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From the Cardiovascular Division, Beth Israel Deaconess Medical Center,
Harvard Medical School, Boston, Mass (R.W.N.) and the Cardiovascular Division,
Bridgeport Hospital, Yale University Medical School, Bridgeport, Conn (S.Z.).
Correspondence to Richard W. Nesto, MD, 110 Francis St, Suite 4B, Boston, MA 02215. E-mail rnesto{at}west.bidmc.harvard.edu
Diabetes mellitus
affects
In the December 16, 1997, issue of Circulation, the GISSI-3
investigators compare the effect of early administration (within 24
hours of admission) of lisinopril in patients with and
without diabetes mellitus in MI.5 Compared with
placebo, lisinopril dramatically reduced both 6-week and
6-month mortality in diabetics versus nondiabetics (6 weeks, 30%
versus 5% and 6 months, 20% and 0%, respectively). Furthermore, the
incidence of drug-related adverse effects was similar between the two
groups within the blood pressure and renal function
parameters used in that study. This experience, along with
the subgroup analyses of SAVE6 and
TRACE,7 should firmly establish an ACE
inhibitor as part of the regimen for the diabetic patient
with MI. In a recent meta-analysis of ACE inhibitor
trials in acute MI, only a 6% relative mortality reduction (without
regard to the presence or absence of diabetes mellitus) was found with
early drug administration.8 Despite these
collective data, ACE inhibitors are generally withheld on
the first day of acute MI to avoid causing hypotension. In CONSENSUS
II,9 hypotension in the enalapril-treated group
negated any potential benefit of early ACE inhibition. This GISSI-3
report also suggests that the diabetic patient may have far more to
gain than the nondiabetic when an ACE inhibitor is
administered within the first day of an acute MI. The putative
mechanisms responsible for the major benefit of lisinopril
in these patients are presented below.
In general, ACE inhibitors are grossly underprescribed in
this setting, despite their recognized
benefits.10 The failure to use them in diabetic
patients may be even more prevalent, for the following reasons: (1)
fear of azotemia with or without preexistent renal disease; (2) fear
that they may cause or contribute to hemodynamic
instability, particularly if diabetes-related autonomic
neuropathy is suspected; (3) fear that they may induce
hyperkalemia, because type 4 RTA or bilateral renal
artery stenoses are more common in diabetics; and (4)
preoccupation with the challenge of glycemic control. A similar paradox
relates to the failure to administer ß-blockers to diabetic patients
in acute MI.11 Compared with placebo in this
setting, ß-blockers provide two to three times the relative benefit
in mortality reduction when diabetes is present compared with when
it is absent.12 However, the risk of masking the
warning signs of hypoglycemia and disturbing glycemic control tends to
limit their use. Although these are valid concerns, insulin-induced
hypoglycemia occurs far less commonly in type II than in type I
diabetic patients, and cardioselective ß-blockers can
be given in doses providing secondary prevention with less effect on
glucose metabolism than nonselective
agents.13 14 Much of the reluctance to administer
these agents stems from warnings issued years ago when only
nonselective ß-blockers were available and were typically prescribed
in much higher dosages.
The GISSI-3 authors address only briefly the potential mechanisms
underlying the benefit of lisinopril in diabetic patients.
Both in-hospital and late mortality after acute MI are highly
correlated with the degree of left ventricular dysfunction.
A major determinant of this prognostic variable is left
ventricular remodeling, a process involving expansion of
the infarcted segment with subsequent ventricular
dilatation and asynergy of the noninfarcted regions. After adjustment
for the size of infarction, diabetic patients experience more
congestive heart failure than nondiabetic patients, which suggests that
the behavior of the noninfarct zone may be an important determinant in
the outcome between the two groups.1 2 For many
years, more extensive coronary artery disease in the diabetic
patient was thought to explain the greater degree of left
ventricular dysfunction. In GUSTO-1, however, the twofold
increase in relative risk of 30-day mortality conferred by the presence
of diabetes remained unaltered after adjustment for extent of
coronary artery disease and a variety of other clinical
factors.4
Many conditions specific to the heart in diabetes affect global
myocardial remodeling. Previous silent infarction may be present in
as many as 40% of these patients at the time they present with
their first clinically recognized MI.5 15 Cardiac
autonomic neuropathy may be present in nearly 50% of
the diabetic population with coronary artery
disease16 and can cause both
diastolic and systolic dysfunction.
Cardiomyopathy secondary to diabetes is often
subclinical, with diastolic dysfunction typically preceding
systolic dysfunction.17 Hypertension and
diabetes together result in more cardiac fibrosis than when either
occurs alone.18 Endothelial
dysfunction may impair coronary perfusion at the microvascular
level, resulting in ischemia.19 Although
the heart utilizes free fatty acids as its major source of energy,
ischemia results in greater expression of GLUT4 transporter
proteins, facilitating glucose entry and glycolysis, a major source of
myocardial ATP in anaerobic
conditions.20 In diabetes, however, ATP
generation is less efficient, because relative insulinopenia results in
increased lipolysis, elevated plasma levels of free fatty acids, and
increased fatty acid oxidation as glycolysis and glucose oxidation are
suppressed.21 In addition, despite the
hyperglycemia most diabetics experience in acute MI, glucose is
unavailable as an energy source, because myocardial GLUT4 transporter
protein levels may be depressed.22 These
metabolic perturbations result in depressed ATP
production, generation of oxygen free radicals, increased
myocardial oxygen consumption, and myocardial contractile dysfunction.
It is not surprising that additional myocardial damage results in heart
failure out of proportion to infarct size in patients with
diabetes.
Several studies support the notion that the structural, functional, and
metabolic factors related to diabetes cited above place the
left ventricle at higher risk for maladaptive remodeling. One study
comparing serial wall motion scores after MI showed that left
ventricular function at discharge and at 6 months remained
stable in nondiabetic patients, whereas it progressively deteriorated
in the patients with diabetes.23 Iwasaka and
coworkers,24 using radionuclide angiography,
found that regional ejection fraction of the noninfarct zone at any
end-diastolic volume 3 weeks after MI was lower in patients
with diabetes, despite infarct size and extent of coronary
artery disease similar to those in the group without diabetes. Diabetic
patients demonstrated more global and regional left
ventricular dysfunction 4 weeks after inferior
MI than their nondiabetic counterparts in another study that used
radionuclide ventriculography.25
Remodeling of the left ventricle consequent to MI is a
time-dependent phenomenon. Increases in end-diastolic and
end-systolic volumes may be seen within 3 hours of
admission26 and serve as strong predictors of
both early and late outcome. In the HEART study, early ramipril
administration in anterior infarction was associated with substantial
recovery of wall motion by 14 days, prompting the investigators to say
that "the major mortality and echocardiographic
studies ... would support early initiation of ACE inhibition in
acute MI, especially in higher-risk individuals in whom this therapy
should be maintained on a long-term basis."27
In the parent GISSI-3 report, nearly one half of the lives saved with
early lisinopril use were a result of a reduction in deaths
secondary to cardiac rupture and pump failure.28
Indeed, diabetes is a risk factor for rupture of the
ventricular free wall complicating
infarction.29
In addition to beneficial effects on ventricular
remodeling, ACE inhibitors can further improve outcomes by
reducing recurrent ischemic events (MI, unstable angina, and
revascularization) after MI. ACE inhibition reduced
recurrent MI by 25% in the SAVE trial30 and was
associated with 37% fewer ischemic events after infarction in
the CATS trial.31 Salutory effects on
neurohumoral activation, oxidative stress, endothelial
function, ischemic preconditioning, and
fibrinolysis provide further insight into the
preferential effect of ACE inhibition in diabetic subjects in the
postinfarction period.
Epidemiologic studies suggest that enhanced sympathetic activity is
associated with an increased risk for ischemic events and
sudden death. Sympathetic activation increases both the
hemodynamic and hemostatic risk factors, leading to
plaque rupture and thrombosis.32 A substantial
number of type I and type II diabetic patients (with or without
clinical signs of autonomic nervous system dysfunction) have diminished
vagal activity, resulting in relatively higher sympathetic activity
(sympathovagal imbalance) during the day and
night.33 Diabetics with autonomic
neuropathy are at increased risk of cardiac events and show
an altered circadian pattern of ischemia compared with
diabetics without autonomic dysfunction.34 In
general, sympathovagal imbalance documented by heart rate variability
studies has been associated with a poor prognosis after MI independent
of left ventricular
dysfunction.35
In GISSI-3, the diabetic subgroup presented with a higher
Killip classification and higher heart rate, suggesting more pronounced
activation of both the adrenergic and renin-angiotensin
systems than in their nondiabetic counterparts. In general, ACE
inhibition is most effective in patients with the greatest degree of
neurohumoral activation, which helps to explain the magnitude of
benefit of ACE inhibitors in diabetics after infarction in
this study.36 ACE inhibitors increase
parasympathetic tone and restore autonomic balance in congestive heart
failure.37 There is increasing evidence that ACE
inhibition may attenuate sympathetic responses. ACE
inhibitors may decrease central sympathetic
outflow,38 alter postsympathetic
Increased oxidative stress brought about by hyperglycemia may be an
important link between diabetes and vascular
events.42 Advanced glycosylated end products
may quench nitric oxide through the generation of oxygen free radicals,
leading to impaired endothelial vasodilatation.
Angiotensin II augments oxidative stress by increasing the
vascular production of superoxide
radicals,43 which in turn interfere with the
bioavailability of nitric oxide. By increasing free radical
production, angiotensin II increases leukocyte
adhesion to the endothelium, platelet aggregation,
and cytokine expression, resulting in macrophage
infiltration at the site of atherosclerotic plaques, leading to
increased plaque vulnerability. ACE accumulation has recently been
demonstrated within inflammatory regions of atherosclerotic
plaque.44 ACE inhibitors improve
endothelial function in atherosclerotic
vessels.45
Diabetes alone or in combination with a variety of risk factors
(hypertension, hypercholesterolemia) can impair
endothelial function. ACE inhibitors have
recently been found to normalize endothelial function
in type I diabetics via a nitric oxide–mediated mechanism in the short
term, with further improvements in vasodilatation after 4 weeks of
treatment.46 Because bradykinin
antagonists have been shown to reverse the salutory changes
of ACE inhibition on endothelium-dependent
vasodilatation, accumulation of endogenous bradykinin,
which directly stimulates nitric oxide production, plays a
major role in the vascular effects of ACE
inhibition.47 Angiotensin II can also
alter vasomotor tone directly or indirectly by increasing endothelin
generation. Because >40% of diabetic patients studied had previously
had angina, ischemic preconditioning might have mitigated the
extent of left ventricular dysfunction. However, more than
three quarters of the study population had type II diabetes, some of
whom were most likely receiving sulfonylureas, which can block
ischemic preconditioning by inhibition of the
potassium-dependent ATP channels.48
Ischemic preconditioning can be augmented by a
bradykinin-dependent mechanism that is potentiated by ACE
inhibitors.49 In diabetic patients,
ACE inhibitors may be particularly beneficial by improving
endothelial function and vascular tone and augmenting
ischemic preconditioning.
Impaired fibrinolysis, as reflected by elevated
plasminogen activator inhibitor
(PAI)-1 levels, has been associated with an increased risk of recurrent
MI.50 Plasma PAI-1 is increased in diabetic
patients and has been linked to vascular
disease.51 The recent ECAT study documented the
association of impaired fibrinolysis,
parameters of endothelial cell dysfunction,
and an inflammatory state with future adverse coronary
events.52 PAI-1 activity and antigen predicted
that cardiac events were related principally to insulin resistance. ACE
inhibitors can suppress plasminogen
activator expression experimentally and improve
fibrinolytic capacity in patients after MI.53 ACE
inhibitors also markedly improve insulin sensitivity and
glycemic control.54 Acute hyperglycemia can in
itself increase vascular tone, presumably by decreasing nitric oxide
availability.55 Because improved glycemic control
is associated with improved mortality after MI in diabetic patients
receiving insulin,56 ACE inhibitors
may improve survival in this group by decreasing insulin resistance,
improving glycemic control, and restoring fibrinolytic capacity.
ACE inhibitors counteract many of the established and
putative mechanisms accounting for the increased mortality of MI in
diabetes mellitus. Is the greater relative mortality reduction in
diabetes simply explained by the fact that these agents defend against
mechanisms shared by both groups, or are there mechanisms specific to
diabetes against which ACE inhibitors might be operative?
The authors of this study broach this question by showing that diabetic
patients benefited more from lisinopril than nondiabetic
patients, independent of other risk factors for elevated mortality. The
prevention or retardation of nephropathy in the diabetic
patient is a good example in which ACE inhibitors act by
diabetes-specific (lowering efferent arteriolar tone) and -nonspecific
(lowering systemic blood pressure) mechanisms. Further elucidation of
the role of the renin-angiotensin system in acute
coronary syndromes in diabetic patients will answer this
question.
It appears that the entire benefit of early administration of
lisinopril in GISSI 3,57 as reported
initially, could be explained by the marked effect in patients with
diabetes, who composed only 6.5% of the total study population. In a
post hoc analysis conducted in ISIS 2,58
the presence of diabetes was the only clinical factor that altered the
interaction of aspirin and streptokinase on mortality in acute MI.
Although the results of these subgroup analyses are
interesting, the implications for practice are somewhat limited by
their post hoc nature. The rewards of specifying a subgroup for
analysis are exemplified in the recent BARI
trial,59 which showed that in the presence of
diabetes, coronary bypass surgery provided a survival benefit
over PTCA in multivessel disease, even though no difference between
treatments was noted for the entire study population. Because diabetes
mellitus profoundly affects the biology of
cardiovascular disease, one could argue that clinical
trials in the future with potential major implications for the care of
patients with heart disease should be specifically designed to evaluate
the effect of therapy in patients with diabetes mellitus.
Acknowledgments
The authors wish to acknowledge Murray Mittleman, MD, for his
review of the manuscript.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1.
Jacoby R, Nesto R. Acute myocardial
infarction in the diabetic patient: pathophysiology, clinical course
and prognosis. J Am Coll Cardiol. 1992;20:736–744.[Abstract]
2.
Aronson D, Rayfield E, Cheseboro J. Mechanisms
determining course and outcome of diabetic patients who have had acute
myocardial infarction. Ann Intern Med. 1997;126:296–306.
3.
Partamian J, Bradley R. Acute myocardial infarction in
258 cases of diabetes. N Engl J Med. 1965;273:455–461.
4.
Woodfield S, Lundergan C, Reiner J, Greenhouse S,
Thompson M, Rohrbeck S, Deychak Y, Simoons M, Califf R, Topol E, Ross
A. Angiographic findings and outcome in diabetic patients treated with
thrombolytic therapy for acute myocardial infarction:
the GUSTO-I experience. J Am Coll Cardiol. 1996;28:1661–1669.[Abstract]
5.
Zuanetti G, Latini R, Maggioni A, Franzosi M, Santoro
L, Tognoni G, on behalf of the GISSI-3 Investigators. Effect of the
ACE-inhibitor lisinopril on mortality in
diabetic patients with acute myocardial infarction: the data from the
GISSI-3 study. Circulation. 1997;96:4239–4245.
6.
Moye LA, Pfeffer MA, Wun CC, Davis BR, Geltman E,
Hayes D, Farnham DJ, Randall OS, Dinh H, Arnold JMO, Kupersmith J,
Hager D, Glasser SP, Biddle T, Hawkins CM, Braunwald E, for the SAVE
Investigators. Uniformity of captopril benefit in the SAVE study:
subgroup analysis. Eur Heart J. 1994;15:2–8.
7.
Torp-Pedersen C, Kober L, Carlsen J, on behalf
of the TRACE Study Group. Angiotensin-converting enzyme
inhibition after myocardial infarction: the Trandolapril Cardiac
Evaluation study. Am Heart J. 1996;132:235–243.[Medline]
[Order article via Infotrieve]
8.
Latini R, Maggioni AP, Flather M, Sleight P, Tognoni
G. ACE inhibitor use in patients with myocardial
infarction. Circulation. 1995;92:3132–3137.
9.
The CONSENSUS II Study Group. Effects of the early
administration of enalapril on mortality in patients with acute
myocardial infarction. N Engl J Med. 1992;327:678–684.[Abstract]
10.
McGovern P, Pankow J, Shahar E, Doliszny K, Folsom A,
Blackburn H, Luepker R, for the Minnesota Heart Survey Investigators.
Recent trends in acute coronary heart disease. N
Engl J Med. 1996;334:884–890.
11.
Viskin S, Kitzis I, Lev E, Zak A, Heller K, Villa Y,
Zajarias A, Laniado S, Belhassen B. Treatment with beta-adrenergic
blocking agents after myocardial infarction: from randomized trials to
clinical practice. J Am Coll Cardiol. 1995;25:1327–1332.[Abstract]
12.
Kjekshus J, Gilpin E, Cali G, Blackey A, Henning H,
Ross J. Diabetic patients and beta-blockers after acute myocardial
infarction. Eur Heart J. 1990;11:43–50.
13.
Wright D, Barber S, Kendall M, Poole P.
Beta-adrenoceptor-blocking drugs and blood sugar control in diabetes
mellitus. Br Med J. 1979;1:159–161.
14.
Waal-Manning H. Metabolic effects of
B-adrenoreceptor blockers. ADIS Press. 1976;1:121–126.
15.
Cabin H, Roberts W. Quantitative comparison of extent
of coronary narrowing and size of healed myocardial infarct in
33 necropsy patients with clinically recognized and in 28 with
clinically unrecognized (`silent') previous acute myocardial
infarction. Am J Cardiol. 1982;50:677–681.[Medline]
[Order article via Infotrieve]
16.
Toyry J, Niskanen L, Mantysaari M, Lansimies E,
Uusitupa M. Occurrence, predictors, and clinical significance of
autonomic neuropathy in NIDDM. Diabetes. 1996;45:308–315.[Abstract]
17.
Zola B, Vinik A. Effects of autonomic
neuropathy associated with diabetes mellitus on
cardiovascular function. Coron Artery Dis. 1992;3:33–41.
18.
van Hoeven K, Factor S. A comparison of the
pathological spectrum of hypertensive, diabetic, and
hypertensive-diabetic heart disease. Circulation. 1990;82:848–855.
19.
Nahser P, Brown R, Oskarsson H, Winniford M, Rossen J.
Maximal coronary flow reserve and metabolic
coronary vasodilation in patients with diabetes mellitus.
Circulation. 1995;91:635–640.
20.
Sun D, Nguyen N, DeGrado T, Schwaiger M, Brosius F.
Ischemia induces translocation of the insulin-responsive
glucose transporter GLUT4 to the plasma membrane of cardiac myocytes.
Circulation. 1994;89:793–798.
21.
Oliver M, Opie H. Effects of glucose and fatty acids on
myocardial ischaemia and arrhythmias. Lancet. 1994;343:155–158.[Medline]
[Order article via Infotrieve]
22.
Stanley W, Hall J, Hacker T, Hernandez L, Whitesell L.
Decreased myocardial glucose uptake during ischemia in diabetic
swine. Metabolism. 1997;46:168–172.[Medline]
[Order article via Infotrieve]
23.
Azzarelli A, Dini F, Cristofani R, Giaconi A, Rossi A,
Volterrani C, Lundardi M, Bernardi D. NIDDM as unfavorable factor to
the postinfarction ventricular function in the elderly:
echocardiography study. Coron Artery
Dis. 1995;6:629–634.[Medline]
[Order article via Infotrieve]
24.
Iwasaka T, Takahashi N, Nakamura S, Sugiura T, Tarumi
N, Kimura Y, Okubo N, Taniguchi H, Matsui Y, Inada M. Residual left
ventricular pump function after acute myocardial infarction
in NIDDM patients. Diabetes Care. 1992;15:1522–1526.[Abstract]
25.
Lomuscio A, Bestetti A, Vergani D, Chiaramello D, Chiti
A, Ruffini L, Pozzoni L, Tarolo G. Radionuclide assessment of left
ventricular function in patients with myocardial infarction
and diabetes mellitus. J Intern Med. 1992;231:73–76.[Medline]
[Order article via Infotrieve]
26.
Korup E, Dalsgaard D, Nyvad O, Jensen T, Toft E,
Berning J. Comparison of degrees of left ventricular
dilation within three hours and up to six days after onset of first
acute myocardial infarction. Am J Cardiol. 1997;80:449–453.[Medline]
[Order article via Infotrieve]
27.
Pfeffer M, Greaves S, Arnold M, Glynn R, LaMotte F, Lee
R, Menapace F, Rapaport E, Ridker P, Rouleau J, Solomon S, Hennekens C,
for the Healing and Early Afterload Reducing Therapy (HEART) Trial
Investigators. Circulation. 1997;95:2643–2651.
28.
GISSI-3 Investigators. Causes of early in-hospital
mortality of patients with acute myocardial infarction: the impact of
ACE-inhibitor treatment. Circulation.
1995;92(suppl I):I-673. Abstract.
29.
Kereiakes D. Myocardial infarction in the diabetic
patient. Clin Cardiol. 1985;8:446–450.[Medline]
[Order article via Infotrieve]
30.
Rutherford JD, Pfeffer MA, Moye LA, Davis BR, Flaker
GC, Braunwald E, on behalf of the SAVE Investigators. Effects of
captopril on ischemic effects after myocardial infarction.
Circulation. 1994;90:1731–1738.
31.
Van Den Heuvale AD, Van Gilst WH, Van Veldhuisen DJ, De
Vries RJ, Dunselman PH, Kingma JH. Long-term anti-ischemic
effects of angiotensin-converting enzyme inhibition in
patients after myocardial infarction. J Am Coll
Cardiol. 1997;30:400–405.[Abstract]
32.
Muller JE, Tofler GH, Stone PH. Circadian variation and
triggers of onset of acute cardiovascular disease.
Circulation. 1989;79:733–743.
33.
Bernardi L, Ricordi L, Lazzari P, Solda P, Calciati A,
Ferrari MR, Vandea I, Finardi G, Fratino P. Impaired circadian
modulation of sympathovagal activity in diabetes.
Circulation. 1992;86:1443–1452.
34.
Zarich S, Waxman S, Freeman RT, Mittleman M,
Hegarty P, Nesto RW. Effect of autonomic nervous system dysfunction on
the circadian pattern of myocardial ischemia in diabetes
mellitus. J Am Coll Cardiol. 1994;24:956–962.[Abstract]
35.
Zuanetti G, Neilson J, Latini R, Santoro E, Maggioni A,
Ewing D. Prognostic significance of heart rate variability in post
myocardial infarction patients in the fibrinolytic era.
Circulation. 1996;94:432–436.
36.
Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G,
Tristani F, Smith R, Dunkman B, Loeb H, Wong M, Bhat G, Goldman S,
Fletcher RD, Doherty J, Hughes CV, Carson P, Clintron G, Shabeti R,
Haakenson C. A comparison of enalapril and
hydralazine-isosorbide dinitrate in the treatment of chronic
congestive heart failure. N Engl J Med. 1991;325:303–310.[Abstract]
37.
Binkley PF, Haas GJ, Starling RC, Nunziata E, Hatton
PA, Leier CV, Cody RJ. Sustained augmentation of parasympathetic tone
with angiotensin-converting enzyme inhibition in patients
with congestive heart failure. J Am Coll Cardiol. 1993;21:655–661.[Abstract]
38.
Grassi G, Cattaneo BM, Seravalle G, Lanfranchi A, Pozzi
M, Morganti A, Carugo S, Mancia G. Effects of chronic ACE inhibition on
sympathetic nerve traffic and baroreflex control of circulation in
heart failure. Circulation. 1997;96:1173–1179.
39.
Lyons D, Roy S, O'Bryne S, Swift CG. ACE inhibition
postsynaptic adrenergic sympatholytic action in men.
Circulation. 1997;96:911–915.
40.
Saino A, Pomidossi G, Perondi R, Valentini R, Rimini A,
Di Francesco L, Mancia G. Intracoronary angiotensin
II potentiates coronary sympathetic vasoconstriction in humans.
Circulation. 1997;96:148–153.
41.
Van Gilst VM, deGraeff PA, Wesseling H, deLangen CDJ.
Reduction of reperfusion arrhythmias in the ischemic
isolated rat heart angiotensin converting enzyme
inhibitors: a comparison of captopril, enalapril and
HOE498. J Cardiovasc Pharmacol. 1986;8:722–728.[Medline]
[Order article via Infotrieve]
42.
Giugliano D, Ceriello A, Paolisso G. Diabetes
mellitus, hypertension, and cardiovascular disease: the
role of oxidative stress? Metabolism. 1995;44:363–368.[Medline]
[Order article via Infotrieve]
43.
Laursen JB, Rajagopalan S, Galis Z, Tarpey M, Freeman
BA, Harrison DG. Role of superoxide in angiotensin
II-induced but not catecholamine-induced hypertension.
Circulation. 1997;95:588–593.
44.
Diet F, Pratt RE, Berry GJ, Momose N, Gibbons GH, Dzau
VJ. Increased accumulation of tissue ACE in human atherosclerotic
coronary artery disease. Circulation. 1996;94:2756–2767.
45.
Mancini GB, Henry GC, Macaya C, O'Neill BJ, Puccilo
AL, Carere RG, Wargovich TJ, Mudra H, Luscher TF, Klibaner MI, Haber
HE, Uprichard AC, Pepine CJ, Pitt B. Angiotensin-converting
enzyme inhibition with quinapril improves endothelial
vasomotor dysfunction in patients with coronary artery disease.
Circulation. 1996;94:258–265.
46.
O'Driscoll G, Green D, Rankin J, Stanton K, Taylor R.
Improvement in endothelial function by
angiotensin converting enzyme inhibition in
insulin-dependent diabetes mellitus. J Clin Invest. 1997;100:678–684.[Medline]
[Order article via Infotrieve]
47.
Hornig B, Kohler C, Drexler H. Role of bradykinin in
mediating vascular effects of angiotensin-converting enzyme
inhibitors in humans. Circulation. 1997;95:1115–1118.
48.
Cleveland JC, Meldrum DR, Cain BS, Banerjee A, Harken
AH. Oral sulfonylurea hypoglycemic agents prevent ischemic
preconditioning in human myocardium.
Circulation. 1997;96:29–32.
49.
Paratt JR, Vegh A, Zeitlin IJ, Ahmad M, Oldroyd K,
Kaszala K, Papp JG. Bradykinin and endothelial-cardiac
myocyte interactions in ischemic preconditioning. Am
J Cardiol. 1997;80:124A–131A.[Medline]
[Order article via Infotrieve]
50.
Hamsten A, Walldius G, Szamosi A, Blomback M.
Plasminogen activator inhibitor in
plasma: risk factor for recurrent myocardial infarction.
Lancet. 1987;3:3–9.
51.
McGill JB, Schneider DJ, Arfken CL, Lucore CL, Sobel
BE. Factors responsible for impaired fibrinolysis in
obese subjects and NIDDM patients. Diabetes. 1994;43:104–109.[Abstract]
52.
Juhan-Vague I, Pyke SD, Alessi MC, Jespersen J,
Haverkate F, Thompson SG. Fibrinolytic factors and the risk of
myocardial infarction or sudden death in patients with angina pectoris.
Circulation. 1996;94:2057–2063.
53.
Vaughan DE, Rouleau JL, Ridker PM, Arnrold JM, Menapace
FJ, Pfeffer MA. Effects of ramipril on plasma fibrinolytic balance in
patients with acute anterior myocardial infarction.
Circulation. 1997;96:442–447.
54.
Torlone E, Britta M, Rambotti AM, Perriello G,
Santeusanio F, Brunetti P, Bolli GB. Improved insulin action and
glycemic control after long-term angiotensin-converting
enzyme inhibition in subjects with arterial hypertension
and type II diabetes. Diabetes Care. 1993;16:1347–1355.[Abstract]
55.
Giugliano D, Marfella R, Coppola L, Verrazzo G,
Acampora R, Giunta R, Nappo F, Lucarelli C, D'Onofrio F. Vascular
effects of acute hyperglycemia in humans are reversed by
L-arginine. Circulation. 1997;95:1783–1790.
56.
Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol
P, Waldenstrom A, et al. Randomized trial of insulin-glucose infusion
followed by subcutaneous insulin treatment in diabetic patients with
acute myocardial infarction (DIGAMI study): effects on mortality at 1
year. J Am Coll Cardiol. 1995;26:57–65.[Abstract]
57.
Gruppo Italiano per lo Studio della Sopravvivenza
nell'Infarto Miocardico. GISSI-3: effects of lisinopril
and transdermal glyceryl trinitrate singly and together on 6 week
mortality and ventricular function after myocardial
infarction. Lancet. 1994;343:1115–1122.[Medline]
[Order article via Infotrieve]
58.
ISIS-2 Collaborative Group. Randomized trial of
intravenous streptokinase, oral aspirin, both or neither
among 17,187 cases of suspected acute myocardial infarction: ISIS-2.
Lancet. 1988;2:349–360.[Medline]
[Order article via Infotrieve]
59.
The Bypass Angioplasty
Revascularization Investigation (BARI)
Investigators. Comparison of coronary bypass surgery with
angioplasty in patients with multivessel disease. N Engl
J Med. 1996;335:217–225.
© 1998 American Heart Association, Inc.
Editorials
Acute Myocardial Infarction in Diabetes Mellitus
Lessons Learned From ACE Inhibition
Key Words: diabetes mellitus • myocardial infarction
6% of the US population but is present in as many as
30% of patients hospitalized with acute coronary syndromes. It
has been recognized for some time that diabetics experience a greater
mortality during the acute phase of myocardial infarction (MI) and a
higher morbidity in the postinfarction period (see recent reviews in
References 1 and 21 2 ). Before the advent of coronary care as we
know it today, mortality among diabetic patients in MI was reported to
be as high as 40%3 and at least double the
mortality rate in patients without diabetes. More extensive
coronary artery disease, additional
cardiovascular risk factors, and other end-organ
disease were thought to be largely responsible for this major
difference in outcome. Current treatment of acute MI derived from large
clinical trials has dramatically improved survival in both nondiabetic
and diabetic patients. However, despite these improvements, diabetes
still doubles the case-fatality rate. In the GUSTO-1 angiography
substudy report,4 this twofold increase in
relative risk of 30-day mortality persisted even after adjustment for
the factors cited above. What is this "diabetic factor"? It is in
this context that new information on this topic must be evaluated. 
-adrenergic
tone,39 and blunt sympathetic coronary
vasoconstriction by decreasing angiotensin II
production.40 Altered sympathetic tone
may also be responsible for the potential of ACE inhibitors
to reduce ventricular
arrhythmias.41 Although ACE
inhibitors may be able to modify sympathovagal balance,
diminishing angiotensin II levels, little is known
regarding their effects on patients with diabetes-related autonomic
neuropathy.
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