Temporary decrease in cardiac parasympathetic tone after acute myocardial infarction

This study demonstrates the physiologic occurrence of wide circadian fluctuations of 2 major determinants of fibrinolytic activity in plasma. In these 6 subjects the variation in plasma activity of the fast-acting PA1 ranged from 55 to 201% of the 24-hour time-averaged value, while that of t-PA varied from 1.3 to 265% of the 24-hour averaged value. These data confirm a previous study that demonstrated a decrease in plasma PA1 activity occurring between 9 A.M. and 3 P.M? Our results are also consistent with reports describing circadian variations, ranging from 2- to lo-fold, of global fibrinolytic activity response, assessed either by clot lysis time8 or the fibrin plate method.g,10In our study, however, the changes in t-PA activity measured with a specific assay are much more striking, in the order of 200-fold. The complementary pattern of t-PA and PA1 changes throughout the 24 hours suggests a strong relation between these 2 factors (Figure 3). Indeed, there is increasing evidence that changes in t-PA activity are regulated by primary changes of its fast-acting inhibitor.6,7 The clinical implications of this study include the demonstration of highest fibrinolytic inhibition and barely detectable t-PA activity in blood at 3 A.M. This marked antifibrinolytic tendency in the early morning hours may

contribute to the reported higher morning incidence of thrombotic cardiovascular events.

1. DeWood MA, Spares J, Notske R, Mouser LT, Burroughs R, Golden MS, Lang HT. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engi J Med 1980;303:897-902. 2. Kunitz SC, Gross CR, Heyman A, Kase CS, Mdhr JP, Price TR, Wolf PA. The Pilot Stroke Data Bank: definition, design, and data. Stroke 1984;15:740-

746. 3. Myocardial Copenhagerr

Infarction Community World

Health

MD, Armand

Rothschild,

1979:

Annex

Health in Europe, II, 188-191.

0015.

4. Muller JE, Ludmer PL, Willich SN, Tofler GH, Aylmer G, Klangos I, Stone PH. Circadian uariation in the frequency of sudden cardiac death. Circulation 1987;75:131-138.

5. Marshall J. Diurnal variation in occurrence of strokes. Stroke 1977;88:230231. 6. Verheijen JH, Rijken DC, Chang GTG, Preston FE, Kluft CModulation of rapidplasminogen 1984;51:396-397.

activator

inhibitor

in plasma

by stanozolol.

Thromb

Haemost

7. Kluft C, Verheijen JH, Rijken DC, Chang GTG, Jie AFH, Onkelinx Diurnalfluctuations in the activity ofthefast-acting t-PA JF, Donati MB, Coccheri S, eds. Progress in Fibrinolysis. Livingstone, 1985.117-l 19. 6. Fearnley GR, Balmforth G, Fear&y E. Evidence of rhythm; with a simple method of measuring natural 1957:16:645-650.

C.

inhibitor. IK Davidson Edinburgh: Churchill a diurnal fibrinolysis.

fibrinolytic Clin Sci

9. Rosing DR, Braktnan P, Redwood DR, Goldstein RE, Beiser GD, Astrup T, Epstein SE. Bloodfibrinolytic activity in man. Diurnal variation and the response to varying

intensities

of exercise.

Circ Res 1970;27:171-184.

10. Cepelak V, Barcal R, Lang N, Cepelakova H. Zum Tag-undNachtrhythmus der Fibrinolyse.

Zschr

Inn Med

Temporary Decrease in Cardiac Parasympathetic After Acute Myocardial Infarction Marylee Rothschild,

Registers. Public

Organization,

1966:21:202-204.

Tone

MD, and Michael Pfeifer, MD

isk stratification after acute myocardial infarction R (AMI) currently involves assessmentof such variables as left ventricular function, ventricular ectopic activity and residual ischemic myocardium. Klieger et al1 recently showed.that decreasedheart rate variability, a measureof cardiac parasympathetic tone, was independently associatedwith increased mortality after AMI. Studies have shown that insufficient parasympathetic tone after AM1 leadsto a relative increasein sympathetic nervoussystemactivity. This increasein sympathetic nervoussystemactivity enhancesthe ventricle’s vulnerability to fibrillation and may predisposeto suddendeath.*g3The length of time that this autonomic imbalanceexistsin the postinfarction state has not been well studied. Impairment of parasympathetic responsesin patients has been shownat leastaslong as3 months after AMI. Using RR variation as a measureof cardiac parasympathetic tone, we examined patients between 1.5 months and 2.5 years From the University of Louisville, Department of Medicine, Divisions of General Internal Medicine, Cardiology and Endocrinology, Louisville, and the Veterans Administration Medical Center, 800 Zorn Avenue, Louisville, Kentucky 40202. This study was supported in part by a Bales Research Grant from the University of Louisville and by funds from Ciba-Geigy Corporation. Manuscript received March 14, 1988; revised manuscript received and accepted May 11, 1988.

after AM1 to gain insight into the chronic condition of the cardiac parasympathetic nervous system. The charts of all patients who underwent cardiac catheterization at the Louisville Veterans Administration Medical Center and Humana Hospital University from July 1983 to June 1987 were reviewed. Significant coronary artery disease(>75% diameter stenosis)was limited to the infarct-related artery. Patients with previous coronary artery bypass surgery, valvular heart disease, complex ventricular arrhythmias (Lown grade 13), left ventricular end-diastolic pressure>I 6 mm Hg, a history of diabetesmellitus, renal disease,chronic lung diseaseor alcohol abusewere excluded. After the 2,400 charts were reviewed, the study population consistedof I7 volunteers. The subjects had a normal screeninghistory and physical examination with normal serum electrolytes, blood urea nitrogen, glucoseand creatinine levels. Subjects could not be taking digoxin, calcium antagonistsor antiarrhythmic drugs. There were 15 men and 2 women. The average age was 52 years. Studies were performed in the Special Studies Unit at the Louisville VeteransAdministration Medical Center after obtaining informed consentfrom each subject. All studies were performed after an overnight fast. No smoking was allowed on the day of the study. No caf-

THE AMERICAN

JOURNAL

OF CARDIOLOGY

SEPTEMBER

15, 1988

637

BRIEF

REPORTS

feine or alcohol was allowed overnight or the morning of the study. Subjects were instructed not to take nonprescription drugs 24 hours before testing and were to take prescribed medications only after testing was completed. Mean RR intervals and RR variation were measured. RR variation is used as an index of a reflex arc that is predominantly controlled by cardiac parasympathetic nervous system activity.j Propranolol, 10 mg, was administered intravenously followed by an infusion of propranolol at 0.1 mg/min. This eliminates the small sympathetic portion of the reflex arc. With the subjects in the recumbent position and 30 minutes after starting the propranolol infusion, RR variation and RR intervals were measured for 5 minutes. RR variation was determined by a vector analysis technique.j Using techniques previously described, dark adapted pupil size during total parasympathetic nervous system blockade was measured as an index of iris sympathetic nervous system activity in 15 subjects. The latency time for the pupillary constriction response following a light stimulus was measured as an index of parasympathetic nervous system activity in 16 subjects.j The Valsalva ratio was then determined. The Valsalvu ratio is derived from the Valsalva maneuver. The Valsalva maneuver is a more general cardiovascular autonomic nervous system test incorporating cardiac parasympathetic and sympathetic nervous system activity as well as vascular sympathetic nervous system activity.6 It was measured in 17 subjects. Statistical analysis included analysis of variance and linear regression. RR variation during /3 blockade was evaluated in 17 subjects. Subjects were divided into 2 groups. The early group consisted of subjects >6 weeks but <6 months since their AM (n = 7). The late group consisted of 10

6or 55 -

In this study we have demonstrated that cardiac parasympathetic tone, as measured by RR variation, is decreased 6 months after AMI. In addition, cardiac parasympathetic tone normalizes with time after AMI. This autonomic dysfunction appears to be limited to the cardiac parasympathetic nervous system since other measures of autonomic nervous system activity including Valsalva ratio and pupillary light responses are not involved. It is well established that AM1 is associated with disturbances of autonomic control of the heart. Kent et al3 showed that vagal stimulation increased the fibrillation threshold in animals and protected the acutely ischemic myocardium against arrhythmias. This effect was particularly evident in cases where sympathetic activity was increased.3 In man, the occurrence of ventricular ectopy is also correlated with vagal-sympathetic interactions.2 Studies suggest that insufficient parasympathetic

= X & SEM

- r p<.Ool 1

50 --

RR Variation

subjects >6 months after infarction. By analysis of variance, we found that RR variation was signtjicantly decreased in the early group (17 f 2 [mean f standard error of the mean] p
45 -

-

40 -

-

35 -

-

30 -

-

25 -

-

I

20 -

10 - 5- -

T

15 -

rl

i

Early n=?

FIGURE farction 638

1. Comp$~n of RR variation group with the late postinfarction THE AMERICAN

JOURNAL

so Late n = 10

TIME

in the early group.

OF CARDIOLOGY

270

postin-

VOLUME

POST

450

INFARCTION

FIGURE 2. Linear regression analysis time after myocardial infarction. 62

630 (in

of RR variation

810 days)

and

tone after infarction may lead to a relative increase in sympathetic nervous system activity. This may increase the ventricle’s vulnerability to fibrillation and may predispose to sudden death. 3,4,6Serial measurements of cardiac parasympathetic tone over time would identify patients with decreased parasympathetic activity (at high risk for sudden death) as well as those whose parasympathetic tone had normalized (no longer at risk for sudden death). Ryan et a1,4 using isometric handgrip, cold pressor and facial immersion, showed that impaired parasympathetic responses existed in patients 3 months after- AMI. Our study used RR variation to study cardiac parasympathetic tone. This method has been shown to be more sensitive, quantitative and reproducible than previous methods.‘j Importantly, and not previously found, cardiac parasympathetic tone normalizes after 6 months. Quantitating cardiac parasympathetic tone after infarction may prove to have prognostic significance by identifying a high risk subgroup that may benefit from sympathetic nervous system blockade. In addition, the

Imaging Doppler

of Coronary Arteries Echocardiography

present study suggests that since cardiac parasympathetic tone improves with time, a patient may not remain at high risk indefinitely. Our study suggests that there is normalization of cardiac parasympathetic tone after 6 months. This may be a key time to reevaluate the risk profile in postinfarction patients. 1. Kleiger RE, Miller JP, Bigger JT, Moss AJ, and the Multicenter Post-Infarction Research Group. Decreased heart rate variability and its association with increased

mortality

256-262. 2. Lawn B. Sudden cardiology.

after acute

cardiac Am J Cardiol

myocardial

infarction.

death: the major challenge 1979:43:313-32X

Am J Cardiol confronting

1987;59:

contemporary

3. Kent KM, Smith ER, Redwood DR, Epstein SE. Electricalstability

of acutely ischemic myocardium. Circulation 1973:47:291-298. 4. Ryan C, Hollenberg M, Harvey D, Gwynn R. Impaired parasympathetic responses in patients after myocardial infarction. Am J Cardiol 1976:37:10131018. 5. Pfeifer MA, Weinberg CR, Cook D, Best JD, Reenan A, Halter JB. Differential changes of autonomic nervous system function with age in man. Am J Med 1983;75:249-258. 6. Rothschild AH, Weinberg CR, Halter JB, Porte D, Pfeifer MA. Sensitivity of RR variation and Vaisalua ratio in assessment of cardiovascular diabetic autonomic neuropathy. Diabetes Care 1987:10:735-741.

by Color-Coded

Transesophageal

Peter Zwicky, MD, Werner G. Daniel, MD, Andreas M@ge, MD, and Paul R. Lichtlen, MD he visualization of coronary arteries by conventionT al 2-dimensional echocardiography has been in use for over 10 years.’ This technique can provide morphologic information, in particular concerning the proximal left coronary artery. Whereas the left main stem has been identified in up to 90% of examinations, the right coronary artery is usually detected in <50%.2 In many cases, however, the imaging quality is too poor to allow an anatomic evaluation. During the last few years, transesophageal echocardiography has been shown to provide optimal imaging quality in virtually all patients and of all cardiac structures including the aortic root at the level of the coronary arteries. 3-5 To our knowledge, studies concerning the evaluation of coronary arteries by the use of transesophageal echocardiography have not been published. In over 1,300 transesophagealechocardiographic examinationsperformed in our laboratory without complications,5 the proximal left and right coronary arteries could be detected only occasionally when a 3.5-MHz transducer system was used. Recently, we applied a 5MHz phased array transducer with incorporated colorcoded Doppler (64 elements,maximal sector angle 90”, Hewlett Packard model 21362A) mounted at the tip of a modified gastroscope(distal tip diameter 16 mm). Using this type of equipment, we have beenable to identify the proximal left and right coronary arteries in all 50 patients studied sofar. Patients were consciousat the time From the Division of Cardiology, Department of Internal Medicine, Hannover Medical School, Konstanty-Gutschow-Strasse 8, D-3000, Hannover, West Germany. Manuscript received November 9, 1987; revised manuscript received and accepted May 10, 1988.

of the study and transesophagealechocardiography was performed for various diagnostic reasonsin the left lateral supine position after at least 4 hours of fasting. Except for a local pharyngeal anesthesiano premedication was administered. The coronary arteries are found just above the level of the aortic valve, which becomes visible when the transducer is inserted to a depth of about 30 to 32 cmfrom the patient’s teeth. In all cases, the transesophagealimaging quality wassuperior to the transthoracic recordings regardlessof whether the precordial examinations were performed using phased array or anular array technology. On the transesophageal image, the coronary arteries can beeasily detectedby the color-coded flow pattern (Figure 1); subsequentmagnification of the area of interestprovides high resolution of anatomic details (Figure 2). The proximal left coronary artery may befollowed to the bifurcation including the proximal segmentsof the left anterior descendingartery and, in particular, the circumflex coronary artery, which can sometimesbe visualized over a distance of 4 to 5 cm (Figure 3). The main stem of the proximal right coronary artery becomesvisible for about 3 cm. However, a clear signal of pulsed Doppler flow curves can usually not be obtained becauseheart movementprevents a stable position of the sample volume within the coronary vessel.

Our preliminary data indicate that transesophageal color-coded Doppler echocardiography allows clear imaging of proximal coronary arteries. A further improvement of resolution and imaging quality may be obtained when higher frequencies of transesophageal transducers become available. Whether this technique represents a reliable tool for noninvasive assessment of significant

THE AMERICAN

JOURNAL

OF CARDIOLOGY

SEPTEMBER

15, 1988

639