| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 2001;37:1053.)
© 2001 American Heart Association, Inc.
Review Article |
Diabetes, Hypertension, and Cardiovascular Disease
An Update
From the SUNY Downstate Medical Center and VAMC (J.R.S.), Brooklyn, NY; the Alton Ochsner Medical Foundation (E.D.F.), New Orleans, La; and VAMC (M.E.), Miami, Fla.
Correspondence to James R. Sowers, MD, Professor of Medicine and Cell Biology, Director, Endocrinology, Diabetes and Hypertension, SUNY HSC at Brooklyn, 450 Clarkson Ave, Box 1205, Brooklyn, NY 11203. E-mail jsowers{at}netmail.hscbklyn.edu
 |
Abstract |
|---|
Top
Abstract
Hypertension in the Diabetic...Abstract—Cardiovascular diseases (CVDs) are the major causes of mortality in persons with diabetes, and many factors, including hypertension, contribute to this high prevalence of CVD. Hypertension is approximately twice as frequent in patients with diabetes compared with patients without the disease. Conversely, recent data suggest that hypertensive persons are more predisposed to the development of diabetes than are normotensive persons. Furthermore, up to 75% of CVD in diabetes may be attributable to hypertension, leading to recommendations for more aggressive treatment (ie, reducing blood pressure to <130/85 mm Hg) in persons with coexistent diabetes and hypertension. Other important risk factors for CVD in these patients include the following: obesity, atherosclerosis, dyslipidemia, microalbuminuria, endothelial dysfunction, platelet hyperaggregability, coagulation abnormalities, and "diabetic cardiomyopathy." The cardiomyopathy associated with diabetes is a unique myopathic state that appears to be independent of macrovascular/microvascular disease and contributes significantly to CVD morbidity and mortality in diabetic patients, especially those with coexistent hypertension. This update reviews the current knowledge regarding these risk factors and their treatment, with special emphasis on the cardiometabolic syndrome, hypertension, microalbuminuria, and diabetic cardiomyopathy. This update also examines the role of the renin-angiotensin system in the increased risk for CVD in diabetic patients and the impact of interrupting this system on the development of clinical diabetes as well as CVD.
Key Words: diabetes • cardiovascular diseases • hypertension, essential • blood pressure
|
Hypertension in the Diabetic Patient |
|---|
The subject of diabetes mellitus as a comorbid disease that frequently confounds hypertension, adding significantly to its overall morbidity and mortality,1 2 will be updated in the present review. Among the complications of diabetes, cardiovascular and renal vascular diseases are among the most costly in terms of human suffering and national healthcare costs. Over the past several years, since the publication of these foregoing reviews, a number of controlled multicenter clinical trials have demonstrated the safety and efficacy of specific antihypertensive therapeutic programs that can significantly alter the outcomes of these cardiovascular and renal complications. The present report summarizes these advances as well as newer fundamental findings that add importantly to our overall knowledge of the cardiovascular complications of diabetes mellitus.
In a recent, large, prospective cohort study that included 12 550 adults, the development of type II diabetes was almost 2.5 times as likely in persons with hypertension than in their normotensive counterparts.3 This, in conjunction with considerable evidence of the increased prevalence of hypertension in diabetic persons,1 2 suggests that these 2 common chronic diseases frequently coexist. Moreover, each pathophysiological disease entity, although independent in its own natural history, serves to exacerbate the other.1 2 In a recent report of Gress et al,3 hypertensive patients who were taking ß-blockers had a 28% higher risk of diabetes than did those taking no medication. In contrast, patients with hypertension who received thiazide diuretics, ACE inhibitors, or Ca2+ antagonists were found not to be at greater risk for subsequent diabetes than were patients who were not receiving any antihypertensive medications. However, that study was not prospective or randomized,3 and other randomized prospective trials have not shown an increase in the development of diabetes with ß-blocker or low-dose diuretic treatment of hypertension.4 5 6 Recent studies have reported that ACE inhibitor therapy reduced the propensity of hypertensive patients to develop type 2 diabetes by 11%7 and 34%8 in trials extending for 6 and 4 years, respectively, suggesting that antihypertensive treatment may have a significant impact on the propensity for the development of diabetes in this population.9 These observations are in contrast to a recent report3 in which no reduction in progression to diabetes on ACE inhibition therapy was observed. Thus, more controlled randomized prospective trials are required to address the potential for ACE inhibitor therapy to reduce the rate of development of diabetes in hypertensive patients.
There is an increasing body of data from controlled clinical
trials indicating that rigorous control of arterial
pressure to levels <140/90 mm Hg markedly reduces
cardiovascular disease (CVD) morbidity and mortality
and the development of end-stage renal disease in persons with type 2
diabetes.6 7 8 9 10 11 12 13
In the Systolic Hypertension in the Elderly Program (SHEP)
study,4 elderly persons with
type 2 diabetes derived more benefit from aggressive systolic
blood pressure lowering in reduction of CVD than did those without
diabetes. Baseline therapy in the SHEP study used a low-dose
diuretic, which is often a necessary component of the
antihypertensive regimen because of the sodium sensitivity and expanded
plasma volume that is often present in diabetic
patients.14 Data from the
subset analysis of type II diabetes in the Hypertension Optimal
Treatment (HOT) trial10
suggest that reduction in diastolic pressures from
<90 mm Hg to values <85 mm Hg is beneficial in reducing
CVD events. The initial drug therapy in HOT was with a
dihydropyridine Ca2+
antagonist, but >70% of diabetic patients required at
least 3 drugs to control the diastolic pressure to levels
<85 mm Hg. Special benefits of aggressive blood pressure
lowering in the diabetic population was observed in a
subanalysis of this cohort in the Systolic Hypertension
in Europe (Syst Eur)
Trial.11 In that trial,
although systolic pressure was reduced by a comparable amount
in each group (-22.0±16 mm Hg [nondiabetic group] versus
-22.1±14 mm Hg [diabetic group]), the risk reduction in
mortality from CVD was 13% in nondiabetic patients versus 76% for the
diabetic patients.11 Again,
diabetic patients required more antihypertensive treatment to achieve
goal blood pressures, with up to two thirds requiring 
2 medications
as previously
observed.4 10
Moreover, the benefit confirmed per mm Hg blood pressure
reduction was greater in diabetic patients than in those patients with
hypertension but without concomitant diabetes mellitus, providing
further evidence for rigorous reduction of arterial
pressure in diabetic patients.
|
United Kingdom Prospective Diabetes Study Group |
|---|
In the United Kingdom Prospective Diabetes Study (UKPDS) group,12 13 blood pressure lowering was similarly effective for captopril- and atenolol-based regimens in reducing the incidence of both microvascular and macrovascular diabetic complications. Many of these type 2 diabetic patients required both drugs plus a diuretic for "tight control" of pressure (ie, 144/82 mm Hg). The necessity for use of at least 3 drugs for tight control was also observed in the diabetic cohorts of the HOT and Syst Eur studies as well.10 11 In the UKPDS, reductions in risk in the group assigned to tight control were 24% in diabetes-related end points, 32% in death-related end points to diabetes, 44% in strokes, and 37% in microvascular end points, especially diabetic retinopathy. Moreover, in the UKPDS trial, the relative benefit on CVD risk reduction was conferred in a far more powerful fashion by intensive blood pressure reduction rather than by tight glucose control.12
ACE inhibitors are currently recognized as
first-line antihypertensive therapy in diabetic persons with
proteinuria,2 15 16
and these agents afford unique benefits in modifying the progression
and severity of CVD as well as of diabetic nephropathy
(Figure 1). Indeed, a cardioprotective effect of ACE
inhibitors has been suggested from results of the
Fosinopril versus Amlodipine Cardiovascular Events
Trial (FACET),17 the
Captopril Prevention Project
(CAPPP),7 the Heart Outcomes
Prevention Evaluation (HOPE)
trial,8 and the Shunt
Thrombotic Occlusion Prevention by Picotamide (STOP)-2 Hypertensive
Trial.6
FACET16 was an open-label
single-center trial designed to compare the effects of fosinopril and
amlodipine on serum lipids and glycemic control. Patients were assigned
to treatment with either amlodipine or fosinopril; if blood pressure
was not controlled, the other drug was added. The incidence of CVD
events was less in the fosinopril-treated group than in the
amlodipine-treated group, but the incidence was least in the group that
received both antihypertensive
agents.18 Furthermore, it
should be noted that there was no placebo group in the FACET study, so
that the impact of Ca2+
antagonists alone could not be ascertained. These results,
as well as those of the Syst
Eur11 and
HOT10 studies, suggest that
the combination of a dihydropyridine
Ca2+ antagonist (such as
amlodipine or nitrendipine) and an ACE inhibitor is an
acceptable approach to the treatment of this high-risk population. It
is clear from these recent studies that reaching goal blood pressure in
diabetic patients, especially if they have renal disease, will require
treatment with several antihypertensive agents. Results of the
SHEP8 and the
UKPDS12 trials suggest that
diuretics and ß-blockers as well as ACE
inhibitors are also useful therapeutic agents in diabetic
hypertensive patients who often require 2 drugs to control blood
pressure adequately19
(Figure 1).
|
|
CAPPP Trial |
|---|
CAPPP7 was an unblinded prospective trial that enrolled 10 985 patients aged 25 to 66 years with diastolic pressure of at least 100 mm Hg. Patients were randomized to receive either captopril (in 1 or 2 doses up to 100 mg/d), with a thiazide diuretic added if necessary, or the clinician’s choice of a thiazide diuretic or ß-blocker, with the alternative agent as add-on therapy if necessary. Over a follow-up period of
6.1 years, in part because of inadequate
randomization for baseline blood pressure, there was a small increase
in stroke in the captopril group and a slight reduction in myocardial
infarction and other cardiovascular deaths in this
treatment group for the nondiabetic cohort. However, the risk of
developing new diabetes was 11% less in the captopril-treated group.
In diabetic patients (n=572), there was a reduction in the CVD end
points (P=0.02) in the group
receiving captopril. In the diabetic cohort, there was a better outcome
with regard to all outcomes in patients randomized to
captopril.7 The study
suggested that although overall events may be similar to
ß-blocker/diuretic treatment compared with an
ACE/diuretic regimen, there appears to be an advantage to the
latter regimen in diabetic persons. |
HOPE Trial |
|---|
HOPE was a randomized double-blind evaluation of the ACE inhibitor ramipril in patients at high risk for vascular disease complications but without clinically evident heart failure.8 The HOPE trial tested the hypothesis that ACE inhibitors in general, and ramipril in particular, have beneficial effects on vascular disease complications above and beyond their effects on blood pressure. However, the small reduction in blood pressure with ramipril may have contributed to its beneficial effects.8
All patients enrolled in the HOPE trial had documented vascular disease, ie, a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes, with 1 additional cardiovascular risk factor. A total of 9297 patients were randomized to either ramipril or matching placebo and were followed for a mean duration of 5 years. The primary end points were myocardial infarction, stroke, or death from a cardiovascular cause. Secondary outcomes were death from all causes, need for coronary artery revascularization, hospitalization for unstable angina, heart failure, and complications related to diabetes.
The 3577 diabetic patients enrolled in the HOPE trial were also examined separately in a substudy of microalbuminuria and cardiovascular and renal outcomes (MICRO-HOPE).20 In keeping with the findings of the major trial, the primary outcome (a composite of myocardial infarction, stroke, or death from a cardiovascular cause) was reduced by 25% (95% CI 12% to 36%, P<0.0004) in diabetic patients treated with ramipril compared with diabetic patients receiving placebo. Secondary outcomes of total mortality and need for revascularization were also significantly lower among diabetic patients receiving ramipril. Admissions to the hospital for unstable angina or heart failure did not differ between patients receiving ramipril and those receiving placebo. However, there was a significant 16% reduction in progression to overt nephropathy (95% CI 1% to 29%, P=0.036), and there were nonsignificant trends toward less laser therapy for retinopathy and less progression to end-stage renal disease in the ramipril group as well.
One of the most striking observations from the HOPE trial is that relatively large reductions in risk were achieved in the face of comparatively small reductions in blood pressure. Patients enrolled in the HOPE trial were not required to be hypertensive, and the average blood pressure on admission was 139/79 mm Hg. By 2 years, when the trends in end points first reached statistical significance, the average reduction in blood pressure was only 3/2 mm Hg. This striking finding points toward possible direct effects of ramipril (and ACE inhibitors as a class) on the heart and vasculature in addition to their additional effect on blood pressure. In the HOPE trial, diabetic patients derived an even greater reduction in CVD than did the rest of the high-risk population.8
The HOPE study also showed a 34% reduction in the development of diabetes in those patients without diabetes at the onset of the study. Furthermore, in another study, the ACE inhibitor perindopril was reported to reduce insulin resistance in obese hypertensive patients without diabetes.21 Thus, the lessons learned from these 3 studies suggest that ACE inhibitor therapy can improve insulin sensitivity and also delay the development of diabetes in patients at high risk for the development of this disease. The mechanism whereby ACE inhibitors improve glucose metabolism and protect against the development of clinical diabetes may involve the improvement of blood flow through the microcirculation to fat and skeletal muscle tissue and/or the improvement of insulin action at the cellular level (by interfering with the angiotensin II [Ang II] antagonism of insulin signaling) (Figure 2). The fact that ACE inhibitors, but not Ang II receptor antagonists, improve insulin resistance21 suggests that their action on glucose metabolism may be mediated via (at least in part) bradykinin metabolism. Significant improvement of insulin responsiveness, which was achieved by the addition of an ACE inhibitor to a tissue culture,22 indicated that the protective effect of ACE inhibition on diabetes is not (or is not solely) related to changes in blood flow. This improvement is also likely mediated at a cellular level, as shown by increases in glucose transporter (GLUT-4) protein and the activity of hexokinase, one of the major enzymes of glucose metabolism, in skeletal muscle of obese rats treated with an ACE inhibitor (Figure 2).
|
Interrupting the effects of the renin-angiotensin system (RAS) may improve the cellular actions of insulin by several mechanisms. Ang II in vascular and heart tissue interferes with insulin stimulation of phosphatidylinositol 3-kinase (PI3-kinase) activation, a major pathway for insulin signal transduction23 24 25 (Figure 2). The relationship between the RAS and insulin is complex and includes several intracellular mechanisms and signaling pathways. Normally, insulin binds to its receptor (IR) on the surface of the insulin-sensitive cell and triggers autophosphorylation of the IR ß-subunit, which, in turn, phosphorylates tyrosine in the IR substrate (IRS) molecules. This allows the regulating p85 subunit of PI3-kinase to connect to the IRS-1 and form an IRS-1/PI3-kinase complex, which is involved in many of the actions of insulin, including chemotaxis, translocation of cellular elements, and glucose transport.26 This pathway has also been implicated in mediating the activation of NO synthase and the Na2+ pump activity in vascular tissue26 27 and in facilitating vascular relaxation.
Ang II, acting via an Ang II type 1 G-protein–linked receptor, phosphorylates a number of proteins, including IRS-1 and -2. Such phosphorylation leads to the activation of catalytic activity of the p110 subunit of PI3-kinase, the same enzyme that belongs to the insulin-signaling pathway. Paradoxically, this process interferes with insulin-dependent activation of PI3-kinase and, therefore, inhibits this major pathway of insulin signaling and decreases the ability of the cell to consume glucose in response to insulin.12 Precise mechanisms of such inhibition remain unclear, but it has been shown that Ang II inhibits the insulin-stimulated association between IRS-1 and the regulatory p85 subunit of PI3-kinase by 30% to 50% in a dose-dependent manner,23 24 interrupts the insulin-signaling cascade, and, therefore, contributes to the development of insulin resistance. This insulin resistance can be manifested as diminished glucose transport in skeletal muscle tissues and adipocytes and impaired vascular relaxation.27
Even though they are not completely understood, the cellular actions of ACE inhibitors on glucose metabolism lead to increases in GLUT-4 concentration and activation of one of the major enzymes of glucose pathway, hexokinase.27 These changes are probably secondary to activation of the PI3-kinase signaling pathway by the enhancement of tyrosine phosphorylation of IRS-1 and the improvement of PI3-kinase/IRS-1 complexing.28 ACE inhibitors are also able to facilitate blood flow through the microcirculation in skeletal muscles.29 This effect is bradykinin dependent and occurs through the activation of cell surface ß2-adrenergic receptors.29 ACE inhibitors prolong the action of bradykinin by blocking its enzymatic breakdown and facilitating its action.29 Facilitation of blood flow to insulin-sensitive tissues, such as skeletal muscle, would lead to an increase in glucose delivery to these tissues. In turn, bradykinin not only causes vasodilation but also independently increases the basal and insulin-stimulated rate of glucose uptake in skeletal muscle in insulin-resistant obese Zucker rats30 by improving postreceptor insulin signaling and enhancing GLUT-4 translocation to the cell membrane.30 Thus, in addition to blocking the negative effect of Ang II on PI3-kinase signaling, there are additional mechanisms by which ACE inhibitor therapy may improve the insulin sensitivity associated with hypertension.31
|
Other Factors Contributing to Increased CVD in Diabetic Patients |
|---|
CVD accounts for up to 80% of the deaths in persons with type 2 diabetes31 (Figure 3). Indeed, age-adjusted relative risk of death due to cardiovascular events in persons with type 2 diabetes is 3-fold higher than in the general population.14 31 A recent population-based study showed that CVD mortality was 7.5 times greater among persons with type 2 diabetes without a previous myocardial infarction than in those without diabetes31 (Figure 3). Furthermore, the incidence of CVD mortality was 3-fold higher among individuals with diabetes who had suffered a myocardial infarction than among nondiabetic individuals.31 Diabetes is associated with a relatively greater risk for CVD in women than in men.32 Moreover, diabetes negates the normal gender differences in the prevalence of CVD, and when adjusted for other risk factors, the risk rate for increased mortality is 2.4 times greater for diabetic men and 3.5 times greater for diabetic women.32 33
|
A number of factors, in addition to hypertension, contribute
to the high prevalence of CVD in type 2 diabetic persons. Within the
Multiple Risk Factor Intervention Trial
(MRFIT),34 >5000 diabetic
patients were followed for 12 years and were compared with >350 000
persons without diabetes. The occurrence of CVD death at the 12-year
follow-up was 3 times more in diabetic men than in their nondiabetic
controls, regardless of systolic pressure, age,
cholesterol, ethnic group, or use of tobacco. This study
also confirmed that systolic hypertension, elevated
cholesterol, and cigarette smoking were independent
predictors of mortality and that the presence of 1 of these risk
factors had a greater impact on increasing CVD mortality in persons
with diabetes than in those without diabetes.
Other risk factors that are involved in the cardiometabolic syndrome, which includes persons with prediabetes, include the following: obesity, hyperlipidemia, hyperuricemia, and albuminuria.15 16 25 The hyperuricemia that occurs in essential hypertension (when not ascribed to gout, diuretic therapy, or other factors known to produce hyperuricemia) is related to reduced renal blood flow and increased renal vascular resistance.25 This elevation in serum uric acid not only accompanies the vascular alterations associated with nephrosclerosis but also follows the development of left ventricular hypertrophy (echocardiographically) and accompanies the foregoing renal hemodynamic involvement in patients with the early stages of essential hypertension, even before the development of proteinuria or impaired renal excretory function.25 On the other hand, microalbuminuria has been reported to develop before any clinical evidence of coronary heart disease (eg, myocardial infarction and cardiac failure) or intrarenal vascular disease in patients having diabetes with or without hypertension.15 16 Nephrosclerosis associated with hypertension and renal diabetic vascular disease affects the intrarenal arterioles, whereas CHD, associated with occlusive epicardial coronary artery disease, as manifested by myocardial infarction, is an arterial disease. In the case of the latter, both hypertension and diabetes exacerbate the atherosclerotic occlusive disease.
|
Diabetic Cardiomyopathy |
|---|
Diabetic cardiomyopathy, a diabetes-related myopathic state, is characterized mainly by impaired diastolic function.35 36 37 38 In experimental diabetes, the mechanical properties of the myocardium and cardiomyocytes in vitro involve prolongation of contraction and relaxation as well as considerable slowing in relaxation velocity.36 37 38 Diabetic cardiomyopathy is observed in chemically induced insulinopenic36 37 as well as in genetically predisposed insulin-resistant38 rodent models. Potential abnormalities underlying this cardiomyopathic state include altered K+ channel function,39 40 41 alterations in Na+ pump function,42 alterations in sarcoplasmic (endoplasmic) reticulum Ca2+-ATPase,43 44 Na+-Ca2+ exchanger45 function, and abnormalities of protein kinase C metabolism.46
Diabetic cardiomyopathy may be associated with a balance between the cardiac RAS and the autocrine/paracrine actions of insulin-like growth factor (IGF)-1. The peptides, Ang II and IGF are generated by cardiomyocytes and exert pleiotropic effects in an autocrine/paracrine fashion.27 47 IGF-1 also has been demonstrated to increase myocardial contractility by increasing [Ca2+]i and cardiomyocyte myofilament Ca2+ sensitivity.47 IGF-1 is synthesized by cardiomyocytes under the control of insulin, Ang II, mechanical stress, and increased total peripheral resistance.47 IGF-1 and Ang II have opposing actions on key signaling pathways of the heart but work synergistically in promoting growth.47 One of the major pathways of IGF-1 signaling involves the activation of the PI3-kinase/IRS-1 complex.48 49 The PI3-kinase pathway is known to mediate many insulin/IGF-1 actions, including receptor trafficking, glucose transport, cytoskeletal reorganization, the Na+,K+-ATPase and K+ channel expression/activity, and myofilament-Ca2+ sensitivity.23 24 27
Ang II, acting via its G-protein–linked receptor, also induces tyrosine phosphorylation of IRS-1.23 24 In cardiac tissue in contrast to insulin/IGF-1, Ang II acutely inhibits basal as well as insulin/IGF-1–stimulated PI3-kinase activity23 47 (Figure 2). Thus, it has been proposed that overexpression of the RAS, as occurs in the diabetic heart, would predispose one to a resistance to the actions of insulin/IGF-1 on the PI3-kinase–mediated activation of K+ channel and Na+ pump expression/activation as well as myofilament-Ca2+ sensitivity.47 Indeed, reduced cardiomyocyte glucose transport and attenuated PI3-kinase response to insulin IGF-1 have been observed in insulin-resistant rodent models.36 50 These abnormalities are associated with decreased expression/activation of the K+ channel and Na+ pump in both type I and type II diabetic states.36 47 51 Resistance to the PI3-kinase–mediated actions of IGF-1 and insulin50 (Figure 2) could explain the abnormalities of both diastolic and systolic function and left ventricular hypertrophy,52 which characterize "diabetic cardiomyopathy." However, unabated action of both IGF-1 and Ang II could help explain why patients with diabetes appear to have greater left ventricular mass than do nondiabetic cohorts with comparable blood pressures.52
|
Microalbuminuria and CVD in Diabetes |
|---|
There is considerable evidence that the presence of hypertension in type 1 diabetes is a consequence rather than a cause of renal disease. For example, with low levels of microalbuminuria, the arterial pressure remains normal, a finding that suggests that nephropathy precedes the raise in blood pressure.2 14 Regardless of whether hypertension in type 1 diabetes is the etiologic factor of nephropathy or a complication of it, it is clear that a genetic predisposition to hypertension is important in the development of nephropathy in those 30% of type 1 diabetics who develop this complication and that nephropathy and hypertension exacerbate each other.53 On the other hand, microalbuminuria is an independent risk factor for the development of CVD and a predictor of cardiovascular mortality in the diabetic population. It is associated with insulin resistance,54 atherogenic dyslipidemia,54 central obesity,54 and the absence of nocturnal drop in both systolic and diastolic pressures55 56 and is a part of the metabolic cardiovascular syndrome associated with hypertension55 57 (Table). Because microalbuminuria is part of the cardiometabolic syndrome54 57 and is related to endothelial dysfunction and increased oxidative stress, it is not surprising that diabetic glomerulosclerosis parallels diabetic atherosclerosis and is a very powerful risk factor for coronary heart disease and stroke in diabetic persons.15 16 57
|
|
Therapeutic Implications |
|---|
It is clear from the foregoing review of newer information concerning the CVD complications of diabetes mellitus and their interaction with hypertension and its complications that the recent national recommendations concerning the treatment of patients with hypertension19 are all the more important. Thus, although there is a necessity for risk stratification of patients with hypertension according to the stage of blood pressure elevation, it is apparent that the inclusion of all patients with hypertension whose systolic and diastolic pressures exceed 130 and/or 85 mm Hg, respectively, should probably receive antihypertensive drug therapy. Although a goal blood pressure of 130/85 mm Hg is relatively arbitrary, it is also recognized by other organizations, such as the Canadian Hypertension Society,58 as a reasonable goal to maximally preserve function and reduce CVD morbidity and mortality. Clearly, lifestyle modifications are important for all patients with diabetes, but in those with even high normal levels of blood pressure elevation, pharmacotherapy of hypertension is particularly important. It is further evident from these Joint National Committee-6 recommendations and recent clinical trial data cited in the present report that the first choice in antihypertensive agents is the selection of an ACE inhibitor. Indeed, ACE inhibitor therapy has been shown to reduce the progression of renal disease20 59 and CVD8 in diabetic persons with "normal blood pressure."
Although it is clearly not our purpose to review the
pharmacological treatment of diabetes and hypertension, a few
compelling observations are in order. A review of recently completed
clinical trials indicates that >65% of people with diabetes and
hypertension will require 2 different antihypertensive medications to
achieve the new suggested target blood pressure of <130/85
mm Hg.19 ACE
inhibitor therapy should be an integral component of any
antihypertensive regime in patients with diabetes, inasmuch as these
agents have been demonstrated to reduce
CVD7 8 and renal
disease53 in this
population. Not every patient with diabetes and hypertension can take
an ACE inhibitor either because of specific side effects
from therapy or because of absolute contraindications. Thus, if a
persistent cough secondary to the ACE is intolerable and precludes its
further use, then selection of an Ang II (type 1) receptor
antagonist appears appropriate. A number of multicenter
trials are ongoing and are directed to support this recommendation.
However, because results supporting their use are not yet available, it
is not unreasonable to conclude that Ang II receptor
antagonists are appropriate choices. Other complications of
ACE inhibitor therapy, particularly in patients with
diabetes, may be the progression of renal functional impairment and/or
hyperkalemia. In these patients, a number of studies
have supported the use of Ca2+
antagonists.19
Finally, the use of ACE inhibitors or Ang II
antagonists in any pregnant woman (including one with
diabetes) is definitely
contraindicated.
Over and above the foregoing therapeutic
recommendations, it is also important to assess the status of the
diabetic patient’s serum concentration of LDL cholesterol
and glycated
hemoglobin.1 2 10 19 59
Thus, in those patients with an LDL cholesterol of 100
mg/dL and glycated hemoglobin of 6.5, more vigorous control of
both lipids and of glycated hemoglobin levels is particularly
indicated. Finally, all diabetic patients should receive aspirin unless
there is absolute
contraindication.60
|
Acknowledgments |
|---|
Work from Dr Sowers’ laboratory was supported by grants from the National Institutes of Health (grant HL-63904-01), American Diabetes Association, and Veterans Administration. The authors wish to thank Paddy McGowan for her excellent work in preparing this review.
Received September 25, 2000; first decision November 8, 2000; accepted January 30, 2001.
|
References |
|---|
1. The National High Blood Pressure Education Program Working Group. National high blood pressure education program working group report on hypertension in diabetes. Hypertension. 1994;23:145–158.
2. Sowers JR, Epstein M Diabetes mellitus and associated hypertension, vascular disease, and nephropathy: an update. Hypertension. 1995;26(pt 1):869–879.
3.
Gress TW, Nieto FJ,
Shahar E, Wofford MR, Brancati FL. Hypertension and antihypertensive
therapy as risk factors for type 2 diabetes mellitus:
Atherosclerosis Risk in Communities Study.
N Engl J Med. 2000;342:905–912.
4.
Curb JD, Pressel
MS, Cutler JA, Savage PJ, Applegate WB, Black H, Camel G, Davis BR,
Frost PH, Gonzalez N, et al. Effect of diuretic-based
antihypertensive treatment on cardiovascular disease
risk in older diabetic patients with isolated hypertension.
JAMA. 1996;276:1886–1892.
5.
Grimm RH Jr, Flack
JM, Grandits GA, Elmer PJ, Neaton JD, Cutler JA, Lewis C, McDonald R,
Schoenberger J, Stamler J. Long-term effects on plasma lipids of diet
and drugs to treat hypertension: Treatment of Mild Hypertension Study
(TOMHS) Research Group. JAMA. 1996;275:1549–1556.
6. Lindholm LH. The outcome of STOP-Hypertension-2 in relation to the 1999 WHO/ISH hypertension guidelines. Blood Press Suppl. 2000;2:21–24.[Medline] [Order article via Infotrieve]
7. Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, Luomanmaki K, Dahlof B, de Faire U, Morlin C, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet. 1999;353:611–616.[Medline] [Order article via Infotrieve]
8.
Yusuf S, Sleight P,
Pogue J, Bosch J, Davies R, Dagenais G. Effects of an
angiotensin-converting-enzyme inhibitor,
ramipril, on cardiovascular events in high-risk
patients: the Heart Outcomes Prevention Evaluation Study Investigators.
N Engl J Med. 2000;342:145–153.
9.
Sowers JR, Bakris
GL. Antihypertensive therapy and the risk of type 2 diabetes mellitus.
N Engl J Med. 2000;342:969–970.
10. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S, for the HOT Study Group. Effects of intensive blood pressure-lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. Lancet. 1998;351:1755–1762.[Medline] [Order article via Infotrieve]
11.
Tuomilehto J,
Rastenyte D, Birkenhager WH, Thijs L, Antikainen R, Bulpitt CJ,
Fletcher AE, Forette F, Goldhaber A, Palatini P, et al, for the
Systolic Hypertension in Europe Trial Investigators. Effects of
calcium channel blockers in older patients with diabetes and
systolic hypertension. N Engl
J Med. 1999;340:677–684.
12.
UKPDS Group. UK
Prospective Diabetes Study 38: tight blood pressure control and risk of
macrovascular and microvascular complications in type 2 diabetes.
BMJ. 1998;317:703–713.
13.
UKPDS Group.
Efficacy of atenolol and captopril in reducing risk of macrovascular
and microvascular complications in type 2 diabetes: UKPDS 39.
BMJ. 1998;317:713–720.
14. Sowers JR, Epstein M. Risk factors for arterial disease in diabetes: hypertension. In: Tooke JE, ed. Diabetic Angiopathy. London, UK: Arnold Publishers; 1999:45–63.
15. Kuusisto J, Mykkanen L, Pyorala K, Laakso M. Hyperinsulinemic microalbuminuria: a new risk indicator for coronary heart disease. Circulation. 1995;90:831–837.
16.
Dinneen SF,
Gerstein HC. The association of microalbuminuria and
mortality in non-insulin-dependent diabetes mellitus: a systematic
overview of the literature. Arch Intern
Med. 1997;157:1413–1418.
17. Tatti P, Pahor M, Byington RP, DiMauro P, Guaresco R, Strollo G, Strotts F. Outcome results of the Fosinopril versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care. 1998;21:579–603.
18. Sowers JR. Comorbidity of hypertension and diabetes: the Fosinopril versus Amlodipine Cardiovascular Events Trial (FACET). Am J Cardiol. 1998;82:15R–19R.[Medline] [Order article via Infotrieve]
19. Sowers JR, Reed J. Clinical advisory treatment of hypertension in diabetes. J Clin Hypertens. 2000;2:132–133.
20. Effects of ramipril on cardiovascular and microvascular outcomes in peoples with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:253–259.[Medline] [Order article via Infotrieve]
21. Fogari R, Zoppi A, Corradi L, Lazzari P, Mugellini A, Lusardi P. ACE inhibition but not angiotensin II antagonism reduced fibrinogen and insulin resistance in overweight hypertensive patients. J Cardiovasc Pharmacol. 1998;32:616–620.[Medline] [Order article via Infotrieve]
22. Caldiz CI, de Cingolani GE. Insulin resistance in adipocytes from spontaneously hypertensive rats: effect of long-term treatment with enalapril and losartan. Metabolism. 1999;48:1041–1046.[Medline] [Order article via Infotrieve]
23. Folli F, Kahn CR, Hansen H, Bouchie JL, Feener EP. Angiotensin II inhibits insulin signaling in aortic smooth muscle cell at multiple levels. J Clin Invest. 1997;100:2158–2169.[Medline] [Order article via Infotrieve]
24.
Velloso LA, Folli
F, Sun XJ, White MF, Saad MJ, Kahn CR. Cross-talk between insulin and
angiotensin signaling systems.
Proc Natl Acad Sci
U S A. 1996;93:12490–12495.
25. Richey JM, Ader M, Moore D, Bergman RN. Angiotensin II induces insulin resistance independent of changes in interstitial insulin. Am J Physiology. 1999;277(pt 1):E920–E926.
26. Romel S, Sumitani S, Taha C, Sweeney G, Klip A. Temporal activation of p70 S6 kinase and Akt1 by insulin: PI3-kinase-dependent and –independent mechanisms. Am J Physiol. 1998;275:E618–E625.
27. Li D, Sweeney G, Wang Q, Klip A. Participation of PI3K and atypical PKC in Na+,K+-ATP pump stimulation by IGF-1 in VSMC. Am J Physiol. 1999;276:H2109–H2116.
28. Nawano M, Anai M, Funaki M, Kobayashi H, Kanda A, Fukushima Y, Inukai K, Ogihara T, Sakoda H, Onishi Y, et al. Imadapril, an angiotensin-converting enzyme inhibitor, improves insulin sensitivity by enhancing signal transduction via insulin receptor substrate proteins and improving vascular resistance in the Zucker fatty rat. Metabolism. 1999;48:1248–1255.[Medline] [Order article via Infotrieve]
29. Erdos EG, Deddish PA, Marcic BM. Potentiating of bradykinin action by ACE inhibitors. Trends Endocrinol Metab. 1999;10:223–229.[Medline] [Order article via Infotrieve]
30. Henriksen EJ, Jacob S, Kinnick TR, Youngblood ER, Schmit MB, Dietze GJ. ACE inhibition and glucose transport in insulin resistant muscle: roles of bradykinin and nitric oxide. Am J Physiol. 1999;277(pt 2):R332–R336.
31.
Haffner SM, Lehto
S, Ronnemma T, Pyorala K, Laakso M. Mortality from coronary
heart disease in subjects with type 2 diabetes and in nondiabetic
subjects with and without myocardial infarction.
N Engl J Med. 1998;339:229–234.
32.
Sowers JR.
Diabetes mellitus and cardiovascular disease in women.
Arch Intern Med. 1998;158:617–621.
33. Garcia MJ, McNamara PM, Gordon T, Kannel WB. Morbidity and mortality in diabetes in the Framingham population: sixteen-year follow-up study. Diabetes. 1974;23:105–111.[Medline] [Order article via Infotrieve]
34. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993;263:2335–2340.
35.
Frohlich ED. Uric
acid: a risk factor for coronary artery disease.
JAMA. 1993;270:354–359.
36. Brown R, Walsh M, Sowers JR. Influence of sex, diabetes and ethanol on intrinsic contractile performance of isolated rat myocardium. Basic Res Cardiol. 1996;91:353–360.[Medline] [Order article via Infotrieve]
37. Ren J, Dominguez LJ, Sowers JR, Davidoff A. Troglitazone attenuates high glucose-induced abnormalities in relaxation and intracellular calcium in rat ventricular myocytes. Diabetes. 1996;45:1822–1825.[Abstract]
38. Ren J, Sowers JR, Walsh MF, Brown RA. Reduced contractile response to insulin and IGF-1 in ventricular myocytes from genetically obese Zucker rats. Am J Physiol. 2000;279:H1708–H1714.
39. Wong D, Kiyosue T, Shigematsu S, Arita M. Abnormalities of K+ and Ca2+ currents in ventricular myocytes from rats with chronic diabetes. Am J Physiol. 1998;269:H1288–H1296.
40.
Shimoni Y, Ewart
H, Severson D. Insulin stimulation of rat ventricular
K+ currents depends on the integrity of the
cytoskeleton. J Physiol
(Lond). 1999;514:735–745.
41. Casis O, Gallego M, Iriarte M, Sanchez-Chapula SA. Effects of diabetic cardiomyopathy on regional electrophysiologic characteristics of rat ventricle. Diabetologia. 2000;43:101–109.[Medline] [Order article via Infotrieve]
42. Golfman L, Dixon IM, Takeda N, Lukas A, Dakshinamurti K, Dhalla NS. Cardiac sarcolemmal Na+-Ca2+ exchange and Na+-K+ ATPase activities and gene expression in alloxan-induced diabetes in rats. Mol Cell Biochem. 1998;188:91–101.[Medline] [Order article via Infotrieve]
43. Ziegelhoffer A, Ravingerova T, Styk J, Sebokova J, Waczulikova I, Breier A, Dzurba A, Volkovova K, Carsky J, Turecky L. Mechanisms that may be involved in calcium tolerance of the diabetic heart. Mol Cell Biochem. 1997;176:191–198.[Medline] [Order article via Infotrieve]
44. Matsubara H, Kanasaki M, Murasawa S, Tsukaguchi Y, Nio Y, Inada M. Differential gene expression and regulation of angiotensin II receptor subtypes in rat fibroblasts and cardiomyocytic in culture. J Clin Invest. 1994;93:592–601.
45.
Schaffer SW,
Ballard-Craft C, Boerth S, Allon SM. Mechanisms underlying
depressed
Na+/Ca2+
exchanger activity in the diabetic heart.
Cardiovasc Res. 1997;34:129–136.
46. Giles TD, Ouyang J, Kerut EK, Given MB, Allen GE, McIwain EF, Greenberg SS. Changes in protein kinase C in early cardiomyopathy and in the gracilis muscle in the BB/W or diabetic rat. Am J Physiol. 1998;4:H295–H307.
47. Ren J, Sampson WK, Sowers JR. Insulin-like growth factor 1 as a cardiac hormone: physiological and pathophysiological implications in heart disease. Mol Cell Cardiol. 1999;31:2049–2061.[Medline] [Order article via Infotrieve]
48.
Cittadini
A, Ishiguro Y, Stromer H, Spindler M, Moses AC, Clark R, Douglas PS,
Ingwall JS, Morgan JP. Insulin-like growth factor but not growth
hormone augments mammalian myocardial contractility by
sensitizing the myofilament to Ca2+ through
a wortmannin-sensitive pathway: studies in rat and ferret isolated
muscles. Circ Res. 1998;83:50–59.
49.
LeRoith D.
Insulin-like growth factors. N Engl
J Med. 1998;336:633–640.
50. Kolter T, Uphues I, Eckel J. Molecular analysis of insulin resistance in isolated ventricular myocytes of obese Zucker rats. Am J Physiol. 1997;36:E59–E67.
51.
Guo W, Kada K,
Kamiya K, Toyama J. IGF-1 regulates
K+-channel expression of cultured neonatal
rat ventricular myocytes.
Am J Physiol. 1997;272:H2599–H2560.
52.
Grossman E,
Shemesh J, Shamiss A, Thaler M, Carroll J, Rosenthal T. Left
ventricular mass in diabetes-hypertension.
Arch Intern Med. 1992;152:1001–1004.
53. Taal MW, Brenner BM. Renoprotective benefits of RAS inhibition: from ACEI to angiotensin II antagonists. Kidney Int. 2000;57:1803–1817.[Medline] [Order article via Infotrieve]
54. Bianchi S, Bigazzi R, Quinones Galvan A, Muscelli E, Baldari G, Pecori N, Ciociaro D, Ferrannini E, Natali A. Insulin resistance in microalbuminuric hypertension: sites and mechanisms. Hypertension. 1995;26:189–195.
55. Pinkney JH, Foyle WJ, Denver AE, Mohamed-Ali V, McKinlay S, Yudkin JS. The relationship of urinary albumin excretion rate to ambulatory blood pressure and erythrocyte sodium-lithium countertransport in NIDDM. Diabetologia. 1995;38:356–362.[Medline] [Order article via Infotrieve]
56. Mitchell TH, Nolan B, Henry M, Cronin C, Baker H, Greely G. Microalbuminuria in patients with non-insulin-dependent diabetes mellitus relates to nocturnal systolic blood pressure. Am J Med. 1997;102:531–535.[Medline] [Order article via Infotrieve]
57. Sowers JR, Lester M. Diabetes and cardiovascular disease. Diabetes Care. 1999;22(suppl 3):C14–C20.
58. Feldman RD. The Canadian recommendations for the management of hypertension: on behalf of the Task Force for the Development of the 1999 Canadian Recommendations for the Management of Hypertension. Can J Cardiol. 1999;15:S57G–S64G.
59.
Ravid M, Lang R,
Rachmani R, Lishner M. Long-term renoprotective effect of
angiotensin-converting enzyme inhibition in
non-insulin-dependent diabetes mellitus: a 7-year follow-up study.
Arch Intern Med. 1996;156:286–289.
60. Colwell JA. Aspirin therapy in diabetes. Diabetes Care. 1997;20:1767–1771. [Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  Z. Bagi Mechanisms of coronary microvascular adaptation to obesity Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2009; 297(3): R556 - R567. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Ishizawa, N. Dorjsuren, Y. Izawa-Ishizawa, R. Sugimoto, Y. Ikeda, Y. Kihira, K. Kawazoe, S. Tomita, K. Tsuchiya, K. Minakuchi, et al. Inhibitory effects of adiponectin on platelet-derived growth factor-induced mesangial cell migration J. Endocrinol., August 1, 2009; 202(2): 309 - 316. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 On behalf of the Canadian Hypertension Education P 2009 Canadian Hypertension Education Program recommendations: An annual update Can Fam Physician, July 1, 2009; 55(7): 697 - 700. [Full Text] [PDF]
|
|
|
|
 |
|
 I. Rutkai, A. Feher, N. Erdei, D. Henrion, Z. Papp, I. Edes, A. Koller, G. Kaley, and Z. Bagi Activation of prostaglandin E2 EP1 receptor increases arteriolar tone and blood pressure in mice with type 2 diabetes Cardiovasc Res, July 1, 2009; 83(1): 148 - 154. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-S. Chen, T.-E. Wu, C.-C. Juan, and H.-D. Lin Myocardial heat shock protein 60 expression in insulin-resistant and diabetic rats J. Endocrinol., February 1, 2009; 200(2): 151 - 157. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Cosentino, L. Rydén, P. Francia, and L. G. Mellbin CHAPTER 14 Diabetes Mellitus and Metabolic Syndrome ESC Textbook of Cardiovascular Medicine, January 1, 2009; 2(1): med-9780199566990-chapter - med-9780199566990-chapter. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. McLean, F. A. McAlister, J. A. Johnson, K. M. King, M. J. Makowsky, C. A. Jones, R. T. Tsuyuki, and for the SCRIP-HTN Investigators A Randomized Trial of the Effect of Community Pharmacist and Nurse Care on Improving Blood Pressure Management in Patients With Diabetes Mellitus: Study of Cardiovascular Risk Intervention by Pharmacists-Hypertension (SCRIP-HTN) Arch Intern Med, November 24, 2008; 168(21): 2355 - 2361. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A Kloner, J. Neutel, E. M Roth, R. Weiss, M. H Weinberger, K. M Thakker, B. Schwartz, H. Shi, A.-M. Gregg, and the ADHT Investigators Blood Pressure Control with Amlodipine Add-on Therapy in Patients with Hypertension and Diabetes: Results of the Amlodipine Diabetic Hypertension Efficacy Response Evaluation Trial Ann. Pharmacother., November 1, 2008; 42(11): 1552 - 1562. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Rossi, A. Nuzzo, G. Origliani, and M. G. Modena Metabolic Syndrome Affects Cardiovascular Risk Profile and Response to Treatment in Hypertensive Postmenopausal Women Hypertension, November 1, 2008; 52(5): 865 - 872. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Ai, M. Rouhanizadeh, J. C. Wu, W. Takabe, H. Yu, M. Alavi, R. Li, Y. Chu, J. Miller, D. D. Heistad, et al. Shear stress influences spatial variations in vascular Mn-SOD expression: implication for LDL nitration Am J Physiol Cell Physiol, June 1, 2008; 294(6): C1576 - C1585. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Baldelli, L. De Marinis, A. Bianchi, R. Pivonello, V. Gasco, R. Auriemma, G. Pasimeni, V. Cimino, M. Appetecchia, M. Maccario, et al. Microalbuminuria in Insulin Sensitivity in Patients with Growth Hormone-Secreting Pituitary Tumor J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 710 - 714. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Z. Duan, M. G. Usher, and R. M. Mortensen Peroxisome Proliferator-Activated Receptor-{gamma}-Mediated Effects in the Vasculature Circ. Res., February 15, 2008; 102(3): 283 - 294. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-L. He, M. Ligueros-Saylan, G. Sunkara, R. Sabo, C. Zhao, Y. Wang, J. Campestrini, F. Pommier, K. Dole, A. Marion, et al. Vildagliptin, a Novel Dipeptidyl Peptidase IV Inhibitor, Has No Pharmacokinetic Interactions With the Antihypertensive Agents Amlodipine, Valsartan, and Ramipril in Healthy Subjects J. Clin. Pharmacol., January 1, 2008; 48(1): 85 - 95. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.A. Connelly, D.J. Kelly, Y. Zhang, D.L. Prior, J. Martin, A.J. Cox, K. Thai, M.P. Feneley, J. Tsoporis, K.E. White, et al. Functional, structural and molecular aspects of diastolic heart failure in the diabetic (mRen-2)27 rat Cardiovasc Res, November 1, 2007; 76(2): 280 - 291. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Okin, R. B. Devereux, K. E. Harris, S. Jern, S. E. Kjeldsen, L. H. Lindholm, B. Dahlof, and for the LIFE Study Investigators In-Treatment Resolution or Absence of Electrocardiographic Left Ventricular Hypertrophy Is Associated With Decreased Incidence of New-Onset Diabetes Mellitus in Hypertensive Patients: The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Study Hypertension, November 1, 2007; 50(5): 984 - 990. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Schindler Review: The metabolic syndrome as an endocrine disease: is there an effective pharmacotherapeutic strategy optimally targeting the pathogenesis? Therapeutic Advances in Cardiovascular Disease, October 1, 2007; 1(1): 7 - 26. [Abstract] [PDF]
|
|
|
|
|
|
A. Whaley-Connell, B. S. Pavey, K. Chaudhary, G. Saab, and J. R. Sowers Review: Renin-angiotensin-aldosterone system intervention in the cardiometabolic syndrome and cardio-renal protection Therapeutic Advances in Cardiovascular Disease, October 1, 2007; 1(1): 27 - 35. [Abstract] [PDF]
|
|
|
|
 |
|
 S. A. Cooper, A. Whaley-Connell, J. Habibi, Y. Wei, G. Lastra, C. Manrique, S. Stas, and J. R. Sowers Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2009 - H2023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Hitomi, H. Kiyomoto, A. Nishiyama, T. Hara, K. Moriwaki, K. Kaifu, G. Ihara, Y. Fujita, T. Ugawa, and M. Kohno Aldosterone Suppresses Insulin Signaling Via the Downregulation of Insulin Receptor Substrate-1 in Vascular Smooth Muscle Cells Hypertension, October 1, 2007; 50(4): 750 - 755. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Honda, A. R. Qureshi, J. Axelsson, O. Heimburger, M. E Suliman, P. Barany, P. Stenvinkel, and B. Lindholm Obese sarcopenia in patients with end-stage renal disease is associated with inflammation and increased mortality Am. J. Clinical Nutrition, September 1, 2007; 86(3): 633 - 638. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Belmadani, J. Bernal, C.-C. Wei, M. A. Pallero, L. Dell'Italia, J. E. Murphy-Ullrich, and K. H. Berecek A Thrombospondin-1 Antagonist of Transforming Growth Factor-{beta} Activation Blocks Cardiomyopathy in Rats with Diabetes and Elevated Angiotensin II Am. J. Pathol., September 1, 2007; 171(3): 777 - 789. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Jonk, A. J. H. M. Houben, R. T. de Jongh, E. H. Serne, N. C. Schaper, and C. D. A. Stehouwer Microvascular Dysfunction in Obesity: A Potential Mechanism in the Pathogenesis of Obesity-Associated Insulin Resistance and Hypertension Physiology, August 1, 2007; 22(4): 252 - 260. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Y. Deng, J.-P. Huang, L.-S. Lu, and L.-M. Hung Impairment of cardiac insulin signaling and myocardial contractile performance in high-cholesterol/fructose-fed rats Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H978 - H987. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. E. Umpierrez, P. Cantey, D. Smiley, A. Palacio, D. Temponi, K. Luster, and A. Chapman Primary Aldosteronism in Diabetic Subjects With Resistant Hypertension Diabetes Care, July 1, 2007; 30(7): 1699 - 1703. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. McAuley, J. N. Myers, J. P. Abella, S. Y. Tan, and V. F. Froelicher Exercise Capacity and Body Mass as Predictors of Mortality Among Male Veterans With Type 2 Diabetes Diabetes Care, June 1, 2007; 30(6): 1539 - 1543. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K. McGahon, D. P. Dash, A. Arora, N. Wall, J. Dawicki, D. A. Simpson, C. N. Scholfield, J. G. McGeown, and T. M. Curtis Diabetes Downregulates Large-Conductance Ca2+-Activated Potassium {beta}1 Channel Subunit in Retinal Arteriolar Smooth Muscle Circ. Res., March 16, 2007; 100(5): 703 - 711. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Hodroj, L. Legedz, N. Foudi, C. Cerutti, M.-C. Bourdillon, P. Feugier, M. Beylot, J. Randon, and G. Bricca Increased Insulin-Stimulated Expression of Arterial Angiotensinogen and Angiotensin Type 1 Receptor in Patients With Type 2 Diabetes Mellitus and Atheroma Arterioscler Thromb Vasc Biol, March 1, 2007; 27(3): 525 - 531. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Erdei, A. Toth, E. T. Pasztor, Z. Papp, I. Edes, A. Koller, and Z. Bagi High-fat diet-induced reduction in nitric oxide-dependent arteriolar dilation in rats: role of xanthine oxidase-derived superoxide anion Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2107 - H2115. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. An and B. Rodrigues Role of changes in cardiac metabolism in development of diabetic cardiomyopathy Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1489 - H1506. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.-I. Tropeano, P. Boutouyrie, B. Pannier, R. Joannides, E. Balkestein, S. Katsahian, B. Laloux, C. Thuillez, H. Struijker-Boudier, and S. Laurent Brachial Pressure-Independent Reduction in Carotid Stiffness After Long-Term Angiotensin-Converting Enzyme Inhibition in Diabetic Hypertensives Hypertension, July 1, 2006; 48(1): 80 - 86. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P Collins Risk factors for cardiovascular disease and hormone therapy in women Heart, May 1, 2006; 92(suppl_3): iii24 - iii28. [Full Text] [PDF]
|
|
|
|
|
|
A. Moran, W. Palmas, T. G. Pickering, J. E. Schwartz, L. Field, R. S. Weinstock, and S. Shea Office and Ambulatory Blood Pressure Are Independently Associated With Albuminuria in Older Subjects With Type 2 Diabetes Hypertension, May 1, 2006; 47(5): 955 - 961. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ronnback, B. Isomaa, J. Fagerudd, C. Forsblom, P.-H. Groop, T. Tuomi, L. Groop, and for the Botnia Study Group Complex Relationship Between Blood Pressure and Mortality in Type 2 Diabetic Patients: A Follow-Up of the Botnia Study Hypertension, February 1, 2006; 47(2): 168 - 173. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Stults and R. E. Jones Management of Hypertension in Diabetes Diabetes Spectr, January 1, 2006; 19(1): 25 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. B. Gurley, S. E. Clare, K. P. Snow, A. Hu, T. W. Meyer, and T. M. Coffman Impact of genetic background on nephropathy in diabetic mice Am J Physiol Renal Physiol, January 1, 2006; 290(1): F214 - F222. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Grosso, F Veglio, M Porta, F M Grignolo, and T Y Wong Hypertensive retinopathy revisited: some answers, more questions Br J Ophthalmol, December 1, 2005; 89(12): 1646 - 1654. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Bagi, N. Erdei, A. Toth, W. Li, T. H. Hintze, A. Koller, and G. Kaley Type 2 Diabetic Mice Have Increased Arteriolar Tone and Blood Pressure: Enhanced Release of COX-2-Derived Constrictor Prostaglandins Arterioscler Thromb Vasc Biol, August 1, 2005; 25(8): 1610 - 1616. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Pulinilkunnil, D. An, S. Ghosh, D. Qi, G. Kewalramani, G. Yuen, N. Virk, A. Abrahani, and B. Rodrigues Lysophosphatidic acid-mediated augmentation of cardiomyocyte lipoprotein lipase involves actin cytoskeleton reorganization Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2802 - H2810. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Hu, P. Jousilahti, N. C. Barengo, Q. Qiao, T. A. Lakka, and J. Tuomilehto Physical Activity, Cardiovascular Risk Factors, and Mortality Among Finnish Adults With Diabetes Diabetes Care, April 1, 2005; 28(4): 799 - 805. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Morganti Should a Diuretic Always Be the First Choice in Patients with Essential Hypertension? The Case for No J. Am. Soc. Nephrol., March 1, 2005; 16(3_suppl_1): S70 - S73. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Fulton, M. B. Harris, B. E. Kemp, R. C. Venema, M. B. Marrero, and D. W. Stepp Insulin resistance does not diminish eNOS expression, phosphorylation, or binding to HSP-90 Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2384 - H2393. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. A. El-Atat, S. N. Stas, S. I. McFarlane, and J. R. Sowers The Relationship between Hyperinsulinemia, Hypertension and Progressive Renal Disease J. Am. Soc. Nephrol., November 1, 2004; 15(11): 2816 - 2827. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. C. Eringa, C. D. A. Stehouwer, G. P. van Nieuw Amerongen, L. Ouwehand, N. Westerhof, and P. Sipkema Vasoconstrictor effects of insulin in skeletal muscle arterioles are mediated by ERK1/2 activation in endothelium Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2043 - H2048. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Jacob, A. Smolenski, S. M. Lohmann, and N. Begum MKP-1 expression and stabilization and cGK I{alpha} prevent diabetes- associated abnormalities in VSMC migration Am J Physiol Cell Physiol, October 1, 2004; 287(4): C1077 - C1086. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Sowers Treatment of Hypertension in Patients With Diabetes Arch Intern Med, September 27, 2004; 164(17): 1850 - 1857. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. S. Lim, R. J. MacFadyen, and G. Y. H. Lip Diabetes Mellitus, the Renin-Angiotensin-Aldosterone System, and the Heart Arch Intern Med, September 13, 2004; 164(16): 1737 - 1748. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. F. Sheard, N. G. Clark, J. C. Brand-Miller, M. J. Franz, F. X. Pi-Sunyer, E. Mayer-Davis, K. Kulkarni, and P. Geil Dietary Carbohydrate (Amount and Type) in the Prevention and Management of Diabetes: A statement by the American Diabetes Association Diabetes Care, September 1, 2004; 27(9): 2266 - 2271. [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Y. Fang, J. B. Prins, and T. H. Marwick Diabetic Cardiomyopathy: Evidence, Mechanisms, and Therapeutic Implications Endocr. Rev., August 1, 2004; 25(4): 543 - 567. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Franco, S. Oparil, and O. A. Carretero Hypertensive Therapy: Part II Circulation, June 29, 2004; 109(25): 3081 - 3088. [Full Text] [PDF]
|
|
|
|
|
|
A. Kubaszek, A. Markkanen, J. G. Eriksson, T. Forsen, C. Osmond, D. J. P. Barker, and M. Laakso The Association of the K121Q Polymorphism of the Plasma Cell Glycoprotein-1 Gene with Type 2 Diabetes and Hypertension Depends on Size at Birth J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2044 - 2047. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Lajoie, A. Calderone, F. Trudeau, N. Lavoie, G. Massicotte, S. Gagnon, and L. Beliveau Exercise training attenuated the PKB and GSK-3 dephosphorylation in the myocardium of ZDF rats J Appl Physiol, May 1, 2004; 96(5): 1606 - 1612. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Ceolotto, M. Bevilacqua, I. Papparella, E. Baritono, L. Franco, C. Corvaja, M. Mazzoni, A. Semplicini, and A. Avogaro Insulin Generates Free Radicals by an NAD(P)H, Phosphatidylinositol 3'-Kinase-Dependent Mechanism in Human Skin Fibroblasts Ex Vivo Diabetes, May 1, 2004; 53(5): 1344 - 1351. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Sowers Insulin resistance and hypertension Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1597 - H1602. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Verdecchia, G. Reboldi, F. Angeli, C. Borgioni, R. Gattobigio, L. Filippucci, S. Norgiolini, C. Bracco, and C. Porcellati Adverse Prognostic Significance of New Diabetes in Treated Hypertensive Subjects Hypertension, May 1, 2004; 43(5): 963 - 969. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Sigurdardottir, B. Fagerberg, and J. Hulthe Preclinical Atherosclerosis and Inflammation in 61-Year-Old Men With Newly Diagnosed Diabetes and Established Diabetes Diabetes Care, April 1, 2004; 27(4): 880 - 884. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. T. Bloomgarden Type 2 Diabetes in the Young: The evolving epidemic Diabetes Care, April 1, 2004; 27(4): 998 - 1010. [Full Text] [PDF]
|
|
|
|
|
|
N. Winer and J. R. Sowers Epidemiology of Diabetes J. Clin. Pharmacol., April 1, 2004; 44(4): 397 - 405. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Hwang, M. H. Ing, A. Salazar, B. Lassegue, K. Griendling, M. Navab, A. Sevanian, and T. K. Hsiai Pulsatile Versus Oscillatory Shear Stress Regulates NADPH Oxidase Subunit Expression: Implication for Native LDL Oxidation Circ. Res., December 12, 2003; 93(12): 1225 - 1232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. I. McFarlane, N. Winer, and J. R. Sowers Role of the Natriuretic Peptide System in Cardiorenal Protection Arch Intern Med, December 8, 2003; 163(22): 2696 - 2704. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G.V. Gill, A. Woodward, S. Pradhan, M. Wallymahmed, T. Groves, P. English, and J.P. Wilding Intensified treatment of type 2 diabetes--positive effects on blood pressure, but not glycaemic control QJM, November 1, 2003; 96(11): 833 - 836. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Guazzi, G. Tumminello, M. Matturri, and M. D. Guazzi Insulin ameliorates exercise ventilatory efficiency and oxygen uptake in patients with heart failure-type 2 diabetes comorbidity J. Am. Coll. Cardiol., September 17, 2003; 42(6): 1044 - 1050. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-L. Chiasson, R. G. Josse, R. Gomis, M. Hanefeld, A. Karasik, and M. Laakso Acarbose Treatment and the Risk of Cardiovascular Disease and Hypertension in Patients With Impaired Glucose Tolerance: The STOP-NIDDM Trial JAMA, July 23, 2003; 290(4): 486 - 494. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Gardner, S. Eguchi, C. M. Reynolds, K. Eguchi, G. D. Frank, and E. D. Motley Hydrogen Peroxide Inhibits Insulin Signaling in Vascular Smooth Muscle Cells Experimental Biology and Medicine, July 1, 2003; 228(7): 836 - 842. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. El-Omar, R. Lord, N. J. Draper, and A. M. Shah Role of nitric oxide in posthypoxic contractile dysfunction of diabetic cardiomyopathy Eur J Heart Fail, June 1, 2003; 5(3): 229 - 239. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Chen, G. Sullivan, L. Q. Yue, A. Katz, and M. J. Quon QUICKI is a useful index of insulin sensitivity in subjects with hypertension Am J Physiol Endocrinol Metab, April 1, 2003; 284(4): E804 - E812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Mancia, M. Brown, A. Castaigne, P. de Leeuw, C. R. Palmer, T. Rosenthal, G. Wagener, and L. M. Ruilope Outcomes With Nifedipine GITS or Co-Amilozide in Hypertensive Diabetics and Nondiabetics in Intervention as a Goal in Hypertension (INSIGHT) Hypertension, March 1, 2003; 41(3): 431 - 436. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. D. Motley, K. Eguchi, C. Gardner, A. L. Hicks, C. M. Reynolds, G. D. Frank, M. Mifune, M. Ohba, and S. Eguchi Insulin-Induced Akt Activation Is Inhibited by Angiotensin II in the Vasculature Through Protein Kinase C-{alpha} Hypertension, March 1, 2003; 41(3): 775 - 780. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. I. McFarlane and J. R. Sowers Aldosterone Function in Diabetes Mellitus: Effects on Cardiovascular and Renal Disease J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 516 - 523. [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Brotman, J. P. Girod, S. Thomas, P. L. Poulsen, K. W. Hansen, C. E. Mogensen, M. L. Caramori, M. Pecis, M. J. Azevedo, R. Marfella, et al. Increase in Nocturnal Blood Pressure and Progression to Microalbuminuria in Diabetes N. Engl. J. Med., January 16, 2003; 348(3): 260 - 264. [Full Text] [PDF]
|
|
|
|
 |
|
 I. L Williams, A. Vazir, and A. G Zaman Review: The management of stable angina in diabetes The British Journal of Diabetes & Vascular Disease, January 1, 2003; 3(1): 18 - 25. [Abstract] [PDF]
|
|
|
|
|
|
J. Yang, A. K. Gillingham, A. Hodel, F. Koumanov, B. Woodward, and G. D. Holman Insulin-stimulated cytosol alkalinization facilitates optimal activation of glucose transport in cardiomyocytes Am J Physiol Endocrinol Metab, December 1, 2002; 283(6): E1299 - E1307. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. C. Eringa, C. D.A. Stehouwer, T. Merlijn, N. Westerhof, and P. Sipkema Physiological concentrations of insulin induce endothelin-mediated vasoconstriction during inhibition of NOS or PI3-kinase in skeletal muscle arterioles Cardiovasc Res, December 1, 2002; 56(3): 464 - 471. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Sowers and S. Haffner Treatment of Cardiovascular and Renal Risk Factors in the Diabetic Hypertensive Hypertension, December 1, 2002; 40(6): 781 - 788. [Full Text] [PDF]
|
|
|
|
 |
|
 R. C. Sampaio, J. E. Tanus-Santos, S. E. S. F. C. Melo, S. Hyslop, K. G. Franchini, I. M. Luca, and H. Moreno Jr Hypertension Plus Diabetes Mimics the Cardiomyopathy Induced by Nitric Oxide Inhibition in Rats Chest, October 1, 2002; 122(4): 1412 - 1420. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Lurbe, J. Redon, A. Kesani, J. M. Pascual, J. Tacons, V. Alvarez, and D. Batlle Increase in Nocturnal Blood Pressure and Progression to Microalbuminuria in Type 1 Diabetes N. Engl. J. Med., September 12, 2002; 347(11): 797 - 805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. H. Opie and H.-H. Parving Diabetic Nephropathy: Can Renoprotection Be Extrapolated to Cardiovascular Protection? Circulation, August 6, 2002; 106(6): 643 - 645. [Full Text] [PDF]
|
|
|
|
 |
|
 D. Kirpichnikov, S. I. McFarlane, and J. R. Sowers Metformin: An Update Ann Intern Med, July 2, 2002; 137(1): 25 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F. Kincer, A. Uittenbogaard, J. Dressman, T. M. Guerin, M. Febbraio, L. Guo, and E. J. Smart Hypercholesterolemia Promotes a CD36-dependent and Endothelial Nitric-oxide Synthase-mediated Vascular Dysfunction J. Biol. Chem., June 21, 2002; 277(26): 23525 - 23533. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Sowers Hypertension, Angiotensin II, and Oxidative Stress N. Engl. J. Med., June 20, 2002; 346(25): 1999 - 2001. [Full Text] [PDF]
|
|
|
|
|
|
J. A. Beckman, M. A. Creager, and P. Libby Diabetes and Atherosclerosis: Epidemiology, Pathophysiology, and Management JAMA, May 15, 2002; 287(19): 2570 - 2581. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. GLICK Screening for traditional risk factors for cardiovascular disease: A review for oral health care providers J Am Dent Assoc, March 1, 2002; 133(3): 291 - 300. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. D. Motley, S. M. Kabir, C. D. Gardner, K. Eguchi, G. D. Frank, T. Kuroki, M. Ohba, T. Yamakawa, and S. Eguchi Lysophosphatidylcholine Inhibits Insulin-Induced Akt Activation Through Protein Kinase C-{alpha} in Vascular Smooth Muscle Cells Hypertension, February 1, 2002; 39(2): 508 - 512. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Nicolaides and C. J. Jones Review: Type 2 diabetes -- implications for macrovascular mechanics and disease The British Journal of Diabetes & Vascular Disease, January 1, 2002; 2(1): 9 - 12. [Abstract] [PDF]
|
|
|
|
|
|
W. A. Hsueh and R. E. Law PPAR{gamma} and Atherosclerosis: Effects on Cell Growth and Movement Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 1891 - 1895. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. D. Frohlich Local Hemodynamic Changes in Hypertension: Insights for Therapeutic Preservation of Target Organs Hypertension, December 1, 2001; 38(6): 1388 - 1394. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. H. Messerli, E. Grossman, and J. R. Sowers Diabetes, Hypertension, and Cardiovascular Disease: An Update Response Hypertension, September 1, 2001; 38 (3): e11 - e11. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||