Aldosterone: Role in the Cardiometabolic Syndrome and Resistant Hypertension

The prevalence of diabetes, hypertension, and cardiovascular disease (CVD) and chronic kidney disease (CKD) is increasing in concert with obesity. Insulin resistance, metabolic dyslipidemia, central obesity, albuminuria. and hypertension commonly cluster to comprise the cardiometabolic syndrome (CMS). Emerging evidence supports a shift in our understanding of the crucial role of elevated serum aldosterone in promoting insulin resistance and resistant hypertension. Aldosterone enhances tissue generation of oxygen free radicals and systemic inflammation. This increase in oxidative stress and inflammation, in turn, contributes to impaired insulin metabolic signaling, reduced endothelial-mediated vasorelaxation, and associated cardiovascular and renal structural and functional abnormalities. In this context, recent investigation indicates that hyperaldosteronism, which is often associated with obesity, contributes to impaired pancreatic β-cell function as well as diminished skeletal muscle insulin metabolic signaling. Accumulating evidence indicates that the cardiovascular and renal abnormalities associated with insulin resistance are mediated, in part, by aldosterone's nongenomic as well as genomic signaling through the mineralocorticoid receptor (MR). In the CMS, there are increased circulating levels of glucocorticoids, which can also activate MR signaling in cardiovascular, adipose, skeletal muscle, neuronal, and liver tissue. Furthermore, there is increasing evidence that fat tissue produces a lipid soluble factor that stimulates aldosterone production from the adrenal zona glomerulosa. Recently, we have learned that MR blockade improves pancreatic insulin release, insulin-mediated glucose utilization, and endothelium-dependent vasorelaxation as well as reduces the progression of CVD and CKD. In summary, aldosterone excess exerts detrimental metabolic effects that contribute to the development of the CMS and resistant hypertension as well as CVD and CKD.     

Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies

Obesity is reaching epidemic proportions with recent worldwide figures estimated at 1.4 billion and rising year‐on‐year. Obesity affects all socioeconomic backgrounds and ethnicities and is a pre‐requisite for metabolic syndrome. Metabolic syndrome is a clustering of risk factors, such as central obesity, insulin resistance, dyslipidaemia and hypertension that together culminate in the increased risk of type 2 diabetes mellitus and cardiovascular disease. As these conditions are among the leading causes of deaths worldwide and metabolic syndrome increases the risk of type 2 diabetes mellitus fivefold and cardiovascular disease threefold, it is of critical importance that a precise definition is agreed upon by all interested parties. Also of particular interest is the relationship between metabolic syndrome and cancer. Metabolic syndrome has been associated with a plethora of cancers including breast, pancreatic, colon and liver cancer. Furthermore, each individual risk factor for metabolic syndrome has also an association with cancer. Our review collates internationally generated information on metabolic syndrome, its many definitions and its associations with life‐threatening conditions including type 2 diabetes mellitus, cardiovascular disease and cancer, providing a foundation for future advancements on this topic.     

Renin inhibition attenuates insulin resistance, oxidative stress, and pancreatic remodeling in the transgenic Ren2 rat

Emerging evidence indicates that pancreatic tissue expresses all components of the renin-angiotensin system. However, the functional role is not well understood. This investigation examined renin inhibition on pancreas structure/function in the transgenic Ren2 rat harboring the mouse renin gene, a model of tissue renin overexpression. Renin is the rate-limiting step in the generation of angiotensin II (Ang II), which stimulates the generation of reactive oxygen species in a variety of tissues. Overexpression of renin in Ren2 rats results in hypertension, insulin resistance, and cardiovascular and renal damage. Young (6-7 wk old) insulin-resistant male Ren2 and age-matched insulin sensitive Sprague Dawley rats were treated with the renin inhibitor, aliskiren (50 mg/kg.d by ip injection), or placebo for 21 d. At 21 d, the Ren2 demonstrated insulin resistance with increased islet insulin, Ang II, and reduced total insulin receptor substrate (IRS)-1, IRS-2, and Akt immunostaining. There was increased islet nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and subunits (p47(phox) and Rac1) as well as increased nitrotyrosine immunostaining (each P < 0.05). These functional abnormalities were associated with a disordered islet architecture; increased islet-exocrine interface, pericapillary fibrosis, and structurally abnormal mitochondria and content in endocrine and exocrine pancreas. In vivo treatment with aliskiren normalized systemic insulin resistance and islet insulin, Ang II, NADPH oxidase activity/subunits, and nitrotyrosine and improved total IRS-1 and Akt phosphorylation (each P < 0.05) as well as islet/exocrine structural abnormalities. Collectively, these data suggest that pancreatic functional/structural changes are driven, in part, by tissue renin-angiotensin system-mediated increases in NADPH oxidase and reactive oxygen species generation, abnormalities attenuated with direct renin inhibition.     

Insulin resistance, diabetes and cardiovascular risk: approaches to treatment

The prevalence of diabetes is increasing worldwide. Insulin resistance and diabetes mellitus are major predictors of cardiovascular ischaemic disease. Other risk factors for cardiovascular death including hypertension, dyslipidaemia, smoking and visceral obesity are especially lethal in diabetics. C-reactive protein, plasminogen activator inhibitor-1, matrix metalloproteinases and other emerging risk factors and their roles are continually being researched and discovered. Treatment of this syndrome must be aimed at lifestyle modification, glycaemic control and management of concomitant risk factors. Diet and exercise play a vital role in the treatment of diabetes and the metabolic syndrome. Weight reduction and increased physical activity will improve insulin resistance, hyperglycaemia, hypertension and dyslipidaemia. Hypertension management has been shown to be especially important in diabetics to prevent cardiovascular events. Likewise, multiple clinical trials show that reduction of cholesterol is even more vital in diabetics than the general population for risk reduction of coronary disease. There is a great deal of evidence that tight control of glycaemia is essential to treatment of this condition. There are a variety of available pharmacological agents available including metformin, insulin secretagogues, alpha-glucosidase inhibitors, thiazolidinediones and insulin. The mechanisms and side effects of these medications are discussed. As macrovascular disease is the major cause of morbidity and mortality, an early, aggressive, multi-factorial approach to treatment of the metabolic syndrome and diabetes is vital to prevent adverse cardiac outcomes.     

Hyperuricemia in chronic heart failure

Development of hyperuricemia is associated with excessive body mass, insulin resistance, metabolic syndrome, overuse of diuretics, elderly age, and abnormal renal function. Data are accumulated on existence of links between elevated uric acid level and arterial hypertension, diabetes mellitus, ischemic heart disease, and chronic heart failure (CHF). Hyperuricemia has been found in 60% of patients hospitalized because of decompensation of CHF. In CHF isolated hyperuricemia (irrespective of the state of renal function and administration of drugs) appears to be a marker of altered oxidative metabolism characterized by elevation of levels of free radicals which damage cardiomyocytes and vascular endothelium inducing disturbances of myocardial contractility and vasoconstriction. Hyperuricemia associated with insulin resistance, tissue hypoxia, elevated production of cytokines and free radicals can negatively affect cardiovascular system and worsen prognosis in patients with CHF.     

Loss of Leptin Actions in Obesity: Two Concepts with Cardiovascular Implications

Obesity is associated with increased risk of hypertension and heart disease. Leptin has recently been linked to increased risk of cardiovascular disease. We review briefly here two concepts regarding loss of leptin actions that have potential implications for cardiovascular disease. These are: 1. the concept of selective leptin resistance; and 2. the concept that loss of leptin action results in lipid accumulation and lipotoxicity of skeletal muscle, pancreatic islet cells, and heart and, thereby, promotes insulin resistance, insulin deficiency and cardiac dysfunction, respectively.     

Loss of leptin actions in obesity: two concepts with cardiovascular implications

Obesity is associated with increased risk of hypertension and heart disease. Leptin has recently been linked to increased risk of cardiovascular disease. We review briefly here two concepts regarding loss of leptin actions that have potential implications for cardiovascular disease. These are: 1. the concept of selective leptin resistance; and 2. the concept that loss of leptin action results in lipid accumulation and lipotoxicity of skeletal muscle, pancreatic islet cells, and heart and, thereby, promotes insulin resistance, insulin deficiency and cardiac dysfunction, respectively.     

The effects of medicinal plants on renal function and blood pressure in diabetes mellitus

Abstract

Diabetes mellitus is one of the most common chronic global diseases affecting children and adolescents in both the developed and developing nations. The major types of diabetes mellitus are type 1 and type 2, the former arising from inadequate production of insulin due to pancreatic β-cell dysfunction, and the latter from reduced sensitivity to insulin in the target tissues and/or inadequate insulin secretion. Sustained hyperglycaemia is a common result of uncontrolled diabetes and, over time, can damage the heart, eyes, kidneys and nerves, mainly through deteriorating blood vessels supplying the organs. Microvascular (retinopathy and nephropathy) and macrovascular (atherosclerotic) disorders are the leading causes of morbidity and mortality in diabetic patients. Therefore, emphasis on diabetes care and management is on optimal blood glucose control to avert these adverse outcomes.Studies have demonstrated that diabetic nephropathy is associated with increased cardiovascular mortality. In general, about one in three patients with diabetes develops end-stage renal disease (ESRD) which proceeds to diabetic nephropathy (DN), the principal cause of significant morbidity and mortality in diabetes. Hypertension, a well-established major risk factor for cardiovascular disease contributes to ESRD in diabetes. Clinical evidence suggests that there is no effective treatment for diabetic nephropathy and prevention of the progression of diabetic nephropathy. However, biomedical evidence indicates that some plant extracts have beneficial effects on certain processes associated with reduced renal function in diabetes mellitus. On the other hand, other plant extracts may be hazardous in diabetes, as reports indicate impairment of renal function. This article outlines therapeutic and pharmacological evidence supporting the potential of some medicinal plants to control or compensate for diabetes-associated complications, with particular emphasis on kidney function and hypertension.     

Subclinical vascular disease in patients with diabetes is associated with insulin resistance

Patients with diabetes experience increased cardiovascular risk that is not fully explained by deficient glycemic control or traditional cardiovascular risk factors such as smoking and hypercholesterolemia. Asymptomatic patients with diabetes show structural and functional vascular damage that includes impaired vasodilation, arterial stiffness, increased intima-media thickness and calcification of the arterial wall. Subclinical vascular injury associated with diabetes predicts subsequent manifestations of cardiovascular disease, such as ischemic heart disease, peripheral artery disease and stroke. Noninvasive detection of subclinical vascular disease is commonly used to estimate cardiovascular risk associated to diabetes. Longitudinal studies in normotensive subjects show that arterial stiffness at baseline is associated with a greater risk for future hypertension independently of established risk factors. In patients with type 2 diabetes, vascular disease begins to develop during the latent phase of insulin resistance, long before the clinical diagnosis of diabetes. In contrast, patients with type 1 diabetes do not manifest vascular injury when they are first diagnosed due to insulin deficiency, as they lack the preceding period of insulin resistance. These findings suggest that insulin resistance plays an important role in the development of early vascular disease associated with diabetes. Cross-sectional and prospective studies confirm that insulin resistance is associated with subclinical vascular injury in patients with diabetes, independently of standard cardiovascular risk factors. Asymptomatic vascular disease associated with diabetes begins to occur early in life having been documented in children and adolescents. Insulin resistance should be considered a therapeutic target in order to prevent the vascular complications associated with diabetes.     

Islet amyloid,metabolic syndrome,and the natural progressive history of type 2 diabetes mellitus

The presence of amyloid within the islet of the pancreas may be one of the best kept secrets in clinical medicine and translation of this century old finding may help to better understand the progressive nature of type 2 diabetes mellitus. Insulin resistance, metabolic syndrome, and type 2 diabetes mellitus are associated with multiple metabolic toxicities which result in an elevated tension of redox stress within the islet. Redox stress is associated with damage to proteins, lipids, and nucleic acids which may have a profound affect upon the structure and function of the islet. Earlier diagnosis at the stage of impaired glucose tolerance (prediabetes) and intervention may have a positive outcome on stabilization of the vulnerable islet and beta cell as well as the multiple diabetic complications. The natural history and a shift in the treatment paradigm of type 2 diabetes mellitus is explored as a result of these century old findings.     

Adipokines in diabetes and cardiovascular diseases

Recent studies suggest that adipocyte-secreted factors called adipokines are involved in obesity-associated complications including hyperlipidemia, diabetes mellitus, arterial hypertension, atherosclerosis, and heart failure. Among those, adiponectin is an antidiabetic and antiatherogenic protein, concentrations of which are decreased in obesity-associated metabolic and vascular disorders. In contrast, leptin, tumor necrosis factor a, interleukin-6, monocyte chemoattractant protein-1, and plasminogen activator inhibitor-1 are upregulated in obesity and contribute to the development of diabetes and vascular disease. In this review, the relevance of adipokines in obesity, insulin resistance, diabetes mellitus, atherosclerosis, and cardiovascular diseases is discussed.     

Hypertension and the cardiometabolic syndrome

Hypertension and cardiovascular disease are leading causes of morbidity and mortality. Accumulating data demonstrate a relationship between hypertension and several vascular and metabolic abnormalities that are components of the cardiometabolic syndrome. The components of the cardiometabolic syndrome include insulin resistance/hyperinsulinemia, central obesity, dyslipidemia, hypertension, microalbuminuria, increased inflammation, and oxidative stress. There is growing evidence that tissue activation of the renin-angiotensin-aldosterone system participates in endothelial dysfunction, microalbuminuria, insulin resistance, and subsequent cardiovascular and chronic kidney disease. The notion that hypertension is a metabolic as well as a vascular disease opens a new paradigm for the treatment of this disorder.     

Cardiovascular outcomes using doxazosin vs. chlorthalidone for the treatment of hypertension in older adults with and without glucose disorders: a report from the ALLHAT study

Insulin resistance underlies most glucose disorders in adults and is associated with an increased risk of cardiovascular disease. Alpha blockers decrease insulin resistance, whereas diuretics increase insulin resistance.
The authors studied the effects of these two classes of hypertension medications (doxazosin, an α blocker, and chlorthalidone, a diuretic) on cardiovascular disease outcomes in adults aged >55 years with hypertension and glucose disorders who were participants in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (8749 had known diabetes mellitus and 1690 had a newly diagnosed glucose disorder [fasting glucose ≥110 mg/dL]). There was no difference in either group between the chlorthalidone- and doxazosin-based treatments with regard to fatal or nonfatal myocardial infarction or all-cause mortality. There was, however, a difference for combined cardiovascular disease (myocardial infarction, revascularization procedures, angina, stroke, heart failure, and peripheral arterial disease) in favor of the diuretic. This difference was due primarily to an increased heart failure risk in those treated with doxazosin (relative risk, 1.85; 95% confidence interval, 1.56–2.19) in the known diabetes mellitus group and a relative risk of 1.63 (95% confidence interval, 1.05–2.55) in those with a newly diagnosed glucose disorder despite lower glucose levels on follow-up in those treated with α blockers. The authors conclude that treatment of hypertension with doxazosin in adults with glucose disorders incurs the same risk of coronary heart disease as treatment with chlorthalidone; however, treatment with doxazosin increases the risk of combined cardiovascular disease and heart failure despite lower glucose levels.     

Diabetes and metabolic dysfunction in COPD

Diabetes mellitus and metabolic syndrome are common in patients with chronic obstructive pulmonary disease (COPD). Metabolic disorders are associated with worse cardiovascular and pulmonary outcomes in COPD patients. This review will consider the prevalence, detection and management of metabolic disorders in COPD.Diabetes mellitus is more common in stable COPD patients than in matched controls. COPD may directly increase insulin resistance through effects of chronic inflammation on insulin receptor signalling and through chronic hypoxia and systemic corticosteroid treatment. COPD patients with diabetes have increased risk of pulmonary infection, structural lung damage, hospitalisation and death. Management of diabetes in COPD should follow treatment guidelines for type 2 diabetes. However oral hypoglycaemic treatment may need to be modified in those with respiratory failure, cachexia or heart failure.Glucose tolerance deteriorates during COPD exacerbations due to physiological stress of acute illness and to increased inflammation, acidosis and corticosteroid dose. Acute hyperglycaemia during COPD exacerbations is associated with prolonged hospital stay, NIV failure and increased risk of death. There is little evidence to guide management of acute hyperglycaemia in COPD, however attention should be given to nutrition and to minimising corticosteroid dose. Intravenous insulin to maintain blood glucose 8–10 mmol.L^?1 may also be of therapeutic value.Insulin resistance commonly occurs with obesity, dyslipidaemia and hypertension. Together these make up the ‘metabolic syndrome’, which is a major determinant of cardiovascular morbidity and mortality. Coordinated management of diverse aspects of the metabolic syndrome is essential to optimise cardiovascular outcomes. Retrospective cohort and population studies have found that use of statins, ACE inhibitors and angiotensin II receptor blocker by COPD patients is associated with improvement in pulmonary function and exercise capacity and reduction in exacerbations and COPD-related mortality. These observations need to be confirmed in large interventional studies.     

Metabolic properties of vasodilating beta blockers: management considerations for hypertensive diabetic patients and patients with the metabolic syndrome

Type 2 diabetes and hypertension are both insulin-resistant states that impose an excessive risk burden for future major cardiovascular events, including coronary heart disease, stroke, and heart failure. beta-adrenergic receptor antagonists are effective for the treatment of hypertension, but they are underused in diabetic patients because of possible adverse effects on carbohydrate and lipid metabolism, including insulin resistance, glucose intolerance, and dyslipidemia. Traditional beta blockers, both nonselective and selective, are vasoconstrictive due to unopposed alpha1 activity; however, vasodilating beta blockers are not associated with these negative metabolic effects. This review discusses the background of insulin resistance and its link to diabetes and hypertension, emphasizing the role of vascular control by the renin-angiotensin and sympathetic nervous systems on insulin sensitivity and glucose utilization. Clinical evidence is reviewed for the use of vasodilating beta blockers in the treatment of hypertension and in reducing cardiovascular risk in the diabetic population.     

Obesity and target organ damage: the heart

In most patients, coronary atherosclerosis or congestive heart failure develop as an integrated response to multiple cardiovascular risk factors. Obesity increases the prevalence of most cardiovascular risk factors and is the predominant cause of diabetes mellitus and arterial hypertension. Moreover, obesity shifts the manifestation of these risk factors to younger age groups, such that subsequent damage results prematurely in clinically overt cardiac diseases. In addition, due to clustering of obesity-related risk factors, obesity may amplify the risk by synergistic mechanisms acting in parallel. Finally, an elevated body mass index (BMI) results in an increase in heart rate and blood volume, as well as increased systolic and diastolic blood pressure. These changes affect cardiac geometry and mass in addition to the alterations of the coronary vasculature. At the population level, the role of obesity in promoting multiple risk factors and, subsequently, the development of heart diseases cannot be underestimated. In individual patients, however, the clinical presentation may be dominated by obesity-related hypertension, diabetes, metabolic and inflammatory derangements or clinical symptoms of heart failure or coronary artery disease. Weight reduction remains a crucial component of the therapeutic strategy to ameliorate insulin resistance, hypertension and left ventricular hypertrophy, among other risk factors, with profound implications for the individual's prognosis.     

Angiotensin-receptor blocking agents and the peroxisome proliferator-activated receptor-γ system

The metabolic syndrome leads to cardiovascular disease and type 2 diabetes mellitus, through multiple risks, such as insulin resistance, dyslipidemia, hyperinsulinemia, and hypertension. It also represents a disorder of partial genetic background as mutations of the peroxisome proliferator-activated receptor-gamma (PPAR-γ). Thiazolidinedione agonists for the PPAR-γ system are effective in control of insulin resistance and diabetes. Telmisartan has a molecular structure that imparts partial agonist properties with the PPAR-γ molecule, which results in reductions in glucose and lipid metabolism. Administration of telmisartan to rats on a high-fat, high-carbohydrate diet leads to reductions in glucose, insulin, and triglyceride levels. The results imply that the ARB agent, telmisartan, could treat both the hemodynamic and metabolic aberrations seen in subjects with the metabolic syndrome, such as insulin resistance, glucose intolerance, and hypertension.     

Heart failure in diabetes mellitus: causal and treatment considerations

The metabolic abnormalities associated with diabetes mellitus result in macrovascular and microvascular complications in multiple organ systems; it is the cardiovascular impact that accounts for the greatest morbidity and mortality associated with this disease. Heart failure, both with reduced and preserved systolic function, is a major complication, arising from the frequent associations with coronary atherosclerosis, hypertension, and a specific heart muscle dysfunction (cardiomyopathy) that occurs independently of coronary artery disease. Hyperglycemia, insulin resistance, and hypertension, together with activation of both circulating and tissue renin-angiotensin-aldosterone systems, contribute to structural fibrosis and autonomic neuropathy. Thus it becomes imperative to identify cardiac abnormalities early in the course of both type 1 and type 2 diabetes in order to allow early and aggressive intervention to control glucose and blood pressure and to normalize blood lipid profiles. Patients with diabetes should be treated to secondary prevention targets, including blood pressure less than 130/80 mm Hg and LDL less than 100 mg/dL. Angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, certain calcium channel blockers, statins, and aspirin have all been demonstrated to significantly reduce cardiovascular morbidity and mortality in patients with diabetes.     

Diabetes in the elderly

The association of diabetes and cardiovascular disease is a major health concern in the elderly population. Patients 65 years of age or older with diabetes have a greater risk of ischemic heart disease and cardiovascular mortality than nondiabetic patients of the same age. In addition, although there has been an overall reduction in cardiovascular disease morbidity and mortality in the United States over the past 50 years, the burden of cardiovascular disease attributable to diabetes mellitus has actually increased over this time. In addition to traditional risk factors (eg, hypertension, dyslipidemia), the effect of nonclassical cardiovascular risk factors, such as exogenous and endogenous insulin, metabolic syndrome, impaired fasting glucose, chronic kidney disease, advanced glycation end products, and adipokines, in elder patients with diabetes is currently being evaluated. This article addresses current evidence related to cardiovascular risk in elderly patients with diabetes.     

Diabetes mellitus and hypertension.

Diabetes mellitus and hypertension are common diseases that coexist at a greater frequency than chance alone would predict. Hypertension in the diabetic individual markedly increases the risk and accelerates the course of cardiac disease, peripheral vascular disease, stroke, retinopathy, and nephropathy. Our understanding of the factors that markedly increase the frequency of hypertension in the diabetic individual remains incomplete. Diabetic nephropathy is an important factor involved in the development of hypertension in diabetics, particularly type I patients. However, the etiology of hypertension in the majority of diabetic patients cannot be explained by underlying renal disease and remains "essential" in nature. The hallmark of hypertension in type I and type II diabetics appears to be increased peripheral vascular resistance. Increased exchangeable sodium may also play a role in the pathogenesis of blood pressure in diabetics. There is increasing evidence that insulin resistance/hyperinsulinemia may play a key role in the pathogenesis of hypertension in both subtle and overt abnormalities of carbohydrate metabolism. Population studies suggest that elevated insulin levels, which often occurs in type II diabetes mellitus, is an independent risk factor for cardiovascular disease. Other cardiovascular risk factors in diabetic individuals include abnormalities of lipid metabolism, platelet function, and clotting factors. The goal of antihypertensive therapy in the patient with coexistent diabetes is to reduce the inordinate cardiovascular risk as well as lowering blood pressure.