STUART ZARICH, MD, FACC, SERGIO WAXMAN, MD, ROY T. FREE ... · with coronary artcv disease arc...

956 JACC Vol. 24, No. 4 Qctohcr l994z95662

STUART ZARICH, MD, FACC, SERGIO WAXMAN, MD, ROY T. FREE MURRAY MITFLEMAN, MD, PATRICIA HEGARTY, RICHARD W. NESTQ, MD, FACC

Bmron, Massachrwtts

The aim of this study WPS to determine the preva- cbaraclerislics of ambulatory mymardial ischemia in

tient,r with dlabetea mellitus and to delineate the relation the presence and severity of aulonomic nervous system ion and Ihe incidence and time of onset of rny~a~~al

iwhemia. ta exist with regard to the circadian

ion aad other cardiovascular events, cbemia, in diabetes.

rmed umbulatory electrocardiographic man. with diabetes and coronary artery disease.

Aulonomk nervous system Ming was performed in a subgroup of 25 patients with myocardial ischemia after disronGnuation of all artiangiual medicalions.

&u&s. Tbirty+ht of 60 patients bad evidence of ambulatory ischemk 91% of all ischemic episodes were asymptomatic. Tbt! 25 patients with ambulatory iscbemia who underwent autonomic nervous system testing had a peak incidence of ischemia between

The vast majority of ischemic episodes occurring in patients with coronary artcv disease arc pain& or “silent” (1.2). Various factors have been postulated to account for this lack of angina1 symptoms, including higher pain threshold, age, extent of ischemia and autonomic ncuropathy (3-6). Patients with diabetes and Lwronary nrtcty disease frequently lack classic angina1 symptoms and prcscnt with a variety of atypical complaints at the time of a myocardial infarction (7-10). Diabetic patients also appear to have a higher incidence of silent myucardial infarction than nondiabetic patients (11,12) and cxpericnce angina less often during myocardial ischemia than nondiabctic patients during exercise testing (6,13).

Defective angina1 perception in the diabetic population appears to correlate with the presence and degree of autonomic nervous system dysfunction (14). Because the character and frequency of angina often determine the need for diag

bm the Inslilutc for the Prevention of Cardiovascular Disease and Dcpartmcnt of Medicine, lhxmess Hospital. Hurvard Medical School. Boston, Massachusetts. This study was funded internally by the Division of Cardiology. D~~xmcss Hospital, Buston, Massachusetts.

Mantipt nxeived December 3.1993; revised manuscript received May 9, FB4, accepted May 12,1994.

: Dr. Richard W. Nesto, Division of Cardiology, Deacuness Hospital, 185 Pilgrim Road, Boston, Massachusetts 02215.

01994 by the American College of Cardiology

modc~te to severe nervous system dysfunction not ex~rience a mo

peak of ischemia, and the nwm~r of ischemic distributed evenly throughout the day (p = 0.4).

Comcfusionu. Silent iscbemia is highly ~~valcnt amung pa lieats with diabetes and coronary artery disease. Time of onset o ischemia in diabetic patients follows a ci a peak incidence in the morning hours. sipilcant autonomic nervous

balance may bave an effect on the ci cular events.

(1 cim Cdl Car&l 199~:24:956-~2~

nostic and therapeutic interventions, patients with diabetes

may escape detection or suffer delay in treatment of coronary

artery disease as a result of dcfcctive symptom recognition

(lSJ6). Diabetic patients, particularly those with autonomic

nervous system dysfunction (16,17), have a severalfold in-

creased mortality from coronary artery disease compared with

nondiabetic patients (18-28). Further delineation of the char-

acteristics of ambulatory ischemia in diabetic patients and its

relation to autonomic nervous system dysfunction is therefore

warranted.

The circadian pattern of ambulatory ischemia parallels the

timing of other cardiovascular events, with an increased inci-

dence of myocardial infarction and sudden death consistently

noted in the early morning hours (29-37). The surge in serum

catecholamines and increased sympathetic tone present on

awakening (38,39) may alter hemodynamic and thrombogenic

forces that predispose vulnerable coronary atherosclerotic

plaques to rupture (40). However, conflicting da!a exist with

regard to the circadian pattern of myocardial infarction in

diabetic patients (41-44). Autonomic dysfunction, prevalent in

patients with diabetes, may affect sympathovagal balance,

platelet reactivity, endothelial function or vasomotor tone,

which could account for a different circadian pattern of

073%1097/94/$7.00

JACC Vol. 24, No. 4 October 1994:%6-62

ZARICH ET AL. CIRCADIAN lSCMEMlA IN DIABETES

957

cardial ischemia.

ischemia.

IlOWll ~Q~Oll~~~ artery

spital and the Joslin

oston, were recruited for CntrilMX into the study. inclusion CAXii~ were diabetes mellitus for 25 years, currently rc~~l~~r~ll~ eitbcr oral agents or insulin, and coronary

, dsfimxl as a history of st art Assoc~at~o~~ fu~~ctiofl~~~

or more of the following: coronaty a~gio~raphy reve:~!ing a lesion with >75% reduction in lumen diameter of a major coronary artery, exercise treadmill test (with or without thallium) positive for iscbemia by standard criteria or a history of previous myocardial infarction with diagnostic Q waves on the rest electrocardiogram (ECQ;). Complications of diabctcs were defined as follows: peripheral neuropathy was present if deep tendon refiexes were diminished or absent in conjunction with decreased vibratory sensation; nephropathy was defined as proteinuria >300 mg124 h, with a serum creatinine concentration ~1.5 mg/dl or proteinuria >l g/24 h, with a normal creatinine concentration; retinopathy was defined as the prcs- ence of microaneutysms, hemorrhages or exudates on fundu- scopic examination.

Patients were excluded if the baseline rest ECG had ST segment abnormalities or changes compatible with left ventricular hypertrophy or left bundle branch block. A complete history was taken, a physical examination was given, and antianginal medications were stopped when possible. Beta- adrenergic blocking agents were tapered to avoid rebound phenomena.

Amb~~~to~ ECG monitoring. Forty-eight-hour ambulatory monitoring was performed using a Cardiodata two- channel AM recorder and bipolar leads (lead V,/V, or modi- fied inferior/lead V,). Whenever possible, ambulatory ECG monitoring was performed 248 h after the cessation of anti- angina1 medications. All patients were instructed to enter symptoms in a diary. Ischemic episodes were defined as

periods >60 s of > 1 mm ST segment depression at 83 ms from the J point. Heart rate at onset was defined as the average heart rate in the 60-s interval before the onset of ST segment deviation. The time of day was noted for the onset of each ischemic episode on each 48-h recording and replotted on a standard 24-h scale. Antianginal medications were promptly restarted at the end of ambulatory ECG monitoring in those

ginal medications were w~thbe~d until

atients with ischemia by ambulatory ECG monitoring after disco~ti~~atio~ of antian-

inal medications. urements of systolic a rate were obtained in

supine position. The following ur standardized tests were performed:

1. iYeQrt me varidon with res~~~~~iolz. Patients were trained to breathe at a rate of 6 breaths/mm in the sitting position. The

ifference between the maximal and minimal heart rate was ated (45). The ratio of the six longest to the six shortest

mtewals was determined (46) (normal >I0 beats/mm). 2. Vd~h tnmeuver. The scald patient was

exhale for 20 s against a resistance of 40 mm oQcl~-loop system. The Valsalva ratio (the ratio of th bcart rate during the expiratory phase to the minimal heart rntc during tbc relaxation pbasc) was calculated (47,48) (normal > 1.25).

3. Isorrierric exercise. The patient was instru a handgrip dynamometer at 30% of maximal Careful attention was paid to ensure adequ patients. The increase in diastolic blood pressure was determined (49) (normal >lO mm Hg increase).

change and heart rate were measured for 5 min after active standing. The changes in heart rate and systolic and diastolic blood pressures were recorded (50). A decline in systolic blood pressure after standing >20 mm Wg was considered abnormal.

Autonomic nervous system testing was carried out in the Autonomic Evaluation Unit of the Deaconess Hospital. Custom-dcsigncd and validated software computed the mca- surements and ratios obtained in each test and stored all data. Age-based laboratory norms were used to classify individual test results as normal or abnormal (>2 SD from normal) (51-53). An autonomic score was derived from the results of these four tests. Patients with 0 to 1 abnormal test results were classified as having no or mild autonomic nervous system dysfunction (group I), whereas those with two or more abnormal test results were classified as having moderate to SCVC!~ autonomic nervous system dysfunction (group II).

Statistical analysis. Clinical characteristics of patients with

and without ischemia by ambulatory ECG monitoring were compared with a Pearson chi-square test and an unpaired Student t test for categoric and continuous variables, respec-

tively. The frequency distribution for the time of onset Of dli

ischemic episodes was plotted over a 24-h period in predeter- mined 6-h blocks starting from midnight for all patients and

then separately by the two subgroups with and without autonomic nervous system dysfunction. The distribution of cpi- sodes of iscbemia was tested for differences among the four 6-h intervals of the day with a chi-square test for goodness of fit. If

958 ZARICH ET AL. CIRCADIAN ISCHEMIA IN DIABETES

this test showed significant diflerence, the period with highest frequency was tested to evaluate its difference from the

average of the other three periods. Two-sided p < 0.05 was

considered significant.

fitients. Sixty patients formed the study group (mean age 60 years, range 25 to 8Q, 42 men [70%], 18 women [29%]). The average duration of diabetes mellitus was 17 years (range 6 to 48). thirty-six patients (60%) were insulin dependent. Thirty xven patients (61%) had a history of a previous myocardial infarction, either symptomatic (n = 17) or asymptomatic (n = 20). The mean duration of angina was 50.5 months (range 6 to .30()). Thirty-one patients ~rf~~rrncd a~: c~~r,ise test according

to a standard Bruce protocol while taking their usual mcdica- tions within 6 weeks of evaluation. Twenty-six patients had positive tindings on the exercise test for ischemia by convcn- tional ECG criteria, and five had nondiagnostic test results because of inudcquatc heart rate response to exercise. Four- teen of the 26 patients with positive exercise test results had

angina1 symptoms during exercise. The onset of ST segment depression occurred at a mean heart rate of 120 beatslmin (range 94 to 160) and double product of 19,356 (range 13, to 27,360). The mean duration of exercise to the onset of ST scgmcnt depression was 246 s (range 98 to 417). Sixteen of 17 patients for whom a thallium imaging scan was available had positive findings for ischemia. Cardiac cathctcrization was pcrformcd in 36 patients: 5 had single-vessel disease; 14 had two-vessel disease: and I7 ha iple-vessel disease.

Ambuletoy isehemla in ul tients. Thirty-eight (63%) of

the 60 patients had ischcmia ring ambulatory ECG monitoring, There were no significant differences bctwccn diabetic patients with or without ischemia in the number of cardiac risk

factors, duration of diabetes mellitus, previous history of myocardial infarction or microvascular complications of diabetes. Twenty&vo patients were taking antirnginal medications at the time of ambulatory ECG monitoring, and these were divided evenly between the groups with and without ischemia. A total of 199 ischemic episodes were recorded for the 38 patients with &hernia on ambulatory ECG monitoring. The total duration of &hernia was 2,708 min. Ninety-one percent

of episodes were asymptomatic, with a duration of 1,460 min. The average number of ischemic episodes per patient, either

tomatic or asymptomatic, was 5.2 (range 1 to 18), with an duration of 14 min/episode. Sixteen patients had

the 48-h of ischemia, and 15 had more than six episodes during monitoring period,

AU ie neem~s system testing. Thirty-eight patients undenvent ambulatory ECG during cessation of antianginal medications. A subgroup of 25 patients with ischemia on ambulatory ECG monitoring while off all antianginal medications underwent autonomic nervous system testing.

The 25 patients were separated into two groups on the basis of the degree of autonomic nervous system dysfunction (see

Methods). Group I included 15 patients (60%) with mild or no

JACC Vol. 24. No. 4 Octohcr i9WY5b-62

Table 1. Autonomic Nervous System Test Results in 25 Diabetic Patients With Coronary Artery Disease and lschemia by 48-h Ambulatory Electrocardiographic Monitoring

Group I Group II

(mean 2 SD) (mean 2 SD)

(n = 15) (n = 10) Q %l!W

MAXMN 13.81 2 8.3 1.6 2 Xi 0006

W (9) (3

Valsillva 1.40 * 0.2 1.34 t a.? 0.48

(10 0) (2)

Is&x 15.3 2 9.0 x.2 lr 6.2 MM

W (6) (4)

STSBP -8.3 2 lo.4 - 15.8 ?: IX.2 0.2

(n) (4 (2)

*Number ofpadents with abnnrmal test r~~lts in each group. Group I = IIO or minimal autonomic dysfunction; Group II = mOdCrilb2 lo scvcrc iwtiNldc

dpftmctian; IsoEx = diastolic blued prcssurc ch;Pngc in respmsc to isometric

exercise; MAXMIN = hcdrt rdtc vmiation with respiration (longcstishartcst RR

intcrvul ratio): STSlP = systolic Mood prcssurc response to standing;

Vulsrlva = heart r;lIc rcspmsc IO VulSAV~~ (masimul hcsr! rate during crpiru-

tionkinimol heart rmc during rclaxalion ratio).

autonomic nervous system dysfunction; group 11 included 10 patients (40%) with moderate to severe autono system dysfunction. The results of ~~~ton~~rn~c nervous system iesting in both groups are shown in Table 1. There was no signilicant difference in the clinical characteristics of patients

two groups, as seen in Table 2. ist~~Mtio~ of ischemia th~~gh~ut t e day. The overall

dist~~b~ti~~ of i~b~mia t ~~~~~~~~~ the day (divided into 6-b

periods) for the 25 patients not taking antianginal medications is shown in Figure 1. A total of 133 ischemic episodes were recorded, of which 122 (92%) were asymptomatic. The peak incidence of ischemia occurred between 6 AM and noon, with

35% (46 of 133) of ischemic episodes occurring during this time period. This peak of ischemic episodes in the hours after awakening was statistically significant (p < 0.007) in contrast to the other three 6-h periods. On the basis of autonomic nervous system dysfunction, hvo distinctly different circadian patterns of ischemia were noted. Group I patients had a significant morning peak in the incidence of ischemic episodes between 6 AM and noon (p = 0.0009), but the patients in group II did not have a morning peak of ischemia, as the number of ischemic episodes was distributed evenly throughout the day (p = 0.4) (Fig. 2). The patients in group I exhibited a total of 91 ischemic episodes (an average of 6.0 episodes of ischemia per patient), and those in group II exhibited a total of 42 ischemic episodes (an average of 3.5 episodes of ischemia per patient). The difference between the groups in number of ischemic episodes per patient was not significant. The change in heart rate during the S-min period preceding the onset of ST segment depression was not significantly different between the two groups (an increase of 5.3 beatslmin in group I vs. 9.3 beat&in in group II). The mean heart rate at the onset of ischemia was also not different between the two groups (99.1 beatslmin in group I vs. 98.4 beatslmin in group II).

JACC Vol. 24. No. 4 October 1994:9x+fL?

Underwent Nervous System Testing

Group 1 (n = Ii)

R&0pithy NephropitIhy

Neuropathy

Corcmry risk filCtO~S

Sacking

l-lypcrtcnsim

Filfllily Iiislory

Hypcrlipidoniia

Previou?; MI

Angina on 48-h Wokr ECO

8 (53%) I (7%) 8 (53%)

60.6 (49-74)

7 (70%)

3 (30%)

5 (50%)

Figure 2. Twenty-four-hour distribution of ambulatory iscbemic episodes in 25 piltkiltS with diabetes chissificd by severity of autonomic ntxvous system dysfunction. Group I (15 pntients) = minimal autonomic dysfunction (soli bans. p = O.ObOC,); 6roup 1Y (IO patients) = ~~~~)~~~r~~t~ to scverc’ autonomic dystimction (hrtehed bars, p = 0.4). The episodes are plotted in 6-h intervals. MN = midnight.

. Diabetic patients have

13). This was evident in our study because 31% of all ischemic episodes were silent. Decreased angina recognition in diabetes m autonomic nervous system dysfunction (14). patients, the proportion of silent ischemic episodes was similar among diabetic patients with minimal autonomic nervous system dysfunction and in those with more extensive autonomic neuropathy. This lack of correlation between the incidence of silent ischemia and the degree of autonomic nervous system dysfunction suggests that factors other than autonomic

Figure 1. Twenty-four-hour distribution of ambulatory ischemic episodes in 25 patients with diabetes who underwent autonomic nervous system testing during discontinuation of antianginiinal medications (solid bars). The episodes are plotted in 6-h intervals. p C 0.007. MN = midnight.

0-B AM B-noon noen. FM 6- MN

dysfunction play a role in determining angina1 deficit in diabetes.

ia. Ambulatory ischemia in our diabetic patients was significantly more frequent in tire

morning hours. However, in the subgroup of patients with moderate to severe autonomic nervous system dysfunction, no morning peak was observed. The temporal onset of ischemia in diabetic patients appears to be related to the degree of autonomic nervous system dysfunction, which may help to explain the conflicting reports on the circadian pattern of cardiovascular events in diabetic patients.

In the general population, the temporal pattern of transient myocardial ischemia mimics the circadian pattern of other

vascular events, such as myocardial infarction, stroke and sudden death (1,30,34,35,54,55). This circadian pattern of cardiovascular events parallels the temporal pattern of physi- ologic processes, such as early morning increases in serum and urinary catecholamines (38), heart rate and blood pressure (56-58) and rest coronary tone (59), all of which may reflect a higher sympathetic tone on awakening. Evidence that increased sympathetic activity on awakening may trigger the onset of cardiovascular events is supported by observations that beta-blockers eliminate the morning peak in the incidence of myocardial infarction (29,60). In addition, beta-blockade blunts the morning peak of sudden cardiac death (61) and attenuates the morning increase in ambulatory ischemia (34). I-be cardioprotective effect of beta-blockers may be achieved in part by blockade of the morning surge in sympathetic activity (fil), thus supporting the concept that the autonomic nervous system plays an important role in determining the circadian pattern of cardiovascular events.

Myocardial ischemia during exercise testing follows a similar circadian pattern, Quyyumi et al. (62) have demonstrated that the ischemic threshold, defined as either the heart rate or rate-pressure product at I-mm ST segment depression during

960 MRICH ET AL. CIRCADIAN ISCHEMIA IN DIABETES

JACC Vol. 24, No. 4 OCtOhCi 1901935-67 ._ _

treadmill exercise, is lower in the early morning hours. They postulated that circadian changes in the determinants of myocardial oxygen supply (vasomotor tone or coronary flow reserve) associated with changes in neurohumoral factors, such as norepinephrine and plasma renin activity, may be responsible for this variable ischemic threshold. Increased coronary tone or vasospasm in the morning may predispose vulnerable plaques to rupture (63) at a time when there is increased

plasma viscosity and platelet aggregability.

E of diabetes on the circadian tern of cardiovascu- c events, In diabetes, however, the ti course of cardiovas-

cular event, remains controversial, Epidemiologic studies in- dicate that the circadian distribution of myocardial infarction may be &red in diabetes, demonstrating a lower morning peak, a second peak in the evening hours and a higher percent of infarctions during the cvcning hours (41-43). Abnormal sympathetic tone may be responsible for the altcrcd temporal onset of cardiovascular events. Bcrnardi et al. (64) recently analyzed 24-h power spectral analysis of RR interval fluctua- tions in diabetic patients with and without signs of autonomic neuropthy. A marked diminution in parasympathetic tone during nighttime and prevalence of sympathetic tone during both day and night were noted in diabetic patients relative to nondiabctic control subjects. Thus, abnormal sympathovagal balance, with sympathetic predominance throughout both day and night, may account for the different circadian distribution of myocardial infarction in diabetic as compared to nondiabetic patients.

Data from the Thrombolysis in Myocardial Infarction (TIMI) II study suggest, howcvcr, that the time of onset of myocardial infarction in diabetics is not altered (44). These ccmtradictory tindings may be explained in part by ditfcrcnt patient characteristics, such as the extent of autonomic nervous system dysfunction. Diabetic patients rcprescnt a hetcroge- neous group and may exhibit ditfercnt circadian patterns of cardiovascular events or ambulatory ischcmia. In support of this concept, diabetic patients in our study were found to hitvc an early morning peak of transient myocardial ischemia. However, the SU~~TNI~ of diabetic patients with more severe autonomic nervous system dysfunction had an equal distribution of ischemic episodes throughout the day. The difference in the patterns of ischemia between those with and without significant autonomic nervous system dysfunction was not statistically significant because of the small sample size. HOW-

ever, these findings suggest, that the time course of ischemia in diabetes is influenced by the degree of autonomic newous system dysfunction and that, indeed, different patterns of timing of cardiovascular events Can occur within the &&tic population. Diabetic patients with significant autonomic ner-

VOUS system dysfunction may have a blunted morning surge of ischemia as 8 result of altered sympathovagal b&~nce as

opposed to diabetic patients with minimal autonomic nervous system involvement.

Diabetic patients with autonomic dysfunction, character-

ized by enhanced sympathetic tone throughout the day and 10s~

Of parasympathetic dominance at night, appear to be at

increased risk for vascular events throughout the day and night. The effect of autonomic nervous system dysfunction on the temporal onset of cardiovascular events may not he limited to changes in heart rate, blood pressure or coronary tone: An increased basal level of platelet a~regability is also seen in diabetic patients, particularly those wit athy (651, and appears to be associated with an i incidence of cardiovascular events (66). The altered morning peak of vascular events in diabetic patients may also reflect a blunted platelet responsiveness to hemody~mic stimuli during this time of day.

Study limitations. We studied a highly select group of long-standing diabetic ~tie~ts with known c~~o~~~ artery disease. The prevalence of ambutato~ ischemia (63%) was high in our study despite 22 of 6 antianginal medications and may bctic ~~~utatio~~ The small nu limitation of the study. Thus, the clinical applicability of our ohscrvations remains to be determined. Causality between the degree of autonomic nervous system dysfunction and timing of ambulatory ischcmia cannot be determined from our study design. Further clinical and epidemiologic studies are needed to address the association between autonomic nervous system dysfunction and the timing of acute cardiovascular events.

~o~c~wsi~~s. Silent ischcmia is highly prevalent Amos

patients with diabetes and known coronary artery disease. In addition, time of onset of ischemia in diabetic patients seems to follow a circadian distribution sirnibr to that observed for other cardiovascular events in other populations with a peak incidcncc in the morning hours. However, patients with severe autollomic nervous system dysfu~cti(~n did not demonstrate such a peak, suggesting that alterations in sympathovagal balance may have an effect on the circadian pattern of cardio- ViK3CUliK events.

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STUART ZARICH, MD, FACC, SERGIO WAXMAN, MD, ROY T. FREE ... · with coronary artcv disease arc...

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