Cardiorenal metabolic syndrome and diabetic cognopathy.

The prevalence of the cardiorenal metabolic syndrome (CRS) is increasing in parallel with obesity, type 2 diabetes mellitus, Alzheimer's disease, and other forms of dementia. Along with metabolic, inflammatory, and immunological abnormalities, there is maladaptive structural remodeling of the heart, kidney, and brain. The term 'diabetic cognopathy' (DC) may be used when discussing functional and structural changes in the brain of the diabetic patient. DC likely represents an advanced form of these changes in the brain that evolve with increasing duration of the CRS and subsequent clinical diabetes. We posit that DC develops due to a convergence of aging, genetic and lifestyle abnormalities (overnutrition and lack of exercise), which result in multiple injurious metabolic and immunologic toxicities such as dysfunctional immune responses, oxidative stress, inflammation, insulin resistance, and dysglycemia (systemically and in the brain). These converging abnormalities may lead to endothelial blood-brain barrier tight junction/adherens junction (TJ/AJ) complex remodeling and microglia activation, which may result in neurodegeneration, impaired cognition, and dementia. Herein, we describe the brain ultrastructural changes evolving from a normal state to maladaptive remodeling in rodent models of CRS including microglia activation/polarization and attenuation and/or loss of the TJ/AJ complexes, pericytes and astrocytes of the neurovascular unit. Further, we discuss the potential relationship between these structural changes and the development of DC, potential therapeutic strategies, and future directions.

How early should blood pressure control be achieved for optimal cardiovascular outcomes?

As a consequence of the aging population and the increasing prevalence rates for conditions such as type 2 diabetes and chronic kidney disease (CKD), management of hypertension will be focusing more and more on the high-risk patient. Clinical practice guidelines for managing hypertension in the United States recommend a target blood pressure (BP) <130/80 mm Hg in patients with diabetes or CKD, notably lower than the 140/90-mm Hg threshold for the general hypertensive population. However, the optimal timeframe from initiation of antihypertensive therapy to attaining these levels of BP control and influencing cardiovascular outcomes is not as well defined. Overall, a series of landmark BP intervention trials in patients with hypertension and additional cardiovascular risk factors collectively support that achieving prompt BP control, ideally within 1-3 months, translates into improved cardiovascular outcomes. Although the consistency of the findings is encouraging, the strength of this conclusion is limited by the available data, which were derived from studies not designed to determine the definition or benefits of early BP reduction. In several of these studies, using a treatment approach with initial monotherapy or combination therapy has clearly demonstrated pronounced BP lowering and high BP control rates within an intensive timeframe of 3-6 months of therapy. Although these studies were not conducted exclusively in high-risk patients, subgroup analyses have demonstrated that the observed outcomes in the overall study populations apply to the diabetic and CKD subsets.

Metabolic risk factors and renal disease.

Accumulating evidence supports that components of the metabolic syndrome coexist with both albuminuria and chronic kidney disease (CKD). The article by Tomaszewski et al. indicates that this interrelation exists in young obese men before overt renal or cardiovascular disease and also suggests that early treatment of hypertension is especially compelling to prevent the evolution of renal hyperfiltration to CKD.

Role of oral anti-diabetic agents in modifying cardiovascular risk factors.

Patients with type 2 diabetes have an increased risk for cardiovascular disease (CVD) and it accounts for up to 80% of excess deaths in these patients. It has been recognized that type 2 diabetes is associated with an increased prevalence of CVD risk factors, including hypertension, dyslipidemia, microalbuminuria, and altered hemostasis. The benefit of cardiovascular protection can only be partially explained by controlling hyperglycemia. Some of the oral agents used to treat hyperglycemia significantly modify other cardiovascular risk factors. This article will review oral agents used to treat type 2 diabetes and their effects on modifying CVD risk factors.

Clinical review 145: Pleiotropic effects of statins: lipid reduction and beyond.

There is accumulating evidence that statins have beneficial effects that are independent of their classical actions on lipoproteins. These effects include reductions in inflammation in the vasculature, kidney, and bone. Potential beneficial effects of these agents include enhancement of nitric oxide production in vasculature and the kidney. These agents appear to reduce bone fractures and may improve insulin sensitivity and reduce the likelihood of persons progressing from impaired glucose tolerance to type II diabetes. Potential beneficial pleiotropic effects of statins are covered in this review.

Hydrocortisone modulates the effect of estradiol on endothelial nitric oxide synthase expression in human endothelial cells.

The interaction between hydrocortisone and estradiol on the regulation of endothelial nitric oxide synthase (eNOS) expression was investigated in human umbilical vein endothelial cells (HUVECs). Following incubation in medium containing dextran-coated-charcoal-stripped serum (DCC-stripped medium) for 4 days, incubation of HUVECs with 0.1 nM estradiol for 24 hr in the absence of hydrocortisone increased levels of eNOS mRNA measured by ribonuclease protection assay above control (0 nM estradiol). 2 microM hydrocortisone applied for 24 hr preceding and during estradiol application inhibited the estradiol-elicited increase in eNOS mRNA levels, reducing mRNA levels from 134% +/- 14% of control to 85% +/- 5% of control. Significant (ANOVA, p<0.01) reductions of estradiol-mediated increases of mRNA levels occurred over a range of hydrocortisone concentrations (10 nM, p<0.05; 2 microM, p<0.05; n=3-12). In the presence of 2 microM hydrocortisone, 10 nM estradiol significantly reduced eNOS mRNA levels to 59% +/- 3% of control. The ability of hydrocortisone to block or reverse the estradiol-mediated increase in eNOS mRNA levels may provide a link between elevated hydrocortisone levels and decreased NO production, potentially contributing to the development of hypertension and cardiovascular disease in vivo and antagonizing cardioprotective effects of estrogens.

Influence of ovariectomy on ventricular myocyte contraction in simulated diabetes.

We studied the effect of ovariectomy (OVX) on cardiac contraction in myocytes maintained under a 'diabetes-simulated high-glucose' environment. Female rats were ovariectomized or sham operated (SHAM) and kept for 6 weeks. Isolated myocytes were maintained in a diabetes-simulated high [glucose] medium (HG; 25.5 mM) for 24 h before mechanical properties were measured. Contractile indices analyzed included peak shortening (PS), time to PS (TPS), time to 90% relengthening (TR90), maximal velocity of shortening and relengthening (+/- dL/dt), intracellular Ca2+ fura-2 fluorescence intensity and decay rate (tau). Nitric oxide synthase (NOS) activity was also evaluated. OVX myocytes displayed a longer TR(90), slower +/- dL/dt, lower fluorescence intensity and higher tau (slower decay rate) when compared to SHAM myocytes. In the SHAM group, HG exerted diabetes-like contractile dysfunctions, including depressed PS, prolonged TR90, reduced fluorescence intensity, higher tau and enhanced NOS activity when compared to myocytes maintained in low [glucose] medium (5.5 mM). Interestingly, the HG- induced mechanical alterations were significantly exaggerated (TPS, TR90 and tau), reversed (PS and NOS) or lost (+/- dL/dt and fluorescence intensity) in the OVX group. These data suggest that ovarian hormones play a role in the regulation of cardiac contractile function, and may have potentially protective effects against diabetes-associated cardiac dysfunction.

Role of PI3-kinase in isoproterenol and IGF-1 induced ecNOS activity.

Phosphatidylinositol 3-kinase (PI3-K) has been shown to mediate insulin and insulin-like growth factor-1 (IGF-1)-induced nitric oxide (NO) generation and, thus, vascular tone. A role for PI3-K in G-protein-coupled receptor signal transduction has been reported. As beta (beta2)-adrenergic vascular actions are partly dependent on NO, we have investigated the role of PI3-K in isoproterenol (Iso) and IGF-1 induced endothelial NO synthase (ecNOS) activity in rat aortic endothelial cells (RAEC). Cell lysates of RAEC, exposed to Iso (10 micromol/L) for 5 min and 6 h, and to IGF-1 (100 nM) for 10 min and 6 h, or pretreated with PI3-K inhibitor Wortmannin (WT), were used for measuring PI3-K activity, p85kDa regulatory protein, and citrulline production. Results show that Iso and IGF-1 increased a p85 subunit and citrulline production, and also enhanced 32P incorporation into PIP3. Pretreatment with WT inhibited Iso-stimulated ecNOS, as well as, PI3-K activity. Iso enhanced association of ecNOS with the triton X-100-insoluble fraction of RAEC. These data indicate that the endothelial cell PI3-K pathway mediates, in part, the release of NO and subsequent vasorelaxation in response to this beta-agonist, as well as, IGF-1.

The effect of antihypertensive drugs on vascular compliance.

Measurement of vascular compliance has assumed increasing importance as a marker of early disease of the vascular wall, a predictor of future vascular disease, and a way to monitor the effects of vasoactive agents on arterial wall stiffness. Vascular compliance can be estimated by several methods: measurement of the pulse pressure, or pulse pressure-stroke volume ratio; analysis of the systolic pulse wave augmentation index and the diastolic pulse wave contour; ultrasonic echo-tracking; and MRI. Because few comparative studies have been done, the physiologic significance of the measures of compliance obtained by each method is uncertain. Antihypertensive drugs may improve vascular compliance by reducing blood pressure, relaxing vascular smooth muscle, or promoting long-term effects on vascular smooth muscle and cardiomyocyte growth and remodeling. Angiotensin converting enzyme (ACE) inhibitors have been reported to improve vascular compliance in nearly all studies, suggesting a beneficial class effect independent of blood pressure reduction. Favorable changes in the vascular wall-lumen ratio of small vessels from subcutaneous gluteal biopsy specimens after treatment with ACE inhibitors and the persistence of improved vascular compliance after withdrawal of therapy indicate that these agents may produce long-term vascular remodeling. Although few studies have been done, angiotensin II receptor antagonists improve vascular compliance, possibly by blocking angiotensin II-mediated cell proliferation and increasing apoptosis via unopposed AT1 receptor stimulation. In contrast, calcium antagonists and beta-blockers have variable effects on vascular compliance, although beta-blockers with intrinsic sympathomimetic activity improve vascular compliance. Diuretics have little effect on vascular compliance beyond their blood pressure-lowering actions, except for spironolactone, which by improving vascular compliance may have contributed to the reduction in heart failure mortality seen in the Randomized Aldactone Evaluation Study.

Gender differences in vascular compliance in young, healthy subjects assessed by pulse contour analysis.

OBJECTIVES: Sex hormones exert important effects on the vasculature. Female sex hormones have been reported to enhance endothelial function, reduce oxidative stress, and protect against atherosclerosis. However, the effects of estrogen on vascular compliance have not been studied. Recently, noninvasive instrumentation that estimates vascular compliance by recording the radial artery pulse contour has been introduced. Reductions in the oscillatory or reflected component of the diastolic waveform have been observed in various clinical conditions, including hypertension, diabetes mellitus, and congestive heart failure, and may reflect endothelial dysfunction at the site of resistance vessels. In this study the authors examined gender-related vascular compliance in a cohort of young, healthy, predominantly nonsmoking, medication-free men and women to determine the influence of cardiovascular risk factors, including family and social history, serum lipids, plasma homocysteine, and insulin levels on vascular compliance. METHODS: The volunteers, consisting of 151 healthy men and women (mean age 24A+/-4 years) completed a questionnaire detailing family and social history, medication use, and exercise habits. Large (C1) and small (C2) vessel compliance and various cardiovascular parameters were derived from arterial pulse wave contour analysis. Systolic, diastolic, and mean arterial blood pressure, pulse pressure, and pulse rate were determined simultaneously by oscillometry. Blood for fasting serum lipids, plasma homocysteine, and serum insulin were obtained in a subset of 135 subjects. RESULTS: The questionnaire revealed that 38% of parents had a history of hypertension, 31% had dyslipidemia, and 15% had coronary heart disease. C2 was lower in subjects with parental dyslipidemia. Compared to men, women had lower C2; lower systolic blood pressure, mean arterial pressure, and pulse pressure; higher serum high-density lipoprotein cholesterol; lower serum triglycerides; and lower plasma homocysteine, but similar serum insulin levels. C1 correlated with height and pulse pressure, whereas C2 was proportional to height and weight and inversely related to systemic vascular resistance. Multivariate regression analysis showed that stroke volume, total vascular impedance, cardiac output, female gender, and systemic vascular resistance independently predicted changes in C2, but that height was not a significant factor. CONCLUSIONS: Women have reduced C2 despite lower systolic blood pressure and pulse pressure and more favorable lipid and homocysteine levels. C2 is independent of height and is lower in subjects with parental dyslipidemia. These data indicate that female sex hormones have unexpected negative effects on small vessel compliance. They may help to explain why premenopausal women hospitalized for myocardial infarction have higher mortality rates than men of the same age.

Diabetes mellitus and diabetes-associated vascular disease.

Diabetes-related cardiovascular disease remains the leading cause of death in patients with type 2 diabetes. Hypertension is common among diabetics and has the same pathogenetic mechanisms as insulin resistance, in which the activated renin-angiotensin system contributes to the emerging high blood pressure and hyperglycemia. Hyperglycemia is one of the triggering factors for vascular dysfunction and clotting abnormalities and, therefore, for accelerated atherosclerosis in diabetes. Glycated hemoglobin levels, as a reflection of the degree of glycemia, are strongly associated with the risk of cardiovascular disease in diabetics and in the general population. Tight glycemic control, the treatment of dyslipidemia and raised blood pressure, in addition to the use of antiplatelet therapy, all powerfully reduce the risks associated with diabetes. Furthermore, angiotensin-converting enzyme inhibitors might offer additional cardioprotection to diabetics above that provided by blood pressure reduction.

Downregulation of K(+) channel genes expression in type I diabetic cardiomyopathy.

Type I diabetic cardiomyopathy has consistently been shown to be associated with decrease of repolarising K(+) currents, but the mechanisms responsible for the decrease are not well defined. We investigated the streptozotocin (STZ) rat model of type I diabetes. We utilized RNase protection assay and Western blot analysis to investigate the message expression and protein density of key cardiac K(+) channel genes in the diabetic rat left ventricular (LV) myocytes. Our results show that message and protein density of Kv2.1, Kv4.2, and Kv4.3 are significantly decreased as early as 14 days following induction of type I diabetes in the rat. The results demonstrate, for the first time, that insulin-deficient type I diabetes is associated with early downregulation of the expression of key cardiac K(+) channel genes that could account for the depression of cardiac K(+) currents, I(to-f) and I(to-s). These represent the main electrophysiological abnormality in diabetic cardiomyopathy and is known to enhance the arrhythmogenecity of the diabetic heart. The findings also extend the extensive list of gene expression regulation by insulin.

Vascular insulin/insulin-like growth factor-1 resistance in female obese Zucker rats.

Because insulin resistance/diabetes may cause inordinate vascular complications in females, we have investigated the effects of insulin and insulin-like growth factor (IGF-1) on vascular reactivity in 12-week-old female Zucker obese (Ob) rats, a rodent model of insulin resistance and its lean (Ln) age-matched counterpart. Endothelium intact aortic rings from Ob animals and their Ln littermates (12 weeks of age) were subjected to contractile concentration responses to phenylephrine (PE) followed by relaxation to isoproterenol (Iso), with and without preincubation for 2 hours with cholera toxin (CTX; 1 microg/mL) or pertussis toxin (PTX; 2 microg/mL) and before and after incubation with either insulin or IGF-1 (100 nmol/L) for 1 hour. Systolic blood pressure was higher (138 +/- 3 v. 109 +/- 4 mm Hg; P <.0001) in the 12-week-old Ob rats. Contractile responses to PE were similar in both groups; however, both insulin and IGF-1 induced a paradoxical increase (P <.001) in contraction in Ob vasculature (929 +/- 92 v. 679 +/- 25 mg, respectively). CTX alone decreased contraction in the Ob (P <.02) and PTX in the Ln (P <.02), but there were no interactions between either IGF-1 or insulin and the toxins. Marked impairment of relaxation to Iso was seen in aortic rings of these female Ob rats (ED(50) = 2.6 micromol/L v. 418 nmol/L, P =.0002), an effect exacerbated by preincubation with either insulin or IGF-1 (P =.0001). Again, no role for G-proteins could be demonstrated. Insulin-dependent glucose uptake was severely impaired (P <.05) in aortic segments of the Ob insulin-resistant rats. Insulin receptor binding, tyrosine kinase activity (TKA), and abundance of several G-protein alpha subunits (inhibitory and stimulatory) in solubilized arterial membrane preparations (assessed by Western blot) were comparable in the 2 groups. These results indicate that resistance to the vascular actions of insulin/IGF-1 in female Ob rats is a postreceptor event that parallels glucose uptake resistance and is independent of G-proteins.

Diabetes, hypertension, and cardiovascular disease: an update.

Cardiovascular diseases (CVDs) are the major causes of mortality in persons with diabetes, and many factors, including hypertension, contribute to this high prevalence of CVD. Hypertension is approximately twice as frequent in patients with diabetes compared with patients without the disease. Conversely, recent data suggest that hypertensive persons are more predisposed to the development of diabetes than are normotensive persons. Furthermore, up to 75% of CVD in diabetes may be attributable to hypertension, leading to recommendations for more aggressive treatment (ie, reducing blood pressure to <130/85 mm Hg) in persons with coexistent diabetes and hypertension. Other important risk factors for CVD in these patients include the following: obesity, atherosclerosis, dyslipidemia, microalbuminuria, endothelial dysfunction, platelet hyperaggregability, coagulation abnormalities, and "diabetic cardiomyopathy." The cardiomyopathy associated with diabetes is a unique myopathic state that appears to be independent of macrovascular/microvascular disease and contributes significantly to CVD morbidity and mortality in diabetic patients, especially those with coexistent hypertension. This update reviews the current knowledge regarding these risk factors and their treatment, with special emphasis on the cardiometabolic syndrome, hypertension, microalbuminuria, and diabetic cardiomyopathy. This update also examines the role of the renin-angiotensin system in the increased risk for CVD in diabetic patients and the impact of interrupting this system on the development of clinical diabetes as well as CVD.

Altered myosin light-chain phosphorylation in resting platelets from premenopausal women with diabetes.

Gender-related differences in the rate of coronary heart disease (CHD) between premenopausal women and men are greatly diminished in women with diabetes mellitus (DM). This may be related, in part, to altered platelet function in premenopausal diabetic women. Hyperglycemia may contribute to increase platelet aggregation through enhancement of oxidative stress, increased nitric oxide (NO) destruction, and increased myosin light-chain (MLC) phosphorylation (MLC-P). Accordingly, we investigated functional and biochemical parameters of platelet function in 32 women (14 premenopausal and postmenopausal controls and 18 age-matched patients with DM); platelet MLC-P and cyclic guanosine monophosphate ([cGMP] reflecting NO) were assessed. Other parameters including age, body mass index (BMI), waist to hip ratio, total cholesterol, and platelet count were not different in the control and diabetic groups. In the premenopausal women, baseline MLC-P was lower in women with DM versus the control group (P = .02). GMP levels were similar in the two groups at baseline (22.7 +/- 3 fmol/mL in controls v 23.1 +/- 3 fmol/mL in diabetic subjects) and 3 minutes after insulin exposure. The platelet content of ascorbic acid (AA), an endogenous antioxidant compound, was elevated in premenopausal women with DM (P = .02) compared with the controls. Despite similar estradiol (beta,E2) levels, platelets of premenopausal women with DM exhibited reduced MLC-P. This paradoxic difference may be accounted for by an increase in platelet AA, as this suggests decreased platelet oxidative stress in this patient population. These observations indicate that an altered redox state and associated MLC-P of platelets does not contribute to enhanced platelet aggregation and CHD in premenopausal women with DM.

Update on the cardiometabolic syndrome.

An array of metabolic, hemodynamic, and renal abnormalities constitutes the cardiometabolic syndrome. A hallmark of this syndrome is visceral obesity and associated insulin resistance/hyperinsulinemia. The syndrome is also associated with essential hypertension, abnormalities in the circadian rhythm of blood pressure and heart rate, the diabetic dyslipidemic syndrome, hypercoagulability, hyperuricemia, increased cardiovascular inflammation, and microalbuminuria, all of which contribute to an increased risk of cardiovascular disease morbidity and mortality. This article reviews current knowledge about the interrelationship of the various factors that make up the cardiometabolic syndrome and its implications for individuals with and without diabetes mellitus.

Reduced contractile response to insulin and IGF-I in ventricular myocytes from genetically obese Zucker rats.

Obesity plays a pivotal role in the pathophysiology of metabolic and cardiovascular diseases. Resistance to insulin is commonly seen in metabolic disorders such as obesity and diabetes. Insulin-like growth factor-I (IGF-I) mimics insulin in many tissues and has been shown to enhance cardiac contractile function and growth. Because IGF-I resistance often accompanies resistance to insulin, we sought to determine whether IGF-I-induced myocardial contractile was elevated and whether heart and kidney size were enlarged in obese compared with lean rats. The myocyte contraction profile in the obese rats showed a decreased peak shortening associated with prolonged relengthening and normal shortening duration, a pattern similar to that observed in diabetes. IGF-I (1-500 ng/ml) caused a dose-dependent increase in peak shortening in lean but not obese animals, but it did not alter the duration of shortening and relengthening. Consistent with contractile data, IGF-I induced a dose-dependent increase in Ca(2+) transients only in myocytes of lean rats. IGF-I receptor mRNA levels were significantly reduced in obese rat hearts. These results suggest that the IGF-I-induced cardiac contractile responses are attenuated in the Zucker model of obesity. The mechanisms underlying this alteration may be related to the decreased receptor number and/or changes in intracellular Ca(2+) handling in these animals.

Basal and ethanol-induced cardiac contractile response in lean and obese Zucker rat hearts.

Obesity plays a pivotal role in metabolic and cardiovascular diseases. Certain types of obesity may be related to alcohol ingestion, which itself leads to impaired cardiac function. This study analyzed basal and ethanol-induced cardiac contractile response using left-ventricular papillary muscles and myocytes from lean and obese Zucker rats. Contractile properties analyzed include: peak tension development (PTD), peak shortening amplitude (PS), time to PTD/PS (TPT/TPS), time to 90% relaxation/relengthening (RT(90)/TR(90)) and maximal velocities of contraction/shortening and relaxation/relengthening (+/-VT and +/-dL/dt). Intracellular Ca(2+) transients were measured as fura-2 fluorescence intensity (DeltaFFI) changes and fluorescence decay time (FDT). In papillary muscles from obese rats, the baseline TPT and RT(90) were significantly prolonged accompanied with low to normal PTD and +/-VT compared to those in lean rats. Muscles from obese hearts also exhibited reduced responsiveness to postrest potentiation, increase in extracellular Ca(2+) concentration, and norepinephrine. By contrast, in isolated myocytes, obesity reduced PS associated with a significant prolonged TR(90), normal TPS and +/-dL/dt. Intracellular Ca(2+) recording revealed decreased resting Ca(2+) levels and prolonged FDT. Acute ethanol exposure (80-640 mg/dl) caused comparable concentration-dependent inhibitions of PTD/PS and DeltaFFI, associated with reduced +/-VT in both groups. Collectively, these results suggest altered cardiac contractile function and unchanged ethanol-induced depression in obesity.

Inhibition of Rho protein stimulates iNOS expression in rat vascular smooth muscle cells.

Inducible nitric oxide synthase (iNOS) in vascular smooth muscle cells (VSMCs) is upregulated in arterial injury and plays a role in regulating VSMC proliferation and restenosis. Inflammatory cytokines [e.g., interleukin-1beta (IL-1beta)] released during vascular injury induce iNOS. Small GTP-binding proteins of the Ras superfamily play a major role in IL-1beta-dependent signaling pathways. In this study, we examined the role of Rho GTPases in regulating iNOS expression in VSMCs. Treatment of VSMCs with mevastatin, which inhibits isoprenylation of Rho and other small GTP-binding proteins, produced significantly higher amounts of IL-1beta-evoked NO and iNOS protein compared with control. Similarly, bacterial toxins [Toxin B from Clostridium difficile and C3 ADP-ribosyl transferase (C3) toxin from Clostridium botulinium] that specifically inactivate Rho proteins increased NOS products (NO and citrulline) and iNOS expression. Toxin B increased the activity of iNOS promoter-reporter construct in VSMCs. Both toxins enhanced IL-1beta-stimulated iNOS expression and NO production. These data demonstrate for the first time that inhibition of Rho induces iNOS and suggest a role for Rho protein in IL-1beta-stimulated NO production in VSMCs.