The obesity epidemic is contributing substantially to the burden of cardiovascular disease including heart disease and congestive heart failure, in the United States and the rest of the world. Overnutrition as a driver of obesity, promotes alterations in fatty acid, lipid, and glucose metabolism that influence myocardial function and progression of heart failure from diastolic to systolic failure. The association of progressive heart failure and progressive chronic kidney disease is well documented and often referred to as the cardiorenal syndrome, as well as a prognosticator for cerebrovascular disease (e.g. stroke). Whether the relationship between obesity, heart disease/failure and risk for chronic kidney disease and stroke is direct or a confluence of risk factors is poorly understood.
Neuroendocrine tumors rarely occur in the cervix or other components of the reproductive system. These tumors have been associated with microsatellite instability, are very aggressive and often associated with poor outcome. Lynch syndrome is an inherited cancer syndrome that has also been associated with microsatellite instability. Here we report a 34-year-old female with Lynch syndrome and a family history of loss of DNA mismatch of the hereditary non-polyposis colorectal cancer repair gene expression who presented with a neuroendocrine tumor of her cervix as the first manifestation of Lynch syndrome. This is the first case reported of a neuroendocrine tumor of the cervix in a patient with Lynch syndrome. We also review the relationship between Lynch Syndrome and neuroendocrine tumors.
neuroendocrine tumors; cervix; Lynch syndrome; gene expression; case report
Diabetes is the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in the United States. There was an estimated 7 million cases of diabetic kidney disease (DKD) in the last National Health and Nutrition Examination survey (2005-2008). High blood pressure, hyperglycemia and other metabolic abnormalities interactively promote DKD, thus there has been increasing interest and renewed focus on the metabolic dysregulation and the interactions between heart and kidney pathologies observed in DKD. Indeed metabolic abnormalities that are observed in overweight or obese individuals are known to impact blood pressure regulation in kidney and cardiovascular disease; e.g. cardiorenal metabolic syndrome. In this context, obesity has been associated with increased blood pressure variability and nocturnal non-dipping which are risk predictors for albuminuria and DKD. These collective metabolic abnormalities have also been observed in earlier stages of DKD in association with micro-albuminuria. Herein we review the current literature regarding the role of blood pressure variability and nocturnal non-dipping of blood pressure as well as the presence of DKD, in the absence of albuminuria, as risk predictors for progressive DKD. We also discuss the importance of glycemic and blood pressure control in patients with diabetes and CKD, and the use of oral hypoglycemic agents and anti-hypertensive agents in this patient cohort.
Albuminuria; Proteinuria; Diabetes; Cardiorenal Syndrome; Diabetic Nephropathy; Chronic Kidney Disease; Blood Pressure Variability
Insulin resistance is a hallmark of obesity, the cardiorenal metabolic syndrome and type 2 diabetes mellitus (T2DM). The progression of insulin resistance increases the risk for cardiovascular disease (CVD). The significance of insulin resistance is underscored by the alarming rise in the prevalence of obesity and its associated comorbidities in the Unites States and worldwide over the last 40-50 years. The incidence of obesity is also on the rise in adolescents. Furthermore, premenopausal women have lower CVD risk compared to men, but this protection is lost in the setting of obesity and insulin resistance. Although systemic and cardiovascular insulin resistance are associated with impaired insulin metabolic signaling and cardiovascular dysfunction, the mechanisms underlying insulin resistance and cardiovascular dysfunction remain poorly understood. Recent studies show that insulin resistance in obesity and diabetes is linked to a metabolic inflammatory response, a state of systemic and tissue specific chronic low grade inflammation. Evidence is also emerging that there is polarization of macrophages and lymphocytes towards a pro-inflammatory phenotype that contribute to progression of insulin resistance in obesity, cardiorenal metabolic syndrome and diabetes. In this review, we provide new insights into factors, such as, the renin-angiotensin-aldosterone system, sympathetic activation and incretin modulators (e.g., DPP-4) and immune responses that mediate this inflammatory state in obesity and other conditions characterized by insulin resistance.
Obesity; DPP-4; immunity; uric acid; gender
The metabolic syndrome is a constellation of metabolic disorders including obesity, hypertension, and insulin resistance, components which are risk factors for the development of diabetes, hypertension, cardiovascular, and renal disease. Pathophysiological abnormalities that contribute to the development of the metabolic syndrome include impaired mitochondrial oxidative phosphorylation and mitochondrial biogenesis, dampened insulin metabolic signaling, endothelial dysfunction, and associated myocardial functional abnormalities. Recent evidence suggests that impaired myocardial mitochondrial biogenesis, fatty acid metabolism, and antioxidant defense mechanisms lead to diminished cardiac substrate flexibility, decreased cardiac energetic efficiency, and diastolic dysfunction. In addition, enhanced activation of the renin–angiotensin–aldosterone system and associated increases in oxidative stress can lead to mitochondrial apoptosis and degradation, altered bioenergetics, and accumulation of lipids in the heart. In addition to impairments in metabolic signaling and oxidative stress, genetic and environmental factors, aging, and hyperglycemia all contribute to reduced mitochondrial biogenesis and mitochondrial dysfunction. These mitochondrial abnormalities can predispose a metabolic cardiomyopathy characterized by diastolic dysfunction. Mitochondrial dysfunction and resulting lipid accumulation in skeletal muscle, liver, and pancreas also impede insulin metabolic signaling and glucose metabolism, ultimately leading to a further increase in mitochondrial dysfunction. Interventions to improve mitochondrial function have been shown to correct insulin metabolic signaling and other metabolic and cardiovascular abnormalities. This review explores mechanisms of mitochondrial dysfunction with a focus on impaired oxidative phosphorylation and mitochondrial biogenesis in the pathophysiology of metabolic heart disease.
Metabolic impairment; Oxidative phosphorylation; Mitochondrial biogenesis
The cardiorenal metabolic syndrome (CRS) consists of a constellation of cardiac, renal, and metabolic disorders including insulin resistance (IR), obesity, metabolic dyslipidemia, high-blood pressure, and evidence of early cardiac and renal disease. Mitochondria dysfunction often occurs in the CRS, and this dysfunction is promoted by excess reactive oxygen species, genetic factors, IR, aging, and altered mitochondrial biogenesis. Recently, it has been shown that there are important sex-related differences in mitochondria function and metabolic, cardiovascular, and renal components. Sex differences in the CRS have mainly been attributed to the estrogen’s effects that are mainly mediated by estrogen receptor (ER) α, ERβ, and G-protein coupled receptor 30. In this review, we discuss the effects of estrogen on the mitochondrial function, insulin metabolic signaling, glucose transport, lipid metabolism, and inflammatory responses from liver, pancreatic β cells, adipocytes, skeletal muscle, and cardiovascular tissue.
The combination of obesity and hypertension is associated with high morbidity and mortality because it leads to cardiovascular and kidney disease. Potential mechanisms linking obesity to hypertension include dietary factors, metabolic, endothelial and vascular dysfunction, neuroendocrine imbalances, sodium retention, glomerular hyperfiltration, proteinuria, and maladaptive immune and inflammatory responses. Visceral adipose tissue also becomes resistant to insulin and leptin and is the site of altered secretion of molecules and hormones such as adiponectin, leptin, resistin, TNF and IL-6, which exacerbate obesity-associated cardiovascular disease. Accumulating evidence also suggests that the gut microbiome is important for modulating these mechanisms. Uric acid and altered incretin or dipeptidyl peptidase 4 activity further contribute to the development of hypertension in obesity. The pathophysiology of obesity-related hypertension is especially relevant to premenopausal women with obesity and type 2 diabetes mellitus who are at high risk of developing arterial stiffness and endothelial dysfunction. In this Review we discuss the relationship between obesity and hypertension with special emphasis on potential mechanisms and therapeutic targeting that might be used in a clinical setting.
Recent data implicate oxidative stress as a mediator of pulmonary hypertension (PH) and of the associated pathological changes to the pulmonary vasculature and right ventricle (RV). Increases in reactive oxygen species (ROS), altered redox state, and elevated oxidant stress have been demonstrated in the lungs and RV of several animal models of PH, including chronic hypoxia, monocrotaline toxicity, caveolin-1 knock-out mouse, and the transgenic Ren2 rat which overexpresses the mouse renin gene. Generation of ROS in these models is derived mostly from the activities of the nicotinamide adenine dinucleotide phosphate oxidases, xanthine oxidase, and uncoupled endothelial nitric oxide synthase. As disease progresses circulating monocytes and bone marrow-derived monocytic progenitor cells are attracted to and accumulate in the pulmonary vasculature. Once established, these inflammatory cells generate ROS and secrete mitogenic and fibrogenic cytokines that induce cell proliferation and fibrosis in the vascular wall resulting in progressive vascular remodeling. Deficiencies in antioxidant enzymes also contribute to pulmonary hypertensive states. Current therapies were developed to improve endothelial function, reduce pulmonary artery pressure, and slow the progression of vascular remodeling in the pulmonary vasculature by targeting deficiencies in either NO (PDE-type 5 inhibition) or PGI2 (prostacyclin analogs), or excessive synthesis of ET-1 (ET receptor blockers) with the intent to improve patient clinical status and survival. New therapies may slow disease progression to some extent, but long term management has not been achieved and mortality is still high. Although little is known concerning the effects of current pulmonary arterial hypertension treatments on RV structure and function, interest in this area is increasing. Development of therapeutic strategies that simultaneously target pathology in the pulmonary vasculature and RV may be beneficial in reducing mortality associated with RV failure.
Pulmonary arterial hypertension; Rosuvastatin; Oxidative stress; Nicotinamide adenine dinucleotide phosphate oxidase; Statins
Two-thirds of American adults are overweight or obese, 75 million have hypertension and another 25 million have diabetes. Cardiovascular disease is the leading cause of morbidity and mortality and a major driver of health care costs in patients with type 2 diabetes. Observational studies suggest that insulin resistance, hypertension and hyperglycemia independently predict cardiovascular disease and chronic kidney disease. Indeed, coexisting hypertension appears to be a most powerful determinant of cardiovascular disease risk in diabetic patients. This update explores recent investigation which sheds light on our understanding of various metabolic and hemodynamic factors which promote vascular disease, as well as strategies to lessen cardiovascular disease in patients with diabetes.
Recent data would suggest pre-menopausal insulin resistant women are more prone to diastolic dysfunction than men, yet it is unclear why. We and others have reported that transgenic (mRen2)27 (Ren2) rats overexpressing the murine renin transgene are insulin resistant due to oxidative stress in insulin sensitive tissues. As increased salt intake promotes inflammation and oxidative stress, we hypothesized that excess dietary salt would promote diastolic dysfunction in transgenic females under conditions of excess tissue Ang II and circulating aldosterone levels.
For this purpose we evaluated cardiac function in young female Ren2 rats or age-matched Sprague-Dawley (SD) littermates exposed to a high (4%) salt or normal rat chow intake for three weeks.
Compared to SD littermates, at 10 weeks of age, female Ren2 rats fed normal chow showed elevations in left ventricular (LV) systolic pressures, LV and cardiomyocyte hypertrophy, and displayed reductions in LV initial filling rate accompanied by increases in 3-nitrotyrosine content as a marker of oxidant stress. Following 3 weeks of a salt diet, female Ren2 rats exhibited no further changes in LV systolic pressure, insulin resistance, or markers of hypertrophy but exaggerated increases in type 1 collagen, 3-nitrotryosine content, and diastolic dysfunction. These findings occurred in parallel with ultrastructural findings of pericapillary fibrosis, increased LV remodeling, and mitochondrial biogenesis.
These data suggest that a diet high in salt in hypertensive female Ren2 rats promotes greater oxidative stress, maladaptive LV remodeling, fibrosis, and associated diastolic dysfunction without further changes in LV systolic pressure or hypertrophy.
angiotensin II; TG (mRen2) 27 rat; Diastolic Dysfunction; Cardiac Remodeling; Oxidative Stress; Perivascular Fibrosis
Obesity has reached epidemic proportions and is a significant public health concern. Obesity is associated with increased diabetes, cardiovascular and kidney disease, and associated morbidity and mortality. Despite the increasing public health problem of obesity, there is a dearth of effective treatment options. Following the FDA mandated withdrawal of sibutramine, the treatment options for obesity were limited to orlistat as the only pharmacological treatment option for long term management of obesity. Recently two new medications (Belviq and Qsymia) were approved by FDA for long term management of obesity. Many other anti-obesity drugs are under development. Bariatric surgery has been shown to be effective in the treatment of obesity and its comorbidities. The available data suggests that even modest weight loss improves diabetes and cardiovascular disease (CVD) risk factors. We summarize the treatment options for obesity and the efficacy of these options in ameliorating cardiovascular risk factors. We also focus on the recently approved anti-obesity drugs.
Diabetes mellitus type 2 (T2DM) is a widespread chronic medical condition with prevalence bordering on the verge of an epidemic. It is of great concern that cardiovascular disease is more common in patients with diabetes than the non-diabetic population. While hypertensive and ischemic heart disease is more common in diabetic patients, there is another type of heart disease in diabetes that is not associated with hypertension or coronary artery disease. This muscle functional disorder is termed “diabetic cardiomyopathy”. Diastolic dysfunction characterized by impaired diastolic relaxation time and reduced contractility precedes systolic dysfunction and is the main pathogenic hallmark of this condition. Even though the pathogenesis of “diabetic cardiomyopathy” is still controversial, impaired cardiac insulin sensitivity and metabolic overload are emerging as major molecular and metabolic mechanisms for cardiac dysfunction. Systemic insulin resistance, hyperinsulinemia, dysregulation of adipokine secretion, increases in circulating levels of inflammatory mediators, aberrant activation of renin angiotensin aldosterone system (RAAS), and increased oxidative stress contribute dysregulated insulin and metabolic signaling in the heart and development of diastolic dysfunction. In addition, maladaptive calcium homeostasis and endothelial cell dysregulation endoplasmic reticular stress play a potential role in cardiomyocyte fibrosis/diastolic dysfunction. In this review, we will focus on emerging molecular and metabolic pathways underlying cardiac dysfunction in diabetes. Elucidation of these mechanisms should provide a better understanding of the various cardiac abnormalities associated with diastolic dysfunction and its progression to systolic dysfunction and heart failure.
Diabetes; RAAS; Cardiac Dysfunction; Cardiorenal Metabolic syndrome; Diabetic Cardiomyopathy; Insulin Resistance
Insulin resistance is frequently associated with endothelial dysfunction and has been proposed to play a major role in cardiovascular diseases. Insulin exerts pro- and anti-atherogenic actions on the vasculature. The balance between nitric oxide (NO)-dependent vasodilator actions and endothelin-1- dependent vasoconstrictor actions of insulin is regulated by phosphatidylinositol 3-kinase-dependent (PI3K) - and mitogen-activated protein kinase (MAPK)-dependent signaling in vascular endothelium, respectively. During insulin-resistant conditions, pathway-specific impairment in PI3K-dependent signaling may cause imbalance between production of NO and secretion of endothelin-1 and lead to endothelial dysfunction. Insulin sensitizers that target pathway-selective impairment in insulin signaling are known to improve endothelial dysfunction. In this review, we discuss the cellular mechanisms in the endothelium underlying vascular actions of insulin, the role of insulin resistance in mediating endothelial dysfunction, and the effect of insulin sensitizers in restoring the balance in pro- and anti-atherogenic actions of insulin.
Nitric Oxide; Insulin Resistance; Endothelial Dysfunction; Metabolic Syndrome
Hypertension is often associated with increased oxidative stress and systemic insulin resistance. Use of β adrenergic receptor blockers in hypertension is limited due to potential negative influence on insulin sensitivity and glucose homeostasis. We sought to determine the impact of nebivolol, a selective vasodilatory β1adrenergic blocker, on whole-body insulin sensitivity, skeletal muscle oxidative stress, insulin signaling and glucose transport in the transgenic TG(mRen2)27rat (Ren2). This rodent model manifests increased tissue renin angiotensin expression, excess oxidative stress, and whole-body insulin resistance.
Research design and methods
Young (age 6-9 wks) Ren2 and age-matched Sprague-Dawley control rats were treated with nebivolol 10 mg/kg/day or placebo for 21 days. Basal measurements were obtained for glucose and insulin to calculate the Homeostasis Model Assessment (HOMA–IR). Additionally, insulin metabolic signaling, NADPH oxidase activity, reactive oxygen species (ROS), and ultrastructural changes as evaluated by transmission electron microscopy were examined ex vivo in skeletal muscle tissue.
The Ren2 rat demonstrated systemic insulin resistance as examined by HOMA-IR, along with impaired insulin metabolic signaling in skeletal muscle. This was associated with increased oxidative stress and mitochondrial remodeling. Treatment with nebivolol was associated with improvement in insulin resistance and decreased NADPH oxidase activity/levels ROS in skeletal muscle tissue.
Nebivolol treatment for 3 weeks reduces NADPH oxidase activity and improves systemic insulin resistance, in concert with reduced oxidative stress in skeletal muscle in a young rodent model of hypertension, insulin resistance and enhanced tissue RAS expression.
Insulin resistance; oxidative stress; skeletal muscle
Insulin resistance and associated reductions in cardiac insulin metabolic signaling is emerging as a major factor for the development of heart failure and assumes more importance because of an epidemic increase in obesity and the cardiorenal metabolic syndrome and our aging population. Major factors contributing to the development of cardiac insulin resistance are oxidative stress, hyperglycemia, hyperlipidemia, dysregulated secretion of adipokines/cytokines and inappropriate activation of renin-angiotensin II-aldosterone system (RAAS) and the sympathetic nervous system. The effects of cardiac insulin resistance are exacerbated by metabolic, endocrine and cytokine alterations associated with systemic insulin resistance. The aggregate of these various alterations leads to an insulin resistant phenotype with metabolic inflexibility, impaired calcium handling, mitochondrial dysfunction and oxidative stress, dysregulated myocardial-endothelial interactions resulting in energy deficiency, impaired diastolic dysfunction, myocardial cell death and cardiac fibrosis. Therefore, understanding the molecular mechanisms linking insulin resistance and heart failure may help to design new and more effective mechanism-based drugs to improve myocardial and systemic insulin resistance.
Cardiac insulin resistance; cardiorenal metabolic syndrome
Cardiovascular disease, which accounts for the highest morbidity and mortality in the United States, has several major risk factors, including aging and diabetes. Overweight and obesity, especially abdominal obesity, have been increasingly implicated as independent risk factors in the development of cardiovascular disease. Metabolic and/or diabetic cardiomyopathy has been especially associated with excess body weight caused by chronic over-nutrition and high-fat feeding. In the initial stages, obesity is now understood to cause significant dysregulation of cardiac fatty acid and glucose metabolism. These abnormalities are due, in part, to increased oxidative stress, which in turn can cause deleterious effects on intracellular signaling pathways that control cellular growth and proliferation. This increase in oxidative stress is coupled with reduced anti-oxidant species and dysregulation of metabolic signaling pathways. The cardiomyopathy seen with obesity is associated with increased interstitial fibrosis and diastolic dysfunction. Over time, evolving abnormalities include hypertrophy and systolic dysfunction, eventually leading to heart failure.
insulin; metabolic; signaling; heart
Strategies that block angiotensin II actions on its angiotensin type 1 receptor or inhibit actions of aldosterone have been shown to reduce myocardial hypertrophy and interstitial fibrosis in states of insulin resistance. Thereby, we sought to determine if combination of direct renin inhibition with angiotensin type 1 receptor blockade in vivo, through greater reductions in systolic blood pressure (SBP) and aldosterone would attenuate left ventricular hypertrophy and interstitial fibrosis to a greater extent than either intervention alone.
We utilized the transgenic Ren2 rat which manifests increased tissue expression of murine renin which, in turn, results in increased renin-angiotensin system activity, aldosterone secretion and insulin resistance. Ren2 rats were treated with aliskiren, valsartan, the combination (aliskiren+valsartan), or vehicle for 21 days.
Compared to Sprague-Dawley controls, Ren2 rats displayed increased systolic blood pressure, elevated serum aldosterone levels, cardiac tissue hypertrophy, interstitial fibrosis and ultrastructural remodeling. These biochemical and functional alterations were accompanied by increases in the NADPH oxidase subunit Nox2 and 3-nitrotyrosine content along with increases in mammalian target of rapamycin and reductions in protein kinase B phosphorylation. Combination therapy contributed to greater reductions in systolic blood pressure and serum aldosterone but did not result in greater improvement in metabolic signaling or markers of oxidative stress, fibrosis or hypertrophy beyond either intervention alone.
Thereby, our data suggest that the greater impact of combination therapy on reductions in aldosterone does not translate into greater reductions in myocardial fibrosis or hypertrophy in this transgenic model of tissue renin overexpression.
Direct Renin Inhibition; Angiotensin II Type 1 receptor; Echocardiography; Ren2 rat
Diabetes and hypertension often coexist and their coexistence substantially promote cardiovascular disease (CVD) and chronic kidney disease. Control of blood pressure to a level of 140/90 mm Hg in people with diabetes can prevent or at least delay CVD and chronic kidney disease.. In the past many society treatment guidelines have stressed tight blood pressure control (=< 130/80) for people with diabetes. But recommendations for such tight blood pressure control have not been supported by recent large randomized control trials, especially in in elderly. Here we review the recent literature regarding the benefits of blood pressure control in elderly patients with diabetics. We further focus on evidence for specific levels of blood pressure treatment goals, in this population subset..
Diabetes; Hypertension; Diabetes complications; Blood pressure control
Epidemiological studies support the notion that arterial stiffness is an independent predictor of adverse cardiovascular events contributing significantly to systolic hypertension, impaired ventricular-arterial coupling and diastolic dysfunction, impairment in myocardial oxygen supply and demand, and progression of kidney disease. Although arterial stiffness is associated with aging, it is accelerated in the presence of obesity and diabetes. The prevalence of arterial stiffness parallels the increase of obesity that is occurring in epidemic proportions and is partly driven by a sedentary life style and consumption of a high fructose, high salt, and high fat western diet. Although the underlying mechanisms and mediators of arterial stiffness are not well understood, accumulating evidence supports the role of insulin resistance and endothelial dysfunction. The local tissue renin-angiotensin-aldosterone system (RAAS) in the vascular tissue and immune cells and perivascular adipose tissue is recognized as an important element involved in endothelial dysfunction which contributes significantly to arterial stiffness. Activation of vascular RAAS is seen in humans and animal models of obesity and diabetes, and associated with enhanced oxidative stress and inflammation in the vascular tissue. The cross talk between angiotensin and aldosterone underscores the importance of mineralocorticoid receptors in modulation of insulin resistance, decreased bioavailability of nitric oxide, endothelial dysfunction, and arterial stiffness. In addition, both innate and adaptive immunity are involved in this local tissue activation of RAAS. In this review we will attempt to present a unifying mechanism of how environmental and immunological factors are involved in this local tissue RAAS activation, and the role of this process in the development of endothelial dysfunction and arterial stiffness and targeting tissue RAAS activation.
renin-angiotensin-aldosterone system; arterial stiffness; insulin resistance; endothelial dysfunction; obesity; diabetes
Insulin (INS) metabolic signaling is important for normal cardiovascular and renal function as well as for exerting the classic actions of INS, such as glucose uptake in skeletal muscle tissue. There is emerging evidence that tyrosine phosphatases as well as protein kinases have important modulating roles in INS metabolic signaling in both cardiovascular and classically INS- sensitive tissues. For example, increases in phosphatase activity may partially explain how angiotensin II and aldosterone attenuate activation of the INS receptor substrate protein 1 (IRS-1)-phosphatidylinositol 3 kinase-protein kinase B pathway, thereby promoting INS resistance. On the other hand, phosphatase activation may also exert beneficial and cardiovascular protective effects in conditions such as overnutrition by blocking serine phosphorylation of IRS-1, thereby improving downstream INS metabolic signaling. Both the beneficial and the detrimental effects exerted by the activation of phosphatases will be covered in this report.
Cell signaling; Hormones; Cytokines; Receptors