Glycaemic control and cardiovascular disease: is there a light at the end of the tunnel?

Patients with type 2 diabetes mellitus (T2DM) have been shown by numerous studies to have a substantially increased risk of cardiovascular disease (CVD), including coronary artery disease, ischemic stroke and heart failure, even after adjusting for other known risk factors.1,2 First reported in the Framingham studies and followed by additional data including a meta-analysis of 102 prospective studies, diabetes confers about a two-fold excess risk for coronary heart disease and ischemic stroke in both men and women, and about a 2-fold and 5-fold excess risk of heart failure in diabetic men and women.1-3 However, there is still a debate as to whether improved glycaemic control reduces the excessive CVD risk of T2DM patients. Large randomised controlled trials (RCTs), aimed at determining the effect of anti-hyperglycaemic agents on CVD, provide a handful of important data, albeit not consistent answers. Nevertheless, looking further into these RCTs provides new perspective on the complex interplay between diabetes treatment and CVD.

Sex differences in risk factors for coronary artery disease and stroke in men and women aged 45-65†years.

BACKGROUND: Coronary artery disease (CAD) and stroke both result from atherosclerosis. Risk factor profiles for CAD and stroke have been reported to differ between middle-aged men and women. OBJECTIVE: To compare, for men and women aged 45-65 years, between risk factor profiles for CAD and stroke. METHODS: This is a retrospective study based on the medical records of 179 women and 270 men diagnosed with CAD, and 114 women and 190 men diagnosed with stroke, hospitalised in one of two medical centres in Jerusalem. We assessed and compared the number of metabolic risk factors (diabetes, hypertension and hypercholesterolaemia) presenting among men and women between the CAD and stroke groups. RESULTS: Among patients with CAD, significantly more women than men presented with diabetes, hypertension and hypercholesterolaemia. In contrast, no statistically significant differences were observed between genders in the prevalence of diabetes, hypertension and hypercholesterolaemia among the stroke patients. Hypertension was more prevalent in both men and women among stroke patients than CAD patients. In the stroke group, 29.1% of the women compared with 14.2% of the men presented with the three metabolic risk factors investigated. CONCLUSIONS: In a middle-aged population, CAD risk factor profiles differed between genders while stroke risk factor profiles did not.

Low dose warfarin treatment for calcinosis in patients with systemic sclerosis.

OBJECTIVE: To evaluate the effect of low doses of warfarin in patients with systemic sclerosis with disseminated subcutaneous calcinosis. METHODS: Three patients with disseminated subcutaneous calcinosis were treated with low doses of warfarin for 1 year. Subcutaneous calcinotic lesions, coagulation blood parameters, and the tendency for bleeding were followed up during the year. RESULTS: Two of the patients, who had newly diagnosed, diffuse, and relatively small calcinotic lesions, responded to warfarin treatment, with complete resolution of the calcinosis. The other patient, with larger and longer standing calcinotic lesions, did not respond to warfarin treatment. None of the three patients showed a prolongation of prothrombin time or partial thromboplastin time, nor did any have an increased tendency for bleeding. CONCLUSIONS: Low dose warfarin may serve as an effective treatment for calcinosis in a selected group of patients who have small and relatively new onset calcinosis. This treatment does not prolong the coagulation of blood and there is no increased tendency for bleeding.

Reduction of jaw opening (trismus) in giant cell arteritis.

OBJECTIVE: To study the prevalence and the clinical characterisation of jaw problems in patients with giant cell arteritis (GCA). METHODS: the prevalence of such symptoms in patients with GCA was evaluated by performing a retrospective analysis of all patients with GCA and polymyalgia rheumatica who were diagnosed during admission to Hadassah University Hospital. Ten patients reported previously in the literature were also evaluated. RESULTS: Six patients out of 88 (6.8%) had complaints of reduction in jaw opening. These six patients seemed to have a much more abrupt onset of disease with shorter duration until diagnosis, higher prevalence of eye involvement (50% v 27%), and a higher rate of positive pathology (100%). CONCLUSIONS: Reduction in jaw opening in the appropriate setting may indicate the presence of GCA. This sign should not be overlooked in the presence of the claudication sign as it seems to reflect more severe GCA disease.

Troponin T elevation in lobar lung disease.

Two patients with a rise in cardiac troponin T (cTnT) concentrations during the course of lobar pneumonia, without any evidence of acute coronary syndrome or renal failure, are presented. The increase in cTnT concentration is considered a highly sensitive marker of cardiac injury, although it may also rise in other conditions and as a result of lobar pneumonia. Thus, this effect should be considered when the possibility of acute coronary syndrome in such patients is addressed.

Gender gap in coronary artery disease: comparison of the extent, severity and risk factors in men and women aged 45-65 years.

This retrospective study aimed to characterize coronary artery disease (CAD) and its risk factors among relatively young women, as compared to men in a similar age group. Confirmed cases of CAD were compared regarding their medical background, performance and outcome of coronary artery procedures, physical profile and lifestyle information. The study population included 179 women and 270 men aged 45-65 years who were hospitalized during the study period 1990-1995 in the Hadassah Medical Centers. Significantly more women presented with histories of prior myocardial infarction and a higher number of vessels occluded by 80% or more and required percutaneous transluminal coronary angioplasty for 3 or more arteries, and the women had a higher incidence of risk factors such as diabetes, hypertension and hypercholesterolemia than their male counterparts.

Association of the MIC-A gene and HLA-B51 with Behçet's disease in Arabs and non-Ashkenazi Jews in Israel.

BACKGROUND: Behçet's disease is known to be strongly associated with HLA-B51 in many different ethnic groups. Recently, it was suggested that MIC-A (major histocompatibility complex class I related gene A) is the pathogenic gene after strong association was found between the MIC-A A6 allele of the transmembrane region and the disease in Japanese and Greek patients, although in Greek patients this association was found to be due to linkage disequilibrium with HLA-B51. OBJECTIVES: To investigate microsatellite polymorphism in Arab and non-Ashkenazi Jewish (NAJ) patients in Israel, to determine whether this association occurs in these groups with Behçet's disease, and elucidate the associated HLA allele of the disease. METHODS: Forty four Israeli patients with Behçet's disease, including 20 Arabs and 24 NAJ, and 130 ethnically matched healthy controls were examined for MIC-A microsatellite polymorphism of the transmembrane region using polymerase chain reaction, autoradiography, and sequence analysis. RESULTS: The MIC-A A6 allele was significantly more frequent in the Arab patient group (19/20 (95%)) than in healthy Arab controls (25/42 (60%)) (p(corr)=0.015, OR=12.92), but not in the NAJ patients (16/24 (67%)) compared with NAJ healthy controls (48 /88 (55%)) (p(corr)=1.02, OR=1.667). In stratification analysis of the Arab subgroup, on the confounding effect of MIC-A A6 on HLA-B51 association and vice versa, Behçet's disease was distinctly associated only with HLA-B51. CONCLUSIONS: These results imply strong association between the MIC-A A6 allele and the disease in Israeli Arabs, but not in Israeli NAJ patients. The stratification analysis indicates that this association results secondarily from a strong linkage disequilibrium with HLA-B51, and the real disease susceptibility gene which plays a part in the development of Behçet's disease is most probably the HLA-B51 allele itself.

Reduced body fat and increased hepatic lipid synthesis in mice bearing interleukin-6-secreting tumor.

Chronic secretion of interleukin-6 (IL-6) in mice causes metabolic alteration in the liver, leading to increased synthesis of hepatic cholesterol and fatty acids (FA). Mice were injected with allogeneic tumor cells transduced with the murine IL-6 gene. During the 3 wk after tumor inoculation, elevated serum IL-6 levels were associated with increased spleen and liver weight. Histological examination of sections from the liver showed increased hepatocyte proliferation, resulting in liver enlargement. Body composition analysis revealed that IL-6 caused a significant loss in fat tissue without affecting lean body mass and water content. Hepatic de novo synthesis of FA and cholesterol, as measured by (3)H(2)O incorporation, was three to five times as high in mice secreting IL-6 (IL-6 mice) as in pair-fed mice bearing nonsecreting tumors. This increase in FA and cholesterol synthesis is sufficient to maintain hepatic triglyceride secretion at levels comparable with those of pair-fed mice bearing nonsecreting tumors and, presumably, is the main source of cholesterol and FA-phospholipids necessary for hepatocyte proliferation.

Molecular properties and involvement of heparanase in cancer progression and mammary gland morphogenesis.

Tumor spread involves degradation of various components of the extracellular matrix and blood vessel wall. Among these is heparan sulfate proteoglycan, which plays a key role in the self-assembly, insolubility and barrier properties of basement membranes and extracellular matrices. Expression of an endoglycosidase (heparanase) which degrades heparan sulfate correlates with the metastatic potential of tumor cells, and treatment with heparanase inhibitors markedly reduces the incidence of metastasis in experimental animals. Heparin-binding angiogenic proteins are stored as a complex with heparan sulfate in the microenvironment of tumors. These proteins are released and can induce new capillary growth when heparan sulfate is degraded by heparanase. Here, we describe the molecular properties, expression and involvement in tumor progression of a human heparanase. The enzyme is synthesized as a latent approximately 65 kDa protein that is processed at the N-terminus into a highly active approximately 50 kDa form. The heparanase mRNA and protein are preferentially expressed in metastatic human cell lines and in tumor biopsy specimens, including breast carcinoma. Overexpression of the heparanase cDNA in low-metastatic tumor cells conferred a high metastatic potential in experimental animals, resulting in an increased rate of mortality. The heparanase enzyme also released ECM-resident bFGF in vitro, and its overexpression elicited an angiogenic response in vivo. Heparanase may thus facilitate both tumor cell invasion and neovascularization, two critical steps in tumor progression. Mammary glands of transgenic mice overexpressing the heparanase enzyme exhibit precocious branching of ducts and alveolar development, suggesting that the enzyme promotes normal morphogenesis and possibly pre-malignant changes in the mammary gland.

Molecular properties and involvement of heparanase in cancer progression and normal development.

Heparan sulfate proteoglycans (HSPGs) play a key role in the self-assembly, insolubility and barrier properties of basement membranes and extracellular matrices. Hence, cleavage of heparan sulfate (HS) affects the integrity and functional state of tissues and thereby fundamental normal and pathological phenomena involving cell migration and response to changes in the extracellular microenvironment. Here, we describe the molecular properties, expression and function of a human heparanase, degrading HS at specific intrachain sites. The enzyme is synthesized as a latent approximately 65 kDa protein that is processed at the N-terminus into a highly active approximately 50 kDa form. The heparanase mRNA and protein are preferentially expressed in metastatic cell lines and human tumor tissues. Overexpression of the heparanase cDNA in low-metastatic tumor cells conferred a high metastatic potential in experimental animals, resulting in an increased rate of mortality. The heparanase enzyme also releases ECM-resident angiogenic factors in vitro and its overexpression induces an angiogenic response in vivo. Heparanase may thus facilitate both tumor cell invasion and neovascularization, both critical steps in cancer progression. The enzyme is also involved in cell migration associated with inflammation and autoimmunity. The unexpected identification of a single predominant functional heparanase suggests that the enzyme is a promising target for drug development. In fact, treatment with heparanase inhibitors markedly reduces tumor growth, metastasis and autoimmune disorders in animal models. Studies are underway to elucidate the involvement of heparanase in normal processes such as implantation, embryonic development, morphogenesis, tissue repair, inflammation and HSPG turnover. Heparanase is the first functional mammalian HS-degrading enzyme that has been cloned, expressed and characterized. This may lead to identification and cloning of other glycosaminoglycan degrading enzymes, toward a better understanding of their involvement and significance in normal and pathological processes.

Transcatheter embolization of renal artery aneurysm in Behçet's disease.

A 20-year-old man with Behçet's disease presented with a ruptured renal artery aneurysm. This patient had previously had aneurysms of the coronary arteries and coronary vein thrombosis that were treated with immunosuppression. A selective transcatheter embolization of the renal artery branch was done successfully and treatment with corticosteroids and methotrexate was added. Presented here is a rare complication of Behçet's disease, with discussion on the pathophysiology, differential diagnosis, and the advantages and disadvantages of the angiographic treatment. This paper is supplemented with a comprehensive review of the literature.

Unusual presentation of familial Mediterranean fever: role of genetic diagnosis.

OBJECTIVE: To describe the role of molecular analysis in the diagnosis of an unusual presentation of familial Mediterranean fever (FMF). CASE REPORT: Two patients presenting with prolonged fever without signs and symptoms of serositis are described. FMF was diagnosed by genetic analysis, which disclosed that both patients were homozygous for the M694V mutation of the Mediterranean fever (MEFV) gene. CONCLUSION: Molecular analysis of FMF should complement the investigation of patients with fever of unknown origin. This test enables a definite diagnosis of the disease and may promote the diagnosis and treatment of patients with an unusual or incomplete clinical picture of FMF.

The influence of a transmucosal cholinergic agonist on pharyngeal muscle activity.

STUDY OBJECTIVE: To assess the effect of high local oral nicotine administration on the upper airway (UA) of normal males during wakefulness. DESIGN: Nonrandomized study. SETTING: Brigham & Women's Hospital General Clinical Research Center. PARTICIPANTS: Two groups of 13 and 12 normal male subjects were evaluated. INTERVENTIONS: A "Fast acting" or "Intermediate acting" 2 mg transmucosal nicotine patch was attached to an upper molar tooth of study participants during wakefulness. MEASUREMENTS: All data were collected prior to, and at several time points after, patch placement. Data measured included serum nicotine levels, genioglossal EMG, and pharyngeal resistance during basal breathing as well as the UA muscle response and UA collapsibility during negative UA pressure pulses. RESULTS: None of the variables measured showed a statistically significant change with either nicotine patch despite a significant rise (p<0.05) in nicotine serum levels post patch placement in both groups. In several subjects, muscle activity and responsiveness to negative pressure increased after application of both patches and returned to near baseline levels at the last time point measured, a response consistent with the time course of nicotine release in both patches. CONCLUSIONS: Oral nicotine administration failed to consistently increase GG muscle activation which may be a problem of local bioavailability of nicotine in the muscle.

Efficacy and safety of cerivastatin for type 2 diabetes and hypercholesterolaemia. Hyperlipidaemia in Diabetes Mellitus investigators.

BACKGROUND: The prevalence of coronary heart disease (CHD) is markedly increased in diabetic patients compared with non-diabetic individuals, and its prognosis is less good. Serum total and low-density lipoprotein (LDL) cholesterol concentrations have been shown to be powerful predictors of CHD morbidity and mortality in patients with type 2 diabetes. The available data suggest that the target cholesterol concentration in patients with diabetes should be similar to that in non-diabetic individuals with a previous myocardial infarction. This led us to investigate the efficacy, tolerability and safety of a new, highly potent statin, cerivastatin, in diabetic hyperlipidaemia. METHODS: This was a multinational, multicentre, double-blind, randomized study in type 2 diabetic patients with hypercholesterolaemia (LDL cholesterol >3.35 mmol/l; triglycerides <4.56 mmol/l). Eligible patients were randomly assigned to groups to receive cerivastatin 0.1 mg or 0.3 mg or placebo in a ratio of 2:2:1 for 12 weeks. They were monitored in the clinic every 4 weeks. RESULTS: Of the 453 patients screened, 265 were allocated to the study groups. Fifty-one received placebo and 107 patients were assigned to each active treatment group (0.1 mg and 0.3 mg cerivastatin). At the close of the study, total cholesterol had decreased by 13.7% and 23.5%, LDL cholesterol decreased by 20.2% and 33.8%, and triglyceride concentrations decreased by 3.9% and 12.3% in the cerivastatin 0.1 mg and 0.3 mg groups, respectively. There was no significant difference between the groups in haemoglobin A1c, adverse events or increases in liver and muscle enzymes during the study period. CONCLUSIONS: Hypercholesterolaemic patients with type 2 diabetes had a significant reduction in LDL cholesterol and total cholesterol concentrations after cerivastatin treatment once daily. The dose of 0.3 mg cerivastatin is effective in diabetic hypercholesterolaemia, with co-reduction of triglyceride concentrations. The effect of cerivastatin on coronary morbidity and mortality is currently being investigated in clinical trials.

Lipoprotein lipase expression exclusively in liver. A mouse model for metabolism in the neonatal period and during cachexia.

Lipoprotein lipase (LPL), the rate-limiting enzyme in triglyceride hydrolysis, is normally not expressed in the liver of adult humans and animals. However, liver LPL is found in the perinatal period, and in adults it can be induced by cytokines. To study the metabolic consequences of liver LPL expression, transgenic mice producing human LPL specifically in the liver were generated and crossed onto the LPL knockout (LPL0) background. LPL expression exclusively in liver rescued LPL0 mice from neonatal death. The mice developed a severe cachexia during high fat suckling, but caught up in weight after switching to a chow diet. At 18 h of age, compared with LPL0 mice, liver-only LPL-expressing mice had equally elevated triglycerides (10,700 vs. 14,800 mg/dl, P = NS), increased plasma ketones (4.3 vs. 1.7 mg/dl, P < 0.05) and glucose (28 vs. 15 mg/dl, P < 0.05), and excessive amounts of intracellular liver lipid droplets. Adult mice expressing LPL exclusively in liver had slower VLDL turnover than wild-type mice, but greater VLDL mass clearance, increased VLDL triglyceride production, and three- to fourfold more plasma ketones. In summary, it appears that liver LPL shunts circulating triglycerides to the liver, which results in a futile cycle of enhanced VLDL production and increased ketone production, and subsequently spares glucose. This may be important to sustain brain and muscle function at times of metabolic stress with limited glucose availability.

Interleukin-6 secretion in mice is associated with reduced glucose-6-phosphatase and liver glycogen levels.

Mice bearing interleukin-6 (IL-6)-secreting tumor were used to study the chronic effect of IL-6 on carbohydrate metabolism. Mice were injected with allogeneic tumor cells transduced with the murine IL-6 gene. Serum IL-6 levels were correlated exponentially with tumor weight. Secretion of IL-6 from the developed tumors was associated with decreased food consumption, reduced body weight, and reduced blood glucose levels. Insulin levels did not change, and 2-deoxyglucose uptake was not affected in most tissues examined. A significant increase of 2-deoxyglucose uptake was measured in the liver. Glycogen content in the liver determined 0, 6, 12, and 18 days after tumor inoculation was 42, 23, 12, and 3 mg/g, respectively. The activity of phosphoenolpyruvate carboxykinase was not affected. The activity of glucose-6-phosphatase (G-6-Phase) determined 6, 12, and 18 days after tumor injection was 84, 70, and 50% of G-6-Pase activity in pair-fed mice bearing nonsecreting tumors, respectively. G-6-Pase mRNA levels were markedly reduced due to inhibition of G-6-Pase gene transcriptional rate.

Resistance to activated protein C: arterial thrombosis associated with autoimmune features.

A 27 year old woman presented with recurrent cerebrovascular strokes in the setting of an ill defined auto-immune disease responsive to corticosteroid therapy. Investigation for a hypercoagulable state revealed activated protein C resistance in the absence of protein C, protein S, or antithrombin III deficiency or anticardiolipin antibodies. Her parents and sibling did not demonstrate APC resistance. This case suggests that activated protein C resistance may be associated with arterial as well as venous thrombotic events and implies that resistance to activated protein C should also be considered in the evaluation of young adults with strokes.

Tumor necrosis factor inhibits the transcriptional rate of glucose-6-phosphatase in vivo and in vitro.

Recombinant human tumor necrosis factor-alpha (TNF) injection in mice was associated with a reduced blood glucose level, already manifest 6 hours following cytokine administration. Insulin levels were not affected. Glycogen content was decreased in a dose-dependent and time-response manner. The activity of glucose-6-phosphatase (G6Pase) was already reduced 6 hours after TNF injection and was sustained 12 hours afterward. Phosphoenolpyruvate carboxykinase (PEPCK) activity was not affected initially (6 hours after injection), but a 50% reduction was observed 12 hours following cytokine administration compared with levels in fasting controls. Both liver G6Pase and PEPCK mRNAs were markedly reduced due to an inhibition of the transcriptional rate. A direct inhibitory effect of TNF on G6Pase promoter activity was demonstrated using HuH-7 cells transiently transfected with G6Pase promoter, fused to a reporter gene.

Co-regulation of apo A-I, apo C-III and apo A-IV gene expression in human intestinal biopsies.

The apo A-I gene is expressed in the liver and small intestine. In order to study the role of human intestinal transcription of the apo A-I gene in determining plasma high-density lipoprotein, (HDL)-cholesterol and apo lipoprotein (apo) A-I concentrations, the authors measured the relative mRNA levels of apo A-I in human intestinal biopsies. Biopsies were taken from 50 fasting subjects (25 males and 25 females). At the same time blood was taken for lipid and lipoprotein analysis. Plasma HDL-cholesterol correlated linearly with plasma apo A-I protein. No correlation could be demonstrated between intestinal apo A-I mRNA and plasma apo A-I or HDL-cholesterol levels. The apo A-I gene resides in an apolipoprotein cluster with the apo C-III and apo A-IV genes. To assess whether there is a coordinated expression of this locus, Northern blot analysis of intestinal RNA was performed. The authors have demonstrated that under fasting conditions mRNA levels of apo A-I, C-III and A-IV are co-regulated in the intestine.