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DM HT Kardio
DM HT Kardio
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/
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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. (Hypertension. 2001;
37:1053-1059.)
Key Words: diabetes 䡲 cardiovascular diseases 䡲 hypertension, essential 䡲 blood pressure
Hypertension in the Diabetic Patient chronic diseases frequently coexist. Moreover, each patho-
The subject of diabetes mellitus as a comorbid disease that physiological disease entity, although independent in its own
frequently confounds hypertension, adding significantly to its natural history, serves to exacerbate the other.1,2 In a recent
overall morbidity and mortality,1,2 will be updated in the report of Gress et al,3 hypertensive patients who were taking
present review. Among the complications of diabetes, cardio- -blockers had a 28% higher risk of diabetes than did those
vascular and renal vascular diseases are among the most taking no medication. In contrast, patients with hypertension
costly in terms of human suffering and national healthcare who received thiazide diuretics, ACE inhibitors, or Ca2⫹
costs. Over the past several years, since the publication of antagonists were found not to be at greater risk for subsequent
these foregoing reviews, a number of controlled multicenter diabetes than were patients who were not receiving any
clinical trials have demonstrated the safety and efficacy of antihypertensive medications. However, that study was not
specific antihypertensive therapeutic programs that can sig- prospective or randomized,3 and other randomized prospec-
nificantly alter the outcomes of these cardiovascular and renal tive trials have not shown an increase in the development of
complications. The present report summarizes these advances diabetes with -blocker or low-dose diuretic treatment of
as well as newer fundamental findings that add importantly to hypertension.4 – 6 Recent studies have reported that ACE
our overall knowledge of the cardiovascular complications of inhibitor therapy reduced the propensity of hypertensive
diabetes mellitus. patients to develop type 2 diabetes by 11%7 and 34%8 in trials
In a recent, large, prospective cohort study that included extending for 6 and 4 years, respectively, suggesting that
12 550 adults, the development of type II diabetes was almost antihypertensive treatment may have a significant impact on
2.5 times as likely in persons with hypertension than in their the propensity for the development of diabetes in this popu-
normotensive counterparts.3 This, in conjunction with con- lation.9 These observations are in contrast to a recent report3
siderable evidence of the increased prevalence of hyperten- in which no reduction in progression to diabetes on ACE
sion in diabetic persons,1,2 suggests that these 2 common inhibition therapy was observed. Thus, more controlled ran-
Received September 25, 2000; first decision November 8, 2000; revision accepted January 30, 2001.
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@netmail.hscbklyn.edu
© 2001 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
1053
1054 Hypertension April 2001
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 -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
Figure 2. Intracellular signaling pathways of insulin/IGF-1. PKB
developing new diabetes was 11% less in the captopril- indicates protein kinase B; NOS, NO synthase.
treated group. In diabetic patients (n⫽572), there was a
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molecules. This allows the regulating p85 subunit of PI3- postreceptor insulin signaling and enhancing GLUT-4 translo-
kinase to connect to the IRS-1 and form an IRS-1/PI3-kinase cation to the cell membrane.30 Thus, in addition to blocking the
complex, which is involved in many of the actions of insulin, negative effect of Ang II on PI3-kinase signaling, there are
including chemotaxis, translocation of cellular elements, and additional mechanisms by which ACE inhibitor therapy may
glucose transport.26 This pathway has also been implicated in improve the insulin sensitivity associated with hypertension.31
mediating the activation of NO synthase and the Na2⫹ pump
activity in vascular tissue26,27 and in facilitating vascular Other Factors Contributing to Increased CVD
relaxation.
in Diabetic Patients
Ang II, acting via an Ang II type 1 G-protein–linked
CVD accounts for up to 80% of the deaths in persons with
receptor, phosphorylates a number of proteins, including
type 2 diabetes31 (Figure 3). Indeed, age-adjusted relative risk
IRS-1 and -2. Such phosphorylation leads to the activation of
of death due to cardiovascular events in persons with type 2
catalytic activity of the p110 subunit of PI3-kinase, the same
diabetes is 3-fold higher than in the general population.14,31 A
enzyme that belongs to the insulin-signaling pathway. Para-
recent population-based study showed that CVD mortality
doxically, this process interferes with insulin-dependent ac-
was 7.5 times greater among persons with type 2 diabetes
tivation of PI3-kinase and, therefore, inhibits this major
without a previous myocardial infarction than in those with-
pathway of insulin signaling and decreases the ability of the
cell to consume glucose in response to insulin.12 Precise out diabetes31 (Figure 3). Furthermore, the incidence of CVD
mechanisms of such inhibition remain unclear, but it has been mortality was 3-fold higher among individuals with diabetes
shown that Ang II inhibits the insulin-stimulated association who had suffered a myocardial infarction than among nondi-
between IRS-1 and the regulatory p85 subunit of PI3-kinase abetic individuals.31 Diabetes is associated with a relatively
by 30% to 50% in a dose-dependent manner,23,24 interrupts greater risk for CVD in women than in men.32 Moreover,
the insulin-signaling cascade, and, therefore, contributes to diabetes negates the normal gender differences in the preva-
the development of insulin resistance. This insulin resistance lence of CVD, and when adjusted for other risk factors, the
can be manifested as diminished glucose transport in skeletal risk rate for increased mortality is 2.4 times greater for
muscle tissues and adipocytes and impaired vascular diabetic men and 3.5 times greater for diabetic women.32,33
relaxation.27 A number of factors, in addition to hypertension, contrib-
Even though they are not completely understood, the cellular ute to the high prevalence of CVD in type 2 diabetic persons.
actions of ACE inhibitors on glucose metabolism lead to Within the Multiple Risk Factor Intervention Trial (MR-
increases in GLUT-4 concentration and activation of one of the FIT),34 ⬎5000 diabetic patients were followed for 12 years
major enzymes of glucose pathway, hexokinase.27 These and were compared with ⬎350 000 persons without diabetes.
changes are probably secondary to activation of the PI3-kinase The occurrence of CVD death at the 12-year follow-up was
signaling pathway by the enhancement of tyrosine phosphory- ⬇3 times more in diabetic men than in their nondiabetic
lation of IRS-1 and the improvement of PI3-kinase/IRS-1 controls, regardless of systolic pressure, age, cholesterol,
complexing.28 ACE inhibitors are also able to facilitate blood ethnic group, or use of tobacco. This study also confirmed
flow through the microcirculation in skeletal muscles.29 This that systolic hypertension, elevated cholesterol, and cigarette
effect is bradykinin dependent and occurs through the activation smoking were independent predictors of mortality and that
of cell surface 2-adrenergic receptors.29 ACE inhibitors prolong the presence of ⱖ1 of these risk factors had a greater impact
the action of bradykinin by blocking its enzymatic breakdown on increasing CVD mortality in persons with diabetes than in
and facilitating its action.29 Facilitation of blood flow to insulin- those without diabetes.
sensitive tissues, such as skeletal muscle, would lead to an Other risk factors that are involved in the cardiometabolic
increase in glucose delivery to these tissues. In turn, bradykinin syndrome, which includes persons with prediabetes, include
Sowers et al Diabetes and Hypertension 1057
the following: obesity, hyperlipidemia, hyperuricemia, and Cardiovascular Risk Factors That Cluster
albuminuria.15,16,25 The hyperuricemia that occurs in essential With Microalbuminuria
hypertension (when not ascribed to gout, diuretic therapy, or Central obesity
other factors known to produce hyperuricemia) is related to
Insulin resistance
reduced renal blood flow and increased renal vascular resis-
Low HDL cholesterol levels
tance.25 This elevation in serum uric acid not only accompa-
nies the vascular alterations associated with nephrosclerosis High triglyceride levels
but also follows the development of left ventricular hypertro- Systolic hypertension
phy (echocardiographically) and accompanies the foregoing Absent nocturnal drop in blood pressure
renal hemodynamic involvement in patients with the early Salt sensitivity
stages of essential hypertension, even before the development Male sex
of proteinuria or impaired renal excretory function.25 On the Increased cardiovascular oxidative stress
other hand, microalbuminuria has been reported to develop
Impaired endothelial function
before any clinical evidence of coronary heart disease (eg,
Abnormal coagulation/fibrinolytic profiles
myocardial infarction and cardiac failure) or intrarenal vas-
cular disease in patients having diabetes with or without
hypertension.15,16 Nephrosclerosis associated with hyperten- basal as well as insulin/IGF-1–stimulated PI3-kinase activi-
sion and renal diabetic vascular disease affects the intrarenal ty23,47 (Figure 2). Thus, it has been proposed that overexpres-
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arterioles, whereas CHD, associated with occlusive epicardial sion of the RAS, as occurs in the diabetic heart, would
coronary artery disease, as manifested by myocardial infarc- predispose one to a resistance to the actions of insulin/IGF-1
tion, is an arterial disease. In the case of the latter, both on the PI3-kinase–mediated activation of K⫹ channel and Na⫹
hypertension and diabetes exacerbate the atherosclerotic oc- pump expression/activation as well as myofilament-Ca2⫹
clusive disease. sensitivity.47 Indeed, reduced cardiomyocyte glucose trans-
port and attenuated PI3-kinase response to insulin IGF-1 have
Diabetic Cardiomyopathy been observed in insulin-resistant rodent models.36,50 These
Diabetic cardiomyopathy, a diabetes-related myopathic state, abnormalities are associated with decreased expression/acti-
is characterized mainly by impaired diastolic function.35–38 In vation of the K⫹ channel and Na⫹ pump in both type I and
experimental diabetes, the mechanical properties of the myo- type II diabetic states.36,47,51 Resistance to the PI3-kinase–
cardium and cardiomyocytes in vitro involve prolongation of mediated actions of IGF-1 and insulin50 (Figure 2) could
contraction and relaxation as well as considerable slowing in explain the abnormalities of both diastolic and systolic
relaxation velocity.36 –38 Diabetic cardiomyopathy is observed function and left ventricular hypertrophy,52 which character-
in chemically induced insulinopenic36,37 as well as in genet- ize “diabetic cardiomyopathy.” However, unabated action of
ically predisposed insulin-resistant38 rodent models. Potential both IGF-1 and Ang II could help explain why patients with
abnormalities underlying this cardiomyopathic state include diabetes appear to have greater left ventricular mass than do
altered K⫹ channel function,39 – 41 alterations in Na⫹ pump nondiabetic cohorts with comparable blood pressures.52
function,42 alterations in sarcoplasmic (endoplasmic) reticu-
lum Ca2⫹-ATPase,43,44 Na⫹-Ca2⫹ exchanger45 function, and Microalbuminuria and CVD in Diabetes
abnormalities of protein kinase C metabolism.46 There is considerable evidence that the presence of hyperten-
Diabetic cardiomyopathy may be associated with a balance sion in type 1 diabetes is a consequence rather than a cause of
between the cardiac RAS and the autocrine/paracrine actions renal disease. For example, with low levels of microalbumin-
of insulin-like growth factor (IGF)-1. The peptides, Ang II uria, the arterial pressure remains normal, a finding that
and IGF are generated by cardiomyocytes and exert pleiotro- suggests that nephropathy precedes the raise in blood pres-
pic effects in an autocrine/paracrine fashion.27,47 IGF-1 also sure.2,14 Regardless of whether hypertension in type 1 diabe-
has been demonstrated to increase myocardial contractility by tes is the etiologic factor of nephropathy or a complication of
increasing [Ca2⫹]i and cardiomyocyte myofilament Ca2⫹ sen- it, it is clear that a genetic predisposition to hypertension is
sitivity.47 IGF-1 is synthesized by cardiomyocytes under the important in the development of nephropathy in those 30% of
control of insulin, Ang II, mechanical stress, and increased type 1 diabetics who develop this complication and that
total peripheral resistance.47 IGF-1 and Ang II have opposing nephropathy and hypertension exacerbate each other.53 On
actions on key signaling pathways of the heart but work the other hand, microalbuminuria is an independent risk
synergistically in promoting growth.47 One of the major factor for the development of CVD and a predictor of
pathways of IGF-1 signaling involves the activation of the cardiovascular mortality in the diabetic population. It is
PI3-kinase/IRS-1 complex.48,49 The PI3-kinase pathway is associated with insulin resistance,54 atherogenic dyslipid-
known to mediate many insulin/IGF-1 actions, including emia,54 central obesity,54 and the absence of nocturnal drop in
receptor trafficking, glucose transport, cytoskeletal reorgani- both systolic and diastolic pressures55,56 and is a part of the
zation, the Na⫹,K⫹-ATPase and K⫹ channel expression/ metabolic cardiovascular syndrome associated with hyperten-
activity, and myofilament-Ca2⫹ sensitivity.23,24,27 sion55,57 (Table). Because microalbuminuria is part of the
Ang II, acting via its G-protein–linked receptor, also cardiometabolic syndrome54,57 and is related to endothelial
induces tyrosine phosphorylation of IRS-1.23,24 In cardiac dysfunction and increased oxidative stress, it is not surprising
tissue in contrast to insulin/IGF-1, Ang II acutely inhibits that diabetic glomerulosclerosis parallels diabetic atheroscle-
1058 Hypertension April 2001
rosis and is a very powerful risk factor for coronary heart Over and above the foregoing therapeutic recommenda-
disease and stroke in diabetic persons.15,16,57 tions, it is also important to assess the status of the diabetic
patient’s serum concentration of LDL cholesterol and gly-
Therapeutic Implications cated hemoglobin.1,2,10,19,59 Thus, in those patients with an
It is clear from the foregoing review of newer information LDL cholesterol of 100 mg/dL and glycated hemoglobin of
concerning the CVD complications of diabetes mellitus and ⱖ6.5, more vigorous control of both lipids and of glycated
their interaction with hypertension and its complications that hemoglobin levels is particularly indicated. Finally, all dia-
the recent national recommendations concerning the treat- betic patients should receive aspirin unless there is absolute
ment of patients with hypertension19 are all the more impor- contraindication.60
tant. Thus, although there is a necessity for risk stratification
of patients with hypertension according to the stage of blood Acknowledgments
Work from Dr Sowers’ laboratory was supported by grants from the
pressure elevation, it is apparent that the inclusion of all
National Institutes of Health (grant HL-63904-01), American Dia-
patients with hypertension whose systolic and diastolic pres- betes Association, and Veterans Administration. The authors wish to
sures exceed 130 and/or 85 mm Hg, respectively, should thank Paddy McGowan for her excellent work in preparing this
probably receive antihypertensive drug therapy. Although a review.
goal blood pressure of 130/85 mm Hg is relatively arbitrary,
it is also recognized by other organizations, such as the References
1. The National High Blood Pressure Education Program Working Group.
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Canadian Hypertension Society,58 as a reasonable goal to National high blood pressure education program working group report on
maximally preserve function and reduce CVD morbidity and hypertension in diabetes. Hypertension. 1994;23:145–158.
mortality. Clearly, lifestyle modifications are important for 2. Sowers JR, Epstein M Diabetes mellitus and associated hypertension,
vascular disease, and nephropathy: an update. Hypertension. 1995;26(pt
all patients with diabetes, but in those with even high normal 1):869 – 879.
levels of blood pressure elevation, pharmacotherapy of hy- 3. Gress TW, Nieto FJ, Shahar E, Wofford MR, Brancati FL. Hypertension
pertension is particularly important. It is further evident from and antihypertensive therapy as risk factors for type 2 diabetes mellitus:
Atherosclerosis Risk in Communities Study. N Engl J Med. 2000;342:
these Joint National Committee-6 recommendations and re- 905–912.
cent clinical trial data cited in the present report that the first 4. Curb JD, Pressel MS, Cutler JA, Savage PJ, Applegate WB, Black H,
choice in antihypertensive agents is the selection of an ACE Camel G, Davis BR, Frost PH, Gonzalez N, et al. Effect of diuretic-based
antihypertensive treatment on cardiovascular disease risk in older diabetic
inhibitor. Indeed, ACE inhibitor therapy has been shown to patients with isolated hypertension. JAMA. 1996;276:1886 –1892.
reduce the progression of renal disease20,59 and CVD8 in 5. Grimm RH Jr, Flack JM, Grandits GA, Elmer PJ, Neaton JD, Cutler JA,
diabetic persons with “normal blood pressure.” Lewis C, McDonald R, Schoenberger J, Stamler J. Long-term effects on
plasma lipids of diet and drugs to treat hypertension: Treatment of Mild
Although it is clearly not our purpose to review the
Hypertension Study (TOMHS) Research Group. JAMA. 1996;275:
pharmacological treatment of diabetes and hypertension, a 1549 –1556.
few compelling observations are in order. A review of 6. Lindholm LH. The outcome of STOP-Hypertension-2 in relation to the
recently completed clinical trials indicates that ⬎65% of 1999 WHO/ISH hypertension guidelines. Blood Press Suppl. 2000;2:
21–24.
people with diabetes and hypertension will require ⱖ2 7. Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A,
different antihypertensive medications to achieve the new Luomanmaki K, Dahlof B, de Faire U, Morlin C, et al. Effect of angio-
suggested target blood pressure of ⬍130/85 mm Hg.19 ACE tensin-converting-enzyme inhibition compared with conventional therapy
on cardiovascular morbidity and mortality in hypertension: the Captopril
inhibitor therapy should be an integral component of any Prevention Project (CAPPP) randomised trial. Lancet. 1999;353:
antihypertensive regime in patients with diabetes, inasmuch 611– 616.
as these agents have been demonstrated to reduce CVD7,8 and 8. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of
an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular
renal disease53 in this population. Not every patient with events in high-risk patients: the Heart Outcomes Prevention Evaluation
diabetes and hypertension can take an ACE inhibitor either Study Investigators. N Engl J Med. 2000;342:145–153.
because of specific side effects from therapy or because of 9. Sowers JR, Bakris GL. Antihypertensive therapy and the risk of type 2
diabetes mellitus. N Engl J Med. 2000;342:969 –970.
absolute contraindications. Thus, if a persistent cough sec- 10. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S,
ondary to the ACE is intolerable and precludes its further use, Menard J, Rahn KH, Wedel H, Westerling S, for the HOT Study Group.
then selection of an Ang II (type 1) receptor antagonist Effects of intensive blood pressure-lowering and low-dose aspirin in
patients with hypertension: principal results of the Hypertension Optimal
appears appropriate. A number of multicenter trials are Treatment (HOT) randomized trial. Lancet. 1998;351:1755–1762.
ongoing and are directed to support this recommendation. 11. Tuomilehto J, Rastenyte D, Birkenhager WH, Thijs L, Antikainen R,
However, because results supporting their use are not yet Bulpitt CJ, Fletcher AE, Forette F, Goldhaber A, Palatini P, et al, for the
Systolic Hypertension in Europe Trial Investigators. Effects of calcium
available, it is not unreasonable to conclude that Ang II
channel blockers in older patients with diabetes and systolic hypertension.
receptor antagonists are appropriate choices. Other compli- N Engl J Med. 1999;340:677– 684.
cations of ACE inhibitor therapy, particularly in patients with 12. UKPDS Group. UK Prospective Diabetes Study 38: tight blood pressure
control and risk of macrovascular and microvascular complications in
diabetes, may be the progression of renal functional impair-
type 2 diabetes. BMJ. 1998;317:703–713.
ment and/or hyperkalemia. In these patients, a number of 13. UKPDS Group. Efficacy of atenolol and captopril in reducing risk of
studies have supported the use of Ca2⫹ antagonists.19 Finally, macrovascular and microvascular complications in type 2 diabetes:
the use of ACE inhibitors or Ang II antagonists in any UKPDS 39. BMJ. 1998;317:713–720.
14. Sowers JR, Epstein M. Risk factors for arterial disease in diabetes:
pregnant woman (including one with diabetes) is definitely hypertension. In: Tooke JE, ed. Diabetic Angiopathy. London, UK:
contraindicated. Arnold Publishers; 1999:45– 63.
Sowers et al Diabetes and Hypertension 1059
15. Kuusisto J, Mykkanen L, Pyorala K, Laakso M. Hyperinsulinemic 38. Ren J, Sowers JR, Walsh MF, Brown RA. Reduced contractile response
microalbuminuria: a new risk indicator for coronary heart disease. Cir- to insulin and IGF-1 in ventricular myocytes from genetically obese
culation. 1995;90:831– 837. Zucker rats. Am J Physiol. 2000;279:H1708 –H1714.
16. Dinneen SF, Gerstein HC. The association of microalbuminuria and 39. Wong D, Kiyosue T, Shigematsu S, Arita M. Abnormalities of K⫹ and
mortality in non-insulin-dependent diabetes mellitus: a systematic Ca2⫹ currents in ventricular myocytes from rats with chronic diabetes.
overview of the literature. Arch Intern Med. 1997;157:1413–1418. Am J Physiol. 1998;269:H1288 –H1296.
17. Tatti P, Pahor M, Byington RP, DiMauro P, Guaresco R, Strollo G, 40. Shimoni Y, Ewart H, Severson D. Insulin stimulation of rat ventricular
Strotts F. Outcome results of the Fosinopril versus Amlodipine Cardio- K⫹ currents depends on the integrity of the cytoskeleton. J Physiol
vascular Events Randomized Trial (FACET) in patients with hyper- (Lond). 1999;514:735–745.
tension and NIDDM. Diabetes Care. 1998;21:579 – 603. 41. Casis O, Gallego M, Iriarte M, Sanchez-Chapula SA. Effects of diabetic
18. Sowers JR. Comorbidity of hypertension and diabetes: the Fosinopril cardiomyopathy on regional electrophysiologic characteristics of rat ven-
versus Amlodipine Cardiovascular Events Trial (FACET). Am J Cardiol. tricle. Diabetologia. 2000;43:101–109.
1998;82:15R–19R. 42. Golfman L, Dixon IM, Takeda N, Lukas A, Dakshinamurti K, Dhalla NS.
19. Sowers JR, Reed J. Clinical advisory treatment of hypertension in Cardiac sarcolemmal Na⫹-Ca2⫹ exchange and Na⫹-K⫹ ATPase activities
diabetes. J Clin Hypertens. 2000;2:132–133. and gene expression in alloxan-induced diabetes in rats. Mol Cell
Biochem. 1998;188:91–101.
20. Effects of ramipril on cardiovascular and microvascular outcomes in
43. Ziegelhoffer A, Ravingerova T, Styk J, Sebokova J, Waczulikova I,
peoples with diabetes mellitus: results of the HOPE study and
Breier A, Dzurba A, Volkovova K, Carsky J, Turecky L. Mechanisms that
MICRO-HOPE substudy. Lancet. 2000;355:253–259.
may be involved in calcium tolerance of the diabetic heart. Mol Cell
21. Fogari R, Zoppi A, Corradi L, Lazzari P, Mugellini A, Lusardi P. ACE
Biochem. 1997;176:191–198.
inhibition but not angiotensin II antagonism reduced fibrinogen and
44. Matsubara H, Kanasaki M, Murasawa S, Tsukaguchi Y, Nio Y, Inada M.
insulin resistance in overweight hypertensive patients. J Cardiovasc Differential gene expression and regulation of angiotensin II receptor
Pharmacol. 1998;32:616 – 620. subtypes in rat fibroblasts and cardiomyocytic in culture. J Clin Invest.
22. Caldiz CI, de Cingolani GE. Insulin resistance in adipocytes from spon-
Downloaded from http://hyper.ahajournals.org/ by guest on February 10, 2017
1994;93:592– 601.
taneously hypertensive rats: effect of long-term treatment with enalapril 45. Schaffer SW, Ballard-Craft C, Boerth S, Allon SM. Mechanisms
and losartan. Metabolism. 1999;48:1041–1046. underlying depressed Na⫹/Ca2⫹ exchanger activity in the diabetic heart.
23. Folli F, Kahn CR, Hansen H, Bouchie JL, Feener EP. Angiotensin II Cardiovasc Res. 1997;34:129 –136.
inhibits insulin signaling in aortic smooth muscle cell at multiple levels. 46. Giles TD, Ouyang J, Kerut EK, Given MB, Allen GE, McIwain EF,
J Clin Invest. 1997;100:2158 –2169. Greenberg SS. Changes in protein kinase C in early cardiomyopathy and
24. Velloso LA, Folli F, Sun XJ, White MF, Saad MJ, Kahn CR. Cross-talk in the gracilis muscle in the BB/W or diabetic rat. Am J Physiol. 1998;
between insulin and angiotensin signaling systems. Proc Natl Acad Sci 4:H295–H307.
U S A. 1996;93:12490 –12495. 47. Ren J, Sampson WK, Sowers JR. Insulin-like growth factor 1 as a cardiac
25. Richey JM, Ader M, Moore D, Bergman RN. Angiotensin II induces hormone: physiological and pathophysiological implications in heart
insulin resistance independent of changes in interstitial insulin. Am J disease. Mol Cell Cardiol. 1999;31:2049 –2061.
Physiology. 1999;277(pt 1):E920 –E926. 48. Cittadini A, Ishiguro Y, Stromer H, Spindler M, Moses AC, Clark R,
26. Romel S, Sumitani S, Taha C, Sweeney G, Klip A. Temporal activation Douglas PS, Ingwall JS, Morgan JP. Insulin-like growth factor but not
of p70 S6 kinase and Akt1 by insulin: PI3-kinase-dependent and –inde- growth hormone augments mammalian myocardial contractility by sensi-
pendent mechanisms. Am J Physiol. 1998;275:E618 –E625. tizing the myofilament to Ca2⫹ through a wortmannin-sensitive pathway:
27. Li D, Sweeney G, Wang Q, Klip A. Participation of PI3K and atypical studies in rat and ferret isolated muscles. Circ Res. 1998;83:50–59.
PKC in Na⫹,K⫹-ATP pump stimulation by IGF-1 in VSMC. Am J 49. LeRoith D. Insulin-like growth factors. N Engl J Med. 1998;336:
Physiol. 1999;276:H2109 –H2116. 633– 640.
28. Nawano M, Anai M, Funaki M, Kobayashi H, Kanda A, Fukushima Y, 50. Kolter T, Uphues I, Eckel J. Molecular analysis of insulin resistance in
Inukai K, Ogihara T, Sakoda H, Onishi Y, et al. Imadapril, an angioten- isolated ventricular myocytes of obese Zucker rats. Am J Physiol. 1997;
sin-converting enzyme inhibitor, improves insulin sensitivity by 36:E59 –E67.
enhancing signal transduction via insulin receptor substrate proteins and 51. Guo W, Kada K, Kamiya K, Toyama J. IGF-1 regulates K⫹-channel
improving vascular resistance in the Zucker fatty rat. Metabolism. 1999; expression of cultured neonatal rat ventricular myocytes. Am J Physiol.
48:1248 –1255. 1997;272:H2599 –H2560.
29. Erdos EG, Deddish PA, Marcic BM. Potentiating of bradykinin action by 52. Grossman E, Shemesh J, Shamiss A, Thaler M, Carroll J, Rosenthal T.
ACE inhibitors. Trends Endocrinol Metab. 1999;10:223–229. Left ventricular mass in diabetes-hypertension. Arch Intern Med. 1992;
30. Henriksen EJ, Jacob S, Kinnick TR, Youngblood ER, Schmit MB, Dietze 152:1001–1004.
GJ. ACE inhibition and glucose transport in insulin resistant muscle: roles 53. Taal MW, Brenner BM. Renoprotective benefits of RAS inhibition: from
ACEI to angiotensin II antagonists. Kidney Int. 2000;57:1803–1817.
of bradykinin and nitric oxide. Am J Physiol. 1999;277(pt 2):R332–R336.
54. Bianchi S, Bigazzi R, Quinones Galvan A, Muscelli E, Baldari G, Pecori N,
31. Haffner SM, Lehto S, Ronnemma T, Pyorala K, Laakso M. Mortality
Ciociaro D, Ferrannini E, Natali A. Insulin resistance in microalbuminuric
from coronary heart disease in subjects with type 2 diabetes and in
hypertension: sites and mechanisms. Hypertension. 1995;26:189–195.
nondiabetic subjects with and without myocardial infarction. N Engl
55. Pinkney JH, Foyle WJ, Denver AE, Mohamed-Ali V, McKinlay S,
J Med. 1998;339:229 –234.
Yudkin JS. The relationship of urinary albumin excretion rate to ambu-
32. Sowers JR. Diabetes mellitus and cardiovascular disease in women. Arch
latory blood pressure and erythrocyte sodium-lithium countertransport in
Intern Med. 1998;158:617– 621. NIDDM. Diabetologia. 1995;38:356 –362.
33. Garcia MJ, McNamara PM, Gordon T, Kannel WB. Morbidity and 56. Mitchell TH, Nolan B, Henry M, Cronin C, Baker H, Greely G. Microalbu-
mortality in diabetes in the Framingham population: sixteen-year minuria in patients with non-insulin-dependent diabetes mellitus relates to
follow-up study. Diabetes. 1974;23:105–111. nocturnal systolic blood pressure. Am J Med. 1997;102:531–535.
34. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk 57. Sowers JR, Lester M. Diabetes and cardiovascular disease. Diabetes
factors and 12-year cardiovascular mortality for men screened in the Care. 1999;22(suppl 3):C14 –C20.
Multiple Risk Factor Intervention Trial. Diabetes Care. 1993;263: 58. Feldman RD. The Canadian recommendations for the management of
2335–2340. hypertension: on behalf of the Task Force for the Development of the
35. Frohlich ED. Uric acid: a risk factor for coronary artery disease. JAMA. 1999 Canadian Recommendations for the Management of Hypertension.
1993;270:354 –359. Can J Cardiol. 1999;15:S57G–S64G.
36. Brown R, Walsh M, Sowers JR. Influence of sex, diabetes and ethanol on 59. Ravid M, Lang R, Rachmani R, Lishner M. Long-term renoprotective
intrinsic contractile performance of isolated rat myocardium. Basic Res effect of angiotensin-converting enzyme inhibition in non-insulin-
Cardiol. 1996;91:353–360. dependent diabetes mellitus: a 7-year follow-up study. Arch Intern Med.
37. Ren J, Dominguez LJ, Sowers JR, Davidoff A. Troglitazone attenuates 1996;156:286 –289.
high glucose-induced abnormalities in relaxation and intracellular 60. Colwell JA. Aspirin therapy in diabetes. Diabetes Care. 1997;20:
calcium in rat ventricular myocytes. Diabetes. 1996;45:1822–1825. 1767–1771.
Diabetes, Hypertension, and Cardiovascular Disease: An Update
James R. Sowers, Murray Epstein and Edward D. Frohlich
Hypertension. 2001;37:1053-1059
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