Hypertension control: multifactorial contributions

Treatment of hypertension reduces the risk of several associated deleterious conditions, although it does not lower risk for all cardiovascular diseases. A new theory suggests that high blood pressure is but one piece in the puzzle of a complex syndrome of inherited risk factors called the hypertension syndrome. Several new findings have emerged theorizing that patients may have coronary artery disease before the actual onset of elevated blood pressure. Epidemiologic studies have found that normotensive patients with a family history of hypertension often have a disease process and prognosis similar to that of hypertensives. It seems that some patients may “inherit” abnormalities that make them prone to the development of hypertension, as well as a complex series of cardiovascular disease risk factors. These include elevated lipids, increased left ventricular hypertrophy, arterial stiffening, insulin resistance, renal function abnormalities, and neuroendocrine changes. It is conceivable that the hypertension syndrome may be reversible if the disease process is diagnosed early, which appears to be well before the actual onset of high blood pressure. High blood pressure may be a risk marker for irreversible vascular disease and early detection of the many components of hypertension syndrome may delay or prevent cardiovascular disease from developing in high-risk patients.     

Thiazolidinediones-improving endothelial function and potential long-term benefits on cardiovascular disease in subjects with type 2 diabetes

Endothelial dysfunction, which leads to impaired vasodilation, is an early event in the development of atherosclerosis. A number of mechanisms involving, for example, cell adhesion molecules, chemokines, and cytokines, contribute to this inflammatory disease, and insulin resistance plays a cardinal role in accelerating these processes. Hyperglycemia and other metabolic abnormalities that are commonly associated with insulin resistance also contribute to impaired endothelial function. In addition, the important role of the endothelium in damage repair following a cardiovascular event is emerging. The combination of proatherogenic factors in patients with type 2 diabetes results in blunted endothelial function and an increased risk of cardiovascular disease. Insulin-sensitizing agents such as thiazolidinediones have demonstrated a number of clinical benefits, including anti-inflammatory and antithrombotic properties, which may impact on the course of atherosclerosis. Recent studies have demonstrated that thiazolidinediones improve endothelial function in subjects with and without type 2 diabetes.     

Hypertension: Where have we gone wrong and how can we fix it?

Hypertension is defined as a disease of elevated systolic and diastolic blood pressure and consequently the goals of treating hypertension have been simply to normalize the blood pressure. However, effective blood pressure control has not resulted in the expected decreases in coronary artery disease. These findings have forced researchers to reexamine the importance of blood pressure in causing coronary artery disease, and to pose the question “Is there more to hypertension than high blood pressure?”Although there are probably several reasons for the poor reduction in the incidence of coronary artery disease in hypertensive patients, one of the most compelling appears to be the realization that hypertension is not simply a disease of numbers, but is a complex inherited syndrome of cardiovascular risk factors, all of which contribute to heart disease in these patients. Included in the hypertension syndrome are abnormalities of lipid profile, insulin resistance, changes in renal function, endocrine changes, obesity, abnormalities of coagulation factors, left ventricular hypertrophy and diastolic dysfunction, and abnormalities of vascular structure and compliance. In many patients, high blood pressure is a late manifestation of this disease process and is preceded by some or all of the associated cardiovascular risk factors.Perhaps where we have gone wrong in the management of hypertension is in the belief that this is simply a disease of numbers. To improve our management, we need to find methods to diagnose these patients early in the course of this disease process, and to treat it as a syndrome rather than as a number.     

Diabetes and Hypertension

The incidence of hypertension is increased in individuals with diabetes mellitus. This is especially true in patients with type 2 diabetes. In these patients high blood pressure is common at the time of diagnosis of diabetes, but the development of diabetes is often preceded by a period during which hyperinsulinemia and insulin resistance is already present. Diabetes represents by itself a major risk of cardiovascular morbidity and mortality. This risk is considerably enhanced by the co-existence of hypertension. One of the main complications of type 2 diabetes is nephropathy, which manifests initially by microalbuminuria, then by clinical proteinuria, leading to a progressive chronic renal failure and end-stage renal disease. Microalbuminuria is considered today as an indicator of renal endothelial dysfunction as well as an independent predictor of the cardiovascular risk. During recent years a number of studies have shown that tight blood pressure control is essential in diabetic patients in order to provide maximal protection against cardiovascular events and the deterioration of renal function. Of note, there is recent evidence indicating that blockade of the renin-angiotensin system with angiotensin II antagonists has marked nephroprotective effects in patients with hypertension and type 2 diabetes, both at early and late stages of renal disease.     

Diabetes and hypertension

The incidence of hypertension is increased in individuals with diabetes mellitus. This is especially true in patients with type 2 diabetes. In these patients high blood pressure is common at the time of diagnosis of diabetes, but the development of diabetes is often preceded by a period during which hyperinsulinemia and insulin resistance is already present. Diabetes represents by itself a major risk of cardiovascular morbidity and mortality. This risk is considerably enhanced by the co-existence of hypertension. One of the main complications of type 2 diabetes is nephropathy, which manifests initially by microalbuminuria, then by clinical proteinuria, leading to a progressive chronic renal failure and end-stage renal disease. Microalbuminuria is considered today as an indicator of renal endothelial dysfunction as well as an independent predictor of the cardiovascular risk. During recent years a number of studies have shown that tight blood pressure control is essential in diabetic patients in order to provide maximal protection against cardiovascular events and the deterioration of renal function. Of note, there is recent evidence indicating that blockade of the renin-angiotensin system with angiotensin II antagonists has marked nephroprotective effects in patients with hypertension and type 2 diabetes, both at early and late stages of renal disease.     

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.     

Insulin resistance in diabetic nephropathy — cause or consequence?

Insulin resistance (IR) is associated with multiple risk factors for cardiovascular disease. Many studies have shown that IR is present in chronic renal failure (CRF), and recent evidence suggests that IR can also occur in the early stages of renal disease. Patients with diabetic nephropathy (DN) have an increase in cardiovascular mortality, and since IR may be a contributing factor, this emphasizes the importance of a detailed understanding of the mechanisms linking IR and renal dysfunction at different stages of DN. IR can be detected early on in DN, e.g. at the stage of microalbuminuria (MA) and this could indicate a common genetic trait for IR and DN. As DN progresses further, IR is aggravated and it may, in addition to other factors, possibly accelerate the decline in renal function toward end-stage renal disease (ESRD). Several potentially modifiable mechanisms including circulating hormones, neuroendocrine pathways and chronic inflammation, are said to contribute to the worsening of IR. In ESRD, uremic toxins are of major importance.In this review article, we address the association between different stages of DN and IR and attempt to summarize major findings on potential mechanisms linking DN and IR. We conclude that IR is a consequence, and potentially also a cause of DN. In addition, there are probably genetic and environmental background factors that predispose to both IR and DN.     

Endothelial dysfunction and the metabolic syndrome

The metabolic syndrome is a highly prevalent multifaceted clinical entity produced through the interaction of genetic, hormonal, and lifestyle factors. A distinctive constellation of abnormalities precedes and predicts the accelerated development of atherogenesis and type 2 diabetes mellitus. Abnormalities of inflammation and coagulation represent emerging risk contributors associated with obesity and insulin resistance, central components of the metabolic syndrome, which act in concert with traditional abnormalities to increase cardiovascular risk. The initiation and progression of atherosclerosis may have its origins in impaired endothelial function that can be detected at the earliest stages of development of the syndrome. The basic elements of the metabolic syndrome and accelerated phase of atherogenesis are often silent partners that present many years before the onset of type 2 diabetes mellitus. The ability to detect and monitor subclinical vascular disease, as a reflection of the multiple factors that contribute to impair arterial wall integrity, holds potential to further refine cardiovascular risk stratification. Noninvasive assessment of vascular health may also aid the clinical decision-making process by guiding therapeutic interventions to optimize vascular protection in the metabolic syndrome.     

Predictors of renal and cardiovascular mortality in patients with non-insulin-dependent diabetes: A brief overview of microalbuminuria and insulin resistance

Both microalbuminuria and insulin resistance are present at some stage in the natural history of non-insulin-dependent diabetes mellitus (NIDDM). Microalbuminuria predicts both progression to endstage renal disease and an increase in cardiovascular mortality compared to diabetic patients without microalbuminuria. Conversely, microalbuminuria is not a strong predictor of either renal or cardiovascular mortality in hypertensive nondiabetic subjects. This difference in risk may relate to the presence of glycated albumin in patients with diabetes. Glycation of albumin occurs because of persistent hyperglycemia. Glycated albumin is directly toxic to both renal and vascular tissue through stimulation of reactive oxygen species by both renal and immune protective cells. Blunting the rise in microalbuminuria with either aggressive blood glucose control or angiotensin-converting enzyme (ACE) inhibition, early in the course of the disease, markedly reduces renal mortality. In contrast to microalbuminuria, which is a reflection of renal injury, insulin resistance is a genetically determined problem that directly relates to peripheral glucose utilization. In most cases, insulin resistance is phenotypically expressed as diabetes as a result of environmental factors such as obesity. Insulin resistance is associated with an increased risk for development of both hypertension and NIDDM as well as atherosclerosis. Diabetic or hypertensive subjects with insulin resistance have an increased risk of cardiovascular but not renal mortality. Sustained weight loss is the best way to reduce insulin resistance and arterial pressure. Additionally, blockers, more than other antihypertensive agents reduce insulin resistance. This class of drugs, however, has not been shown to reduce either microalbuminuria or overall cardio-renal mortality.     

Cardiometabolic features of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a complex disorder comprising both hormonal and metabolic abnormalities that include impaired glucose tolerance, type 2 diabetes, vascular disease, dyslipidemia, and obstructive sleep apnea. Insulin resistance is a central pathogenetic factor in PCOS that seems to result from a post-receptor-binding defect in insulin action. Insulin resistance and the consequent development of hyperinsulinemia contribute to the constellation of cardiometabolic abnormalities noted above. Although there is a paucity of data in regard to cardiovascular event rates and mortality in PCOS, an increased prevalence of cardiovascular risk factors has been well documented. Attention to the metabolic risks associated with PCOS, starting as early as adolescence, is essential to the medical care of these patients.     

Role of mitochondrial dysfunction in insulin resistance

Insulin resistance is characteristic of obesity, type 2 diabetes, and components of the cardiometabolic syndrome, including hypertension and dyslipidemia, that collectively contribute to a substantial risk for cardiovascular disease. Metabolic actions of insulin in classic insulin target tissues (eg, skeletal muscle, fat, and liver), as well as actions in nonclassic targets (eg, cardiovascular tissue), help to explain why insulin resistance and metabolic dysregulation are central in the pathogenesis of the cardiometabolic syndrome and cardiovascular disease. Glucose and lipid metabolism are largely dependent on mitochondria to generate energy in cells. Thereby, when nutrient oxidation is inefficient, the ratio of ATP production/oxygen consumption is low, leading to an increased production of superoxide anions. Reactive oxygen species formation may have maladaptive consequences that increase the rate of mutagenesis and stimulate proinflammatory processes. In addition to reactive oxygen species formation, genetic factors, aging, and reduced mitochondrial biogenesis all contribute to mitochondrial dysfunction. These factors also contribute to insulin resistance in classic and nonclassic insulin target tissues. Insulin resistance emanating from mitochondrial dysfunction may contribute to metabolic and cardiovascular abnormalities and subsequent increases in cardiovascular disease. Furthermore, interventions that improve mitochondrial function also improve insulin resistance. Collectively, these observations suggest that mitochondrial dysfunction may be a central cause of insulin resistance and associated complications. In this review, we discuss mechanisms of mitochondrial dysfunction related to the pathophysiology of insulin resistance in classic insulin-responsive tissue, as well as cardiovascular tissue.     

Is insulin resistance atherogenic? A review of the evidence

Several factors that increase the risk of cardiovascular disease tend to cluster together in the same individual. Insulin resistance is believed to be a pathophysiological disturbance that underlies many of the risk factors. Whether insulin resistance per se is a cardiovascular risk factor is uncertain. Insulin resistance of myocardial muscle has been documented both in patients with type 2 diabetes and in nondiabetic subjects with angiographically proven coronary artery disease. In addition, in diabetic patients there is a mismatch between the redistribution of blood flow and glucose uptake during insulinization. Finally, the endothelial dysfunction and the hyperinsulinemia that accompany insulin resistance may adversely affect myocardial function. The evidence from epidemiological studies or clinical trials is, however, mixed. In at least one recent prospective study in patients with congestive heart failure, insulin resistance was an independent predictor of cardiac death. Conclusive proof would require a prospective study in which insulin resistance is measured directly and adequate account is taken of the classical cardiovascular risk factors.     

类风湿关节炎患者心血管风险的管理

类风湿关节炎(rheumatoid arthritis,RA)患者心血管病发病率和死亡率的风险增加。吸烟、高血压、血脂异常、胰岛素抵抗、糖尿病、肥胖和体力活动缺乏传统危险因素不能完全解释RA心血管风险。炎性反应在RA和心血管病之间起着重要作用,不仅参与动脉粥样硬化的各个阶段:内皮功能障碍、斑块破裂和血栓形成,而且还能加速传统心血管风险,如血脂异常、肥胖和胰岛素抵抗。目前关于RA和心血管病之间确切的发病机制尚不清楚,对RA心血管风险管理是必要的。     

Obesity and insulin resistance as risk factors for chronic kidney disease

The cardiometabolic syndrome is a state of metabolic and vascular dysregulation. The cardiometabolic syndrome is clinically composed of a cluster of metabolic abnormalities including insulin resistance/hyperinsulinemia, central/visceral obesity, dyslipidemia, hypertension, microalbuminuria, fibrinolytic and inflammatory abnormalities, endothelial dysfunction, oxidative stress, and hypercoagulability, which collectively lead to an increased risk of cardiovascular and renal outcomes. The development of microalbuminuria is now accepted as a marker of systemic endothelial dysfunction and, if it progresses to macroalbuminuria (i.e., >200 mg/d albuminuria), then kidney disease is evident. Collectively, visceral obesity, insulin resistance/hyperinsulinemia, and other components of the cardiometabolic syndrome lead to an increased risk of microalbuminuria and progressive loss of renal function. Hence, aggressive management of risk factors for the metabolic syndrome, nonpharmacologic and pharmacologic, is essential to prevent or delay the progressive loss of renal function and chronic kidney disease.     

Fibrinogen and Fibrin Clot Structure in Diabetes

Diabetes is associated with an increased risk of developing cardiovascular disease, which is not fully accounted for by the accumulation of classic cardiovascular risk factors in patients. Recent evidence has demonstrated fibrinogen to be a powerful independent risk marker for cardiovascular disease in the general population, and it is also likely to contribute toward the increased atherosclerotic risk in diabetes. The etiology of hyperfibrinogenemia in diabetes is likely to be multifactorial, and at present the mechanisms involved have not been clarified. However, insulin, insulin resistance and inflammation are likely to be involved, especially in type 2 diabetes. The influence of diabetes in determining an individual's atherothrombotic risk is likely to extend beyond that of elevated fibrinogen levels, and may also act via changes in the structure and function of the fibrin clot that forms. Further research is needed to determine the mechanisms underlying these changes, which may lead to development of future interventions to reduce the excessive vascular risk associated with this disease.     

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.     

Renal function as a predictor of prognosis in chronic heart failure

The incidence of chronic heart failure (CHF) has been increasing, particularly because of the aging of the population and the improved survival of patients with coronary artery disease. Therefore, the current pathophysiological and clinical considerations in the diagnosis and treatment of CHF will need further improvement in terms of cardiovascular risk profiling, preventive measures, earlier intervention, and patient-tailored disease management. To date, the role of the kidney in CHF is mainly considered within the context of excessive salt and water retention, due to reduced renal blood flow. However, recent data indicate that the kidney may play a more decisive role in the progression and prognosis of the disease. It has been demonstrated that renal function is independently associated with an increased risk for all-cause mortality and cardiovascular morbidity. Furthermore, moderate renal insufficiency is a common phenomenon in this patient population and, for example, left ventricular ejection fraction, glomerular filtration rate, and New York Health Association class are not only prognostically important but are also acting independently, and support the hypothesis that cardiac function, clinical status, and renal function represent, in part, different prognostic entities of CHF. It could be questioned why an impaired renal function adds prognostic risk to develop CHF? A subclinically decreased renal function is unlikely to be the direct cause. Renal function is known to correlate with a variety of cardiovascular risk factors. Similar risk factors could contribute to the pathogenesis of intrarenal disease. Furthermore, a large number of metabolic abnormalities are related to impaired renal function and induce myocardial dysfunction and damage. Finally, neurohormonal activation is apparent in patients with chronic heart failure. Angiotensin II, the central product of the renin-angiotensin system, may play a central role in the pathophysiology and progression of cardiovascular and renal diseases. In conclusion, to prevent cardiovascular morbidity and mortality, new therapeutic strategies might be triggered by focussing on increasing our knowledge concerning adaptive and maladaptive mechanisms of the kidney involved in CHF.     

Essential hypertension

Essential hypertension can be defined as a rise in blood pressure of unknown cause that increases risk for cerebral, cardiac, and renal events. In industrialised countries, the risk of becoming hypertensive (blood pressure >140/90 mm Hg) during a lifetime exceeds 90%. Essential hypertension usually clusters with other cardiovascular risk factors such as ageing, being overweight, insulin resistance, diabetes, and hyperlipidaemia. Subtle target-organ damage such as left-ventricular hypertrophy, microalbuminuria, and cognitive dysfunction takes place early in the course of hypertensive cardiovascular disease, although catastrophic events such as stroke, heart attack, renal failure, and dementia usually happen after long periods of uncontrolled hypertension only. All antihypertensive drugs lower blood pressure (by definition) and this decline is the best determinant of cardiovascular risk reduction. However, differences between drugs exist with respect to reduction of target-organ disease and prevention of major cardiovascular events. Most hypertensive patients need two or more drugs for blood-pressure control and concomitant statin treatment for risk factor reduction. Despite the availability of effective and safe antihypertensive drugs, hypertension and its concomitant risk factors remain uncontrolled in most patients.     

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.     

Homocysteine and carotid atherosclerosis in chronic renal failure--the confounding effect of renal function

Since total homocysteine (tHcy) level is markedly elevated in patients with chronic renal failure (CRF), it has been presented as a potential factor contributing to the high risk of cardiovascular disease (CVD) in CRF. Our aim was to examine the significance of elevated tHcy level and other cardiovascular risk factors for carotid atherosclerosis in patients with CRF. In this cross-sectional study, 135 study patients with CRF (52 +/- 11 years) included 58 patients with moderate to severe predialysis CRF, 36 dialysis patients and 41 renal transplant recipients. In addition, 58 control subjects were examined. The association of tHcy level and classic risk factors for atherosclerosis with common carotid artery intima-media thickness (IMT) or carotid artery plaque score was examined. We found no association between tHcy and carotid IMT or a high carotid plaque score in the CRF patient groups. No consistent association was found between elevated tHcy and coronary artery disease, cerebrovascular disease or peripheral arterial disease. Renal function, described as creatinine clearance, was the strongest determinant for tHcy level. Significant predictors of carotid atherosclerosis were age, duration of hypertension and elevated low-density lipoprotein cholesterol level. In conclusion, the present study shows no apparent association between tHcy level and atheromatous carotid findings in patients with CRF. However, because of the changing renal function in the course of renal disease, the strong confounding effect of renal function may not be adequately controlled for the analysis of the significance of elevated tHcy level for CVD in patients with CRF.