had type 2 diabetes. Of the approximately 1800 women who were assessed for HbA1c, LDL-C, TGs, apo A-I, apo B, and fibrinogen, 70 (3.9%) had type 2 diabetes at baseline. Compared with placebo, raloxifene did not significantly affect HbA1c, FPG, HDL-C, or TGs in women with or without diabetes. Raloxifene produced statistically significant reductions in TC, LDL-C, and fibrinogen both in women with diabetes (all P < or = 0.004) and without diabetes (all P < 0.001). Raloxifene significantly increased apo A-I (P < 0.001) and reduced apo B (P < 0.001) in women without diabetes. In the raloxifene-treated group, body weight increased by a mean 0.31 kg (P < 0.001) in women without diabetes. CONCLUSIONS In osteoporotic postmenopausal women with or without type 2 diabetes, raloxifene 60 mg/d did not affect glycemic control and had favorable effects on TC, LDL-C, and fibrinogen levels.

Extrarenal renin-secreting tumors : insights into hypertension and ovarian renin production

Although renin-secreting tumors are rare, they must be considered in the differential diagnosis of hypertension associated with hypokalemia, which occurs commonly in the hypertensive population. The finding of an ovarian renin-secreting tumor emphasizes the potential importance of the ovary as an extrarenal source of renin; the local ovarian renin-angiotensin system may play a key role in reproductive function by regulating vascular reactivity, local blood flow, steroidogenesis and other physiologic effects. In the illustrative case presented, a renin-secreting ovarian leiomyosarcoma was obtained from a women who presented with hypertension and hypokalemia. Plasma prorenin levels were markedly elevated. Tumor excision was quickly followed by a fall in prorenin levels and tumor recurrence was accompanied by an increase in prorenin levels. Active renin concentration in the tumor homogenates was similar to that found in kidney homogenates while the tissue prorenin concentration was approximately 20 times that found in kidney tissue. When cultured for up to 4 weeks, ovarian tumor cells secreted greater than 95% prorenin. Immunoblot analysis demonstrated that tumor renin had a molecular weight of 47,000, similar to that of human recombinant prorenin. Immunohistochemical staining of tumor tissue with antibodies against human renal renin at the electron microscopic level demonstrated the presence of renin primarily in membrane-bound vesicles and rarely in dense-core secretory granules. These findings suggest that prorenin in this ovarian tumor was secreted by the constitutive pathway, which is mediated by these amorphous vesicles.

The Potential of SERMs for Reducing the Risk of Coronary Heart Disease

Selective estrogen receptor modulators (SERMs) represent a growing class of compounds that act as either estrogen receptor agonists or antagonists in a tissue-selective manner. Preclinical and clinical studies have shown that estrogen has favorable effects on serum lipids and might affect processes at the blood vessel wall to inhibit atherosclerosis. SERMs with the appropriate selectivity profile offer the opportunity to dissociate these favorable cardiovascular effects of estrogen from its unfavorable stimulatory effects on the breast and uterus. This article reviews the data from both animal and human studies that document the cardiovascular effects of SERMs and discusses the clinical implications of these results.