Diabetes,Hypertension, and Cardiovascular Disease: Clinical Insights and Vascular Mechanisms

Hypertension and type 2 diabetes are common comorbidities. Hypertension is twice as frequent in patients with diabetes compared with those who do not have diabetes. Moreover, patients with hypertension often exhibit insulin resistance and are at greater risk of diabetes developing than are normotensive individuals. The major cause of morbidity and mortality in diabetes is cardiovascular disease, which is exacerbated by hypertension. Accordingly, diabetes and hypertension are closely interlinked because of similar risk factors, such as endothelial dysfunction, vascular inflammation, arterial remodelling, atherosclerosis, dyslipidemia, and obesity. There is also substantial overlap in the cardiovascular complications of diabetes and hypertension related primarily to microvascular and macrovascular disease. Common mechanisms, such as upregulation of the renin-angiotensin-aldosterone system, oxidative stress, inflammation, and activation of the immune system likely contribute to the close relationship between diabetes and hypertension. In this article we discuss diabetes and hypertension as comorbidities and discuss the pathophysiological features of vascular complications associated with these conditions. We also highlight some vascular mechanisms that predispose to both conditions, focusing on advanced glycation end products, oxidative stress, inflammation, the immune system, and microRNAs. Finally, we provide some insights into current therapies targeting diabetes and cardiovascular complications and introduce some new agents that may have vasoprotective therapeutic potential in diabetes.     

Mechanisms and Clinical Significance of Endothelial Dysfunction in High-Risk Pregnancies

The maternal cardiovascular system undergoes critical anatomic and functional adaptations to achieve a successful pregnancy outcome which, if disrupted, can result in complications that significantly affect maternal and fetal health. Complications that involve the maternal cardiovascular system are among the most common disorders of pregnancy, including gestational hypertension, preeclampsia, gestational diabetes, and impaired fetal growth. As a central feature, maternal endothelial dysfunction is hypothesized to play a predominant role in mediating the pathogenesis of these high-risk pregnancies, and as such, might proceed and precipitate the clinical presentation of these pregnancy disorders. Improving or normalizing maternal endothelial function in high-risk pregnancies might be an effective therapeutic strategy to ameliorate maternal and fetal clinical outcomes.     

Abnormal Myocardial Dietary Fatty Acid Metabolism and Diabetic Cardiomyopathy

Patients with diabetes are at very high risk of hospitalization and death from heart failure. Increased prevalence of coronary heart disease, hypertension, autonomic neuropathy, and kidney failure all play a role in this increased risk. However, cardiac metabolic abnormalities are now recognized to play a role in this increased risk. Increased reliance on fatty acids to produce energy might predispose the diabetic heart to oxidative stress and ischemic damage. Intramyocellular accumulation of toxic lipid metabolites leads to a number of cellular abnormalities that might also contribute to cardiac remodelling and cardiac dysfunction. However, fatty acid availability from circulation and from intracellular lipid droplets to fuel the heart is critical to maintain its function. Fatty acids delivery to the heart is very complex and includes plasma nonesterified fatty acid flux as well as triglyceride-rich lipoprotein-mediated transport. Although many studies have shown a cross-sectional association between enhanced fatty acid delivery to the heart and reduction in left ventricular function in subjects with prediabetes and diabetes, these mechanisms change very rapidly during type 2 diabetes treatment. The present review focuses on the role of fatty acids in cardiac function, with particular emphasis on the possible role of early abnormalities of dietary fatty acid metabolism in the development of diabetic cardiomyopathy.     

Disasters and the heart: a review of the effects of earthquake-induced stress on cardiovascular disease.

There is growing evidence that stress contributes to cardiovascular disease. Chronic stress contributes to the atherosclerotic process through increased allostatic load, which is mediated by the neuroendocrine and immune systems (sympathetic nervous system and hypothalamus-pituitary adrenal axis) and related chronic risk factors (insulin resistance syndrome, hypertension, diabetes, and hyperlipidemia). In addition, acute stress can trigger cardiovascular events predominantly through sympathetic nervous activation and potentiation of acute risk factors (blood pressure increase, endothelial cell dysfunction, increased blood viscosity, and platelet and hemostatic activation). Earthquakes provide a good example of naturally occurring acute and chronic stress, and in this review we focus mainly on the effects of the Hanshin-Awaji earthquake on the cardiovascular system. The Hanshin-Awaji earthquake resulted in a 3-fold increase of myocardial infarctions in people living close to the epicenter, particularly in women, with most of the increase occurring in nighttime-onset events. There was also a near doubling in the frequency of strokes. These effects may be mediated by changes in hemostatic factors, as demonstrated by an increase of D-dimer, von Willebrand factor, and tissue-type plasminogen activator (tPA) antigen. Blood pressure also increased after the earthquake, and was prolonged for several weeks in patients with microalbuminuria.     

The role of the sympathetic nervous system in obesity-related hypertension

Obesity is recognized as a major health problem throughout the world. Excess weight is a major cause of increased blood pressure in most patients with essential hypertension and greatly increases the risk for diabetes, cardiovascular diseases, and end-stage renal disease. Although the mechanisms by which obesity raises blood pressure are not completely understood, increased renal sodium reabsorption, impaired pressure natriuresis, and volume expansion appear to play important roles. Several potential mechanisms have been suggested to contribute to altered kidney function and hypertension in obesity, including activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system, as well as physical compression of the kidneys, especially when visceral obesity is present. Activation of the sympathetic nervous system in obesity may be due, in part, to hyperleptinemia and other factors secreted by adipocytes and the gastrointestinal tract, activation of the central nervous system melanocortin pathway, and baroreceptor dysfunction.     

Renal Sympathetic Nerve Ablation: The New Frontier in the Treatment of Hypertension

The sympathetic nervous system plays an important role in circulatory and metabolic control and has clearly been established as a major contributor to the development of hypertension, as elevated sympathetic nerve activity initiates and sustains the elevation of blood pressure. Increased sympathetic outflow to the heart, resulting in increased cardiac output and neurally mediated vasoconstriction of peripheral blood vessels, is an obvious example of a neural pathophysiologic pathway leading to elevated blood pressure. The consequences of increased sympathetic outflow to the kidneys, perhaps most important in this context, are sodium and water retention, increased renin release, and alterations of renal blood flow—effects that contribute substantially to both acute and long-term blood pressure elevations. Accordingly, renal sympathetic nerve ablation appears to be a logical therapeutic approach for the treatment of hypertension. Recent reports on a novel catheter-based renal nerve ablation procedure reviewed in this article are promising.     

Update: systemic diseases and the cardiovascular system (i): obesity and the heart

Excess weight is the most prevalent cardiovascular risk factor and certainly the factor that improves the least over time among those with established cardiovascular disease. The association between obesity and cardiovascular disease is complex and not limited to the standard risk factors like hypertension, dyslipidemia, and type 2 diabetes mellitus. In recent years, multiple studies have shown that obesity may cause cardiovascular diseases via multiple disease mechanisms like subclinical inflammation, endothelial dysfunction, increased sympathetic tone, atherogenic lipid profiles, enhanced thrombogenic factors and also through obstructive sleep apnea.Despite the overwhelming data linking obesity to cardiovascular disease, several studies have shown a paradoxical association between obesity and prognosis among those with coronary disease and heart failure, which may be due to limitations of the way we currently define obesity. There is abundant data suggesting that measuring central obesity or total body fat content might be more appropriate than using the body mass index alone.The management of obesity is challenging and studies using lifestyle modification alone or with pharmacologic agents generally have limited success and high levels of weight regain. Bariatric surgery has proven to be an effective and safe way to induce and maintain significant weight loss but is limited to those with medically complicated obesity or people who are severely obese.Full English text available from: www.revespcardiol.org     

Insulin, insulin sensitivity and hypertension

The sensitivity of tissue to insulin is of physiological, pathophysiological and therapeutic relevance. The quantity of insulin and the response to insulin are paramount complementary factors in the regulation of glucose metabolism, and may, at least under certain pathophysiological conditions, also affect cardiovascular function. Hypertension has a high prevalence among subjects with decreased insulin sensitivity and/or hyperinsulinaemia due to obesity, impaired glucose tolerance, non-insulin-dependent diabetes mellitus, and certain other conditions. There is evidence that, even in the absence of obesity or diabetes mellitus, essential hypertension tends to be associated with insulin resistance. The latter elicits a compensatory increase in insulin secretion. Hyperinsulinaemia also occurs in diabetes type 1 as a consequence of insulin treatment. Considering the acute effects of insulin on sympathetic nervous activity, transmembranous cation transport, renal sodium reabsorption, cellular proliferation and lipid metabolism, insulin resistance and/or hyperinsulinaemia may possibly contribute to the genesis of essential, obesity-associated and diabetes-associated hypertension, and may also promote dyslipidaemia in these disorders.     

The causes of raised blood pressure in insulin-dependent and non-insulin-dependent diabetes

Blood pressure is generally normal in insulin-dependent diabetic patients in the absence of nephropathy. Despite this, exchangeable sodium is increased. Blood pressure rises with the development of incipient nephropathy, and hypertension is common in patients with overt nephropathy. Exchangeable sodium is then markedly increased, but plasma renin is not suppressed. Raised BP in diabetic nephropathy is probably sustained, in part at least, by sodium retention and inappropriate activity of the renin-angiotensin system. There is an increased prevalence of hypertension among patients with non-insulin-dependent diabetes (NIDDM). In normotensive patients, exchangeable sodium is elevated and plasma renin is suppressed. In hypertensive patients, exchangeable sodium is less markedly increased, while plasma renin is again suppressed. These findings are in contrast with those in diabetic nephropathy, and are in keeping with the hypothesis that hypertension in NIDDM is usually due to coexisting essential hypertension. Also in keeping with this suggestion is an increased prevalence of raised BP among the siblings of NIDDM patients. Prolonged hyperinsulinaemia precedes the diagnosis of NIDDM, and hypertension is often present at the time of diagnosis. Insulin resistance and compensatory hyperinsulinaemia might lead to an increase in BP by a number of putative mechanisms, such as enhancing renal sodium retention, by an effect on cell membrane ion exchange mechanisms or by enhancing activity of the sympathetic nervous system. This seems a fertile area for further research, although a causal link between insulin resistance and hyperinsulinaemia on the one hand, and raised BP on the other, remains to be proved.     

Pathways from obesity to hypertension: from the perspective of a vicious triangle

Obesity and arterial hypertension are important public health problems. Both overweight and hypertension predispose to cardiovascular diseases, such as myocardial infarction, stroke and renal failure. Moreover, overweight clearly predisposes to hypertension, and thus to an increased prevalence of cardiovascular diseases. This in turn favors inactivity and further weight gain, leading to an exacerbation of cardiovascular disorders. Obesity, hypertension and cardiovascular diseases thus contribute to three corners of a vicious triangle. It is within this conceptual framework that this paper reviews the pathogenesis of obesity-related hypertension, which is highly complex. Many factors act together to promote vasoconstriction and sodium retention. Leptin, free fatty acids and insulin, whose levels are increased in obesity, may act synergistically to stimulate sympathetic activity and vasoconstriction. In addition, obesity-induced insulin resistance and endothelial dysfunction may operate as amplifiers of the vasoconstrictor response. Finally, increased renal tubular reabsorption of sodium may also occur, caused by an increased renal sympathetic nerve activity, the direct effect of insulin, hyperactivity of the renin-angiotensin system and possibly by an alteration of intrarenal physical forces. All together, these factors will lead to sustained hypertension. Because the prevalence of obesity was steadily increasing in the last decades, leading to an increased prevalence of hypertension and cardiovascular disorders, obesity and hypertension will most likely become the health challenges of the twenty-first century.     

Role of leptin in the cardiovascular and endocrine complications of metabolic syndrome

AIM: To review the potential role of leptin, hyperleptinaemia and leptin resistance in the cardiovascular and endocrine complications of metabolic syndrome. METHODS: Review of literature listed in Medline. RESULTS: Hyperleptinaemia is common in obesity and reflects increased adiposity and leptin resistance. Nevertheless, leptin resistance may not be complete as several actions of leptin, such as cardiovascular sympatho-activation, might be preserved in obese subjects known to be resistant to the metabolic effects of leptin (i.e. selective leptin resistance). Notably, the renal and sympathetic actions of leptin may play an important role in the pathogenesis of hypertension related to obesity and metabolic syndrome. Furthermore, the lipotoxic effect of leptin resistance may cause insulin resistance and beta cell dysfunction, increasing the risk of type 2 diabetes. Leptin has also been shown to possess proliferative, pro-inflammatory, pro-thrombotic, and pro-oxidative actions. CONCLUSION: Hyperleptinaemia and leptin resistance may contribute to hypertension, impaired glucose metabolism, and pro-atherogenic state in obesity and metabolic syndrome.     

Possible Mechanisms of Sodium-Dependent Hypertension: Volume Expansion or Vasoconstriction?

A series of experiments was designed to explore the mechanisms contributing to hypertension caused by an acute or chronic sodium load. Acute salt-loading in totally or subtotally nephrectomized animals caused hypertension mediated partly through stimulation of excessive vasopressin release and partly through adrenergic stimulation. Chronic high-salt diet in rats submitted to partial nephrectomy, mineralocorticoid excess or one-kidney-one-clip renovascular hypertension caused blood pressure elevation mediated through a central neurogenic mechanism that could be reversed by administration of an inhibitor of phenyl-ethanolamine-N-methyltransferase, the enzyme catalyzing conversion of norepinephrine to epinephrine. Thus, two vasopressor mechanisms were stimulated by sodium excess: an acute, transient, partly vasopressin- mediated phase seemed to be followed by a chronic phase mediated through stimulation of central sympathetic neurons. In neither phase was blood pressure related to intravascular fluid volume expansion.     

SYMPATHETIC NERVOUS SYSTEM,DIABETES, AND HYPERTENSION

Hypertension is twice as frequent in diabetic patients than in the general population. Its prevalence is higher in Type 2 than in Type 1 diabetes: in the former, the onset of hypertension often precedes the diagnosis of diabetes, whereas, in the latter it is strictly related to the presence of nephropathy. Sympathetic nerve overactivity is crucial in the pathogenesis of hypertension in diabetes. It can be related to the activation of the renin-angiotensin-aldosterone (RAA) system in Type 1 diabetic patients with chronic renal failure, or to a condition of insulin resistance/hyperinsulinemia in Type 2 patients with the metabolic syndrome. In patients with early autonomic neuropathy, vagal impairment can lead to a relative predominance of sympathetic activity in the sympatho-vagal balance. In these patients, the onset of hypertension is frequently preceded by reduced nocturnal dipping. Sympathetic overactivity stimulates RAA activity, promotes sodium reabsorption, and increases heart rate, stroke volume and peripheral vascular resistance, thus inducing hypertension and increasing cardiovascular risk. A number of drugs acting either directly or indirectly on sympathetic activity are available for the treatment of hypertension in diabetic subjects. Opinions on the potential advantages of the metabolic profile of some of these drugs are as yet conflicting.     

Sympathetic nervous system, diabetes, and hypertension

Hypertension is twice as frequent in diabetic patients than in the general population. Its prevalence is higher in Type 2 than in Type 1 diabetes: in the former, the onset of hypertension often precedes the diagnosis of diabetes, whereas, in the latter it is strictly related to the presence of nephropathy. Sympathetic nerve overactivity is crucial in the pathogenesis of hypertension in diabetes. It can be related to the activation of the renin-angiotensin-aldosterone (RAA) system in Type 1 diabetic patients with chronic renal failure, or to a condition of insulin resistance/hyperinsulinemia in Type 2 patients with the metabolic syndrome. In patients with early autonomic neuropathy, vagal impairment can lead to a relative predominance of sympathetic activity in the sympatho-vagal balance. In these patients, the onset of hypertension is frequently preceded by reduced nocturnal dipping. Sympathetic overactivity stimulates RAA activity, promotes sodium reabsorption, and increases heart rate, stroke volume and peripheral vascular resistance, thus inducing hypertension and increasing cardiovascular risk. A number of drugs acting either directly or indirectly on sympathetic activity are available for the treatment of hypertension in diabetic subjects. Opinions on the potential advantages of the metabolic profile of some of these drugs are as yet conflicting.     

Diabetes mellitus and arterial hypertension. In search of the connecting link]

Late diabetic effects are the sequelae of for a long time super elevated blood sugar levels. The diabetic nephropathy is the cause of the secondary arterial hypertension. The investigation seeks for the connections between the diabetes mellitus and the essential, that is primary hypertension. The two diseases frequently appear and clearly increase in the second half of life. Moreover, they are above average frequently associated with each other. Among brothers and sisters of diabetic hypertensives in comparison to normal cohorts clearly increased high blood pressure prevalences were found. The insulin resistance which could be proved in a great number of hypertensive and which has been known since more than two decades might be the connecting link between hypertension and diabetes mellitus. Like the obesity the essential hypertension can be associated with all degrees of an insulin hyposensitiveness. The sodium-retaining effect of the insulin might explain the increased sodium content of the body in hypertensives. The differential diagnostics of the essential hypertension should therefore seek for conditions of an insulin resistance. The type II diabetic lacks a release of bradykinin during muscle work. Thus the glucose uptake into the cell is unfavourable influenced and demands an increased insulin excretion. This genetically (?) fixed defect is found also in essential hypertensives. It could be the connecting link between the two diseases. ACE-inhibitors have via a kininase II inhibition an effect also on the bradykinin decomposition and can favourable influence the glucose uptake into the muscle. An improved insulin effect among the ACE-inhibitors was described. Therefore, they should be preferred in the treatment of hypertensive diabetics.     

Treatment of hypertension in diabetic men: problems with sexual dysfunction

Hypertension occurs 2 to 3 times more frequently in diabetic persons than in nondiabetic persons. Care must be taken in treating hypertension in diabetic patients because the choice of antihypertensive agent may worsen the diabetic state or its complications or cause additional health problems for the patient. Sexual dysfunction is a common problem in diabetic patients; however, diabetes need not be the cause. Diabetic men with hypertension have an increased sensitivity to the side effect of sexual dysfunction, which occurs from the use of centrally acting antihypertensive agents. By using prazosin, an alpha 1-adrenergic blocking agent, this cause of sexual dysfunction was eliminated. The reasons for the increased prevalence of hypertension in diabetic patients are discussed and a rational approach is given for the treatment of elevated blood pressure in these individuals.     

Orthostatic hypertension: Recognizing an underappreciated clinical condition

Orthostatic hypertension refers to an increase in the blood pressure upon assuming an upright posture. This clinical condition has been understudied and is often underappreciated in clinical practice probably because of its unfamiliarity to many clinicians including subspecialists. We report a case of severely symptomatic orthostatic hypertension in a Caucasian female, which was likely secondary to an autonomic dysfunction caused by an underlying vascular adrenergic hypersensitivity and possibly also due to uncontrolled diabetes mellitus (causing baroreflex dysfunction associated with excessive sympathetic stimulation). The case work-up also illustrates a schematic diagnostic and management approach to this rarely encountered clinical entity.     

High and low renin subgroups of essential hypertension: Differences and similarities in their renin and sympathetic responses to neural and nonneural stimuli

This study was designed to test the hypothesis that the abnormally high and abnormally low levels of renin observed in essential hypertension may reflect different levels of sympathetic nervous activity and to evaluate the alternative possibility that they are due to different levels of renin responsiveness to neurogenic stimuli. Thus, plasma norepinephrine, epinephrine and renin activity were measured at rest and during 30 minutes of head-up tilt in 43 patients with uncomplicated essential hypertension classified as having high, normal and low plasma renin activity during a constant sodium intake of 100 mEq/day. In addition, to investigate the renin responsiveness to nonneural stimuli, the same humoral variables were measured at rest in 18 patients after dietary sodium restriction.While patients were consuming the 100 mEq sodium diet, supine plasma norepinephrine and epinephrine concentrations were similar, whereas supine plasma renin activity was significantly different among the three subgroups. During tilt, 40 percent of patients in the high renin subgroup had vasovagal episodes whereas only 5 percent in the normal renin and none in the low renin subgroup experienced similar reactions. Excluding the data obtained from patients who fainted, the tilt-induced absolute increments in norepinephrine and epinephrine were again similar whereas the percent renin responses were significantly greater in the high than in the low renin subgroups. In contrast, sodium deprivation caused similar percent increases in supine plasma renin activity without inducing significant changes in plasma norepinephrine and epinephrine.To the extent that plasma catecholamine measurements reflect sympathetic nervous activity, the results indicate that the differences in plasma renin activity among patients with essential hypertension cannot be attributed to differences in neural activity or in ability to produce renin, but rather are due to discrepancies in renin responsiveness to neural stimuli. Because the renin response to tilt is mediated through the juxtaglomerular beta adrenoreceptors, it is possible that patients with high and low renin activity have different sensitivities of these receptors to similar adrenergic stimulation.     

Two forms of vasoconstriction in systemic hypertension

Clinical, pharmacologic and biochemical evidence characterizes essential hypertension as a heterogeneous spectrum of pathophysiologic substances rather than the single entity it has long been presumed to be. Although the causes of essential hypertension remain obscure, 2 different mechanisms for long-term vasoconstriction that sustain diastolic hypertension in the experimental and clinical forms of primary aldosteronism and renovascular hypertension can also be identified and quantified among patients with essential hypertension. The first mechanism is renin independent, requires antecedent sodium retention and appears related to abnormal membrane transport of calcium. This vasoconstriction is identified by low plasma renin and ionized calcium and is correctable by sodium depletion or calcium channel or alpha blockade. The second vasoconstrictor mechanism is renin mediated and involves an increase in cytosolic calcium. This mechanism is quantifiable by the plasma renin level or the hypotensive response to an antirenin-system drug (converting enzyme inhibitor, beta blocker or saralasin). Depending on the state of sodium balance, these 2 mechanisms contribute reciprocally to maintenance of arteriolar tone in experimental models, in both normal and hypertensive people, and in patients with congestive heart failure. In these situations, at the extremes of the range of plasma renin values, one or the other mechanism predominates, whereas in the medium range of renin values both mechanisms can be operative. These interrelations provide a basis for applying more precisely tailored therapy and for stratifying patients pathophysiologically for further study.     

Hypertension Management and Microvascular Insulin Resistance in Diabetes

Type 2 diabetes is in essence a vascular disease and is frequently associated with hypertension, macrovascular events, and microvascular complications. Microvascular dysfunction, including impaired recruitment and capillary rarefaction, has been implicated in the pathogenesis of diabetic complications. Microvascular insulin resistance and renin-angiotensin system upregulation are present in diabetes, and each contributes to the development of hypertension and microvascular dysfunction. In the insulin-sensitive state, insulin increases microvascular perfusion by increasing endothelial nitric oxide production, but this effect is abolished by insulin resistance. Angiotensin II, acting via the type 1 receptors, induces inflammation and oxidative stress, leading to impaired insulin signaling, reduced nitric oxide availability, and vasoconstriction. Conversely, it acts on the type 2 receptors to cause vasodilatation. Because substrate and hormonal exchanges occur in the microvasculature, antihypertensive agents targeted to improve microvascular insulin sensitivity and function may have beneficial effects beyond their capacity to lower blood pressure in patients with diabetes.