CLINICAL

Clinical Conference

Editorial

Therapeutic

THERAPEUTIC

CONFERENCE

Conference

Board

John C. Somberg, MD, Editor Hector Gomez, MD, Associate

Editor

Robert Piepho, PhD Andrew Whelton, MD Gilbert Mayor. MD Harold Neu, MD Atul Laddu. MD CASE

PRESENTATION

Present

Medical

History:

aches, been years.

B. is a 66-year-old man who came for a routine Cardiology Clinic visit in April1991. He has a long-standing history of coronary artery disease and was admitted to Illinois Masonic Hospital in June 1984 because of severe retrosternal chest pains of 4 hours’ duration, associated with diaphoresis. Electrocardiogram disclosed a 2-mm ST elevation in leads Vito V4. Along with other supportive measures, he received 1.5 million units intravenous streptokinase therapy. Chest pains were reportedly resolved. The electrocardiogram, however, showed Q waves in VI to V3 leads. One week later, he underwent cardiac catheterization, which showed 100% occlusion of the left anterior descending artery at the level of the first diagonal. The left circumflex and right coronary systems were normal. The left ventricular angiogram showed anterior, septal, and apical akinetic segments. The patient remained symptom free throughout his hospitalization. His medications were nifedipine 20 mg three times daily (tid), digoxin 0.025 mg daily (qd), captopnil 12.5 mg twice daily (bid). lasix 20 mg qd, coumadin 2.5 mg qd, and aspirin 325 mg I tablet qd. Coumadin therapy was discontinued at the 6-month follow-up. He had a subsequent hospitalization for chest pain in April 1985 at the Veterans Affairs Medical Center, North Chicago. Evaluation at that time did not show myocardial infarction. He was given a low-salt, low-cholesterol diet. Nifedipine was increased to 30 mg tid, captopril was increased to 25 mg bid, and nitroglycerin was added. His digoxin was discontinued in November 1989. In February 1991, calcium channel blockers were stopped and captopril was increased to 37.5 mg tid. He has had stable angina since then, manifested by occasional chest discomfort on exertion, such as working on the lawn or washing his car. He admits to shortness of breath when climbing one flight on stairs or walking one block. The patient denies any paroxysmal nocturnal dyspnea, orthopnea, or leg swelling. He claims to be functionally the same since his heart attack in 1984. His hypertension, fairly controlled,

680

and

Mr.

which also was diagnosed in 1984. is he denies any visual problems, head-

#{149} J Clin Pharmacol

1992;32:680-684

or dizziness. He taking medications

Cardiac

Risk

Factors:

is compliant for high Hypertension;

with his cholesterol

diet for

and has about 2

hypercholesterol-

e mia.

Past

Medical

nary

disease;

History: Mild chronic obstructive pulmoarthritis for 20 years. Family History: Father died of unknown illness at age 69; mother died of a heart attack at age 74. The patient had three siblings. One sister died of leukemia at age 47; another sister, age 70, is alive, but suffers from dementia. A brother died of a heart attack at age 57. Social History The patient was born and raised in Chicago. He is a Veteran of World War II and was in the Army from 1943 through 1946. He is divorced, lives alone, and is the father of three children. He worked as a milk delivery man and retired in 1984. He does not smoke or drink. He enjoys watching television. Allergies:Penicillin; lidocaine. Present Medications: Gemfibrozil 600 mg bid; captopril 37.5 mgbid; isodil 10 mgtid; furosemide 20 mgqd; aspirin I tablet qd. Physical

Examination:

General: Pleasant, elderly gentleman, cooperative and oriented to time, place, and person. Height: 5’lO”, Weight: 207 lbs. Vital signs: Blood pressure 150/100mm Hg; Pulse 82/mm; Respiratory rate 16/mm, Temperature 98#{176}F HEENT: Pupils small, equal in size, and reactive to light. Extraocular muscles intact. Minimal arteriolar narrowing bilaterally on funduscopic examination. Neck: Supple; no jugular venous distension; no bruit; no thyromegaly. Lungs: Clear to auscultation and percussion. Heart: Point of maximum intensity at left fifth intercostal space, at midclavicular line. Normal S1, S2 and S4 at apex; grade Il/VI systolic murmur at the apical area, no radiation. Peripheral pulses: Present and unremarkable. Abdomen: Soft; no visceromegaly, no bruit. Normal bowel sounds. Extremities: No clubbing, cyanosis, or edema. Neurologic: No focal deficits.

CONTROLLING

VENTRICULAR

DILATATION

The

A few comments about the preventive cardiology aspects of this case should be made. This patient’s blood pressure cannot really be characterized as fairly controlled when the diastolic blood pressure was persistently 95 to 100 mm Hg. I also do not believe a good enough job was done to lower the serum cholesterol. As mentioned, his low-density lipoprotein should be under 130 mg/dL, and closer to 100 mg/dL. If it cannot be lowered by nutritional means alone, which should be and was the first course of action, then certainly he should be on drug therapy. Gemfibrozil is not the best drug for him because his triglycerides were only modestly elevated in October 1990, and they were normal in July 1990. A bile acid resin or Lovastatin would be preferable. There is good evidence from two recent studies12 that people with significant coronary disease who really lower their lipids, especially the low-density lipoprotein, and, if possible, raise the highdensity lipoprotein, can prevent some of the progression of disease in the coronary arteries and even induce some regression. I think we could have done a little better in that aspect with this patient. Finally, I would like to take exception to the classification of this pleasant 66-year-old gentleman as being elderly. In the 1990s, 66 is more upper middle age than elderly. We will now proceed to the subject of controlling ventricular dilatation in patients with compromised myocardia. Coronary heart disease presents as a spectrum progressing from risk factors to atherosclerosis, ischemia, infarction, arrhythmia, ventricular enlargement, congestive heart failure, and death. We have already talked about risk factors. Certainly one of the major reasons there has been a decline in coronary mortality rate over the past 25 years has been the change in risk factor status in the United States. We have intervened with remarkable success in treating myocardial ischemia with medications and both coronary artery bypass graft surgery and percutaneous transluminal coronary

angioplasty.

We

are

successfully

treating

coronary

by arwe

to

treat and prevent ventricular enlargement, however, and that is the subject of my discussion with you today: the remodeling of the ventricle that occurs after some myocardial infarctions with the sequelae of congestive heart failure, and eventually end-stage heart disease. After myocardial infarction, there is a decrease in ven-

tricular creases,

ejection. according

To compensate, the to the Frank Starling

creased ejection and price of some increase ventricle. In addition,

CLININICAL

restored in wall there

THERAPEUTIC

stroke stress may

heart volume principle, with

volume, because be infarct

CONFERENCE

THE

COMPROMISED

both in the infarcted sulting in late heart

DISCUSSION: CONTROLLING VENTRICULAR DILATION IN THE COMPROMISED MYOCARDIUM

thrombosis with thrombolytic therapy, as illustrated this patient. We have made some progress in treating rhythmias with electrical devices, but not as much as would like with drugs. The results of the Cardiac Arrhythmia Suppression Trial3 study have caused us to reconsider our therapy in this area. We have not done very much

IN

inin-

but all at the of the dilated expansion,

MYOCARDIUM

and failure.

Framingham4

noninfarcted

study

assessed

myocardium, the

risk

re-

of developing

clinical congestive heart failure after a first recognized myocardial infarction. There is a progressive increase in incidence over time, with 5% at 1 year and 10% at 3 years after infarction. Framingham also studied the survival once congestive heart failure has been diagnosed and found about a 50% mortality rate at 5 years. In contrast to the 50% 5-year mortality rate in this community study, a VA5 study of a referral center population found a 1-year mortality rate that approached 50%. Recent efforts to prevent this high mortality rate have concentrated on the

concept of infarct expansion. Infarct expansion is defined as the dilatation and thinning in the area of infarction that is not explained by additional necrosis. This is in contrast to infarct extension, which is a new area of necrosis.6 The result of infarct expansion is a distortion in the topography of the ventricle with a disproportionate thinning and dilatation of the infarcted segments so that the area and the circumference of the left ventricle, which is occupied by this thinned area, is enlarged. Not only is the infarcted segment involved, but later there may be hypertrophy and dilatation of the noninfarcted segment as well. This leads to a change in the geometry of the ventricle. It becomes more spherical, with a deleterious change in the volumemass relationship, leading to increasing wall stress. Sometimes early in the course of infarction this could lead to rupture. Later there may be the development of aneurysm, congestive heart failure, and eventually death. Several mechanisms for infarct expansion.7 tion in intracellular

have been postulated to account These include cell rupture, reducspace, stretching of the myocytes, and

cell slippage. Investigative studies in experimental animals, and to a lesser extent in humans, indicate that cell slippage and stretching are the primary mechanisms. Cell slippage is a rearrangement of cells or groups of cells with no decrease in the total number of cells. Myocyte stretching results in lengthening and thinning of the myocytes, but no rearrangement. Most authorities believe that in the infarct area itself, about 80% of the expansion is due to cell slippage and 20% to stretching. In the remote areas of the myocardium, it is all due to slippage. A contrary view of Dr. Anversa and co-workers8 is that in the area remote from the infarct, with lengthening Drs. Hutchins study of patients

the and and who

major mechanism is cell stretching hypertrophy of the myocytes. Bulkley6 performed a postmortem died up to 30 days after a myocardial

infarction. They noted there were a significant number that had no expansion and no change in the thickness of the infarcted segment in relation to the rest of the myocardium. Conversely, moderate, and

some

This

occurred

cardial

there

expansion infarction,

with and

were some marked

with slight, degrees of

very

after

could

early continue

some with expansion.

the onset for

up

of myo-

to 30

days.

They also noted that most of the expansion occurred in large anterior wall infarcts. We know that myocardial expansion can occur within 24 hours and can continue for at least

sively

30 days

and

in transmural

probably

infarcts,

longer.

and

It occurs

is more

almost

common

exclu-

in ante-

681

BERKSON

nor infarcts. It may occur in up to 35 to 40% anterior wall infarcts. Our patient certainly category. Many

of the

studies

of infarct

expansion

of transmural fits into that have

relied

on

mones tion,

Adrenaline myocardial ure. On failure, there is 2 days

echocardiographic measurements using the short view with the papillary muscles as the dividing line tween the anterior and posterior-inferior segment. Dr. ton and his colleagues,9 studied a group of postinfarction patients by this method. They found that expansion

axis beEawas

start

frequent, occurring time of the infarct

the does

ure

early in others.

in

some and They found

remote that not

from only

the infarcted segment itself lengthen, but there is also some lengthening of the opposite segment, that is, the noninfarcted area. A typical case will show thinning and dilatation at 7 days with progression at 11 to 21 days. The resulting

infarct

in the

geometry

In a small

with

anterior

ment

also

expansion

of the

study,

Erlebacher

wall have

produces

infarcts

an

dilatation

and

change

ventricles. et al.1#{176} showed

who

increased

have

that

a dilated

segmental

dilatation

segin

the

posterior wall that was not involved by the infarction. In contrast, those who did not expand their infarcts had no significant increase in either the anterior or the posterior wall. It is now clear that not only does the infarct expand, but there are changes in the rest of the myocardium as well. This is well illustrated by McKay et al., in two angiographic studies illustrating progressive thinning of the infarcted segments with later dilatation of the infarcted and the noninfarcted areas. The end result is ventricular dilatation

and

There tricular Warren

an

increase

in ventricular

volume.

therapy

measuring

their

ventricular

vol-

umes over a 10#{189}-month period and found a gradual increase in left ventricular end-diastolic volume.12 Twenty of the 36 patients showed an increase in ventricular volume, the average being 20%. Many years ago it was shown that ventricular volume correlated with mortality rate over time.13 The larger the volume, both end-systolic and end-diastolic, the greater the number of deaths per patient-years. More recently, White

and

his

colleagues14

studied

end-systolic

volume

and concluded that it is the most potent predictor of survival, even better than the ejection fraction. With similar ejection fraction between 40% and 50%, when end-systolic volume is less than 95 mL, there is a greater survival than patients with end-systolic volume greater than 95 mL. In fact, the survival with end-systolic volume less than 95 mL and ejection fraction of 40 to 50% is as good as that of patients with ejection fraction over 50%. With lower ejection fractions, the same dichotomy continues, suggesting that the end-systolic volume may be a better indicator of survival than our cherished ejection fraction. And, as most of you know, the ejection fraction really does not correlate well with the clinical picture in terms of congestion itself. Until

now

we

have

discussed

prognostic significance of infarct discuss some of the clinical studies

682

#{149} .J ClIn Pharmacol

the

pathogenesis

and

the

expansion. Now we will of the role of neurohor-

1992;32:680-684

rising

and

very

after

shortly

the

after

first

day

without failure. More vival and Ventricular gress,

indicate

that

admission

in patients

in patients

who

recent data Enlargement

have

coming study,

at 4 to 16 days

after

in fail-

infarction

from which

the Suris in pro-

myocardial

infarc-

tion there is an elevation in the serum levels of norepinephrifle, renin, arginine vasopressor, and atrial natriuretic peptide.16 hospital

These discharge.

levels sometimes They are not

however,

and

there

all

remain elevated

is not good

up

even in the

after same

cross-correlation.

Levels are highest in older people and those with the lowest ejection fractions. With this as a background. experimental animal studies have been conducted using angiotensin-converting enzyme (ACE) inhibitors. Pfeffer et al.17 produced myocardial infarction in rats and then randomized the animals to captopnil and water, tracking 1-year survival. In the very large infarcts, there was no difference, but in the small to

moderate infarcts, captopril-treated More recently, transmyocardial

have been several studies that confirm that venvolume increases after myocardial infarction. et al.12 studied a group of patients who underwent

thrombolytic

myocardial infarction. Very early after infarcis an increase in neurohormone secretion.15 and angiotensin II levels have been studied in

infarction patients with and without heart failadmission, both with and without left ventricular adrenaline levels are elevated, being higher when clinical failure. They return to normal after about in the heart failure patient. Angiotensin II levels

patients.

patients

infarct

after there

there group.

was

an increased

a small study DC electroshock

survival

by McDonald to produce

in the

et al.18 used small areas of

localized myocandial damage in dogs.18 They randomly treated eight dogs with ACE inhibitors and compared them with eight control animals. In the controls, there was an initial increase in left ventricular mass, but no increase in volume as measured with elegant magnetic resonance imaging

techniques.

increase

further,

Sixteen

weeks

later,

the

mass

did

not

volume was increased. In contrast, in the group given the ACE inhibitors, there was no significant change in mass or volume, and when they withdrew the ACE inhibitors at 16 to 24 weeks, there was still no change. This lack of change was independent of blood pressure, and they hypothesize that it may be a local effect of the ACE inhibitor. There are two pertinent clinical studies by Sharpe et al.192#{176} In the earlier study, a group of patients I week after myocardial

but

the

infarction

was

randomized

to either

placebo,

40 mg furosemide daily, or 25 mg captopril three times a day, and followed for 1 year with echocardiographic measurements. In the placebo and furosemide groups, there was a slight increase in end-diastolic volume, whereas there was a decrease in the captopnil-treated group. Similarly, end-systolic volume decreased in the captopniltreated group and showed only a modest change in the other two groups. Stroke volume index and ejection fraction rose in the captopnil group, but did not change in the other groups. Because there were already some adverse changes in ventricular volume in this group of patients at I week after infarction, Dr. Sharpe conducted a second study,

captopril

recently

treatment

reported

and

in Lancet,

placebo

were

of 100

patients

administered

where

within

CONTROLLING

VENTRICULAR

DILATATION

24 to 48 hours. The results were similar to the first study, and captopril was found to, at least in part, prevent the early (1 week) increases in ventricular volume found in the earlier study. Lamas and co-workers21 have studied changes in ventricular shape after infarction. They found that in some patients the heart loses its elliptical shape and becomes more spherical. They investigated a group of 40 patients 2 weeks after anterior wall myocardial infarction with biplane angiography. tricular tertile

the

They created shape, dividing was the most

lowest

ventricle. function

tertile

a “sphericity index” based on venthe group into tertiles. The highest spherical or globular ventricle, and

the

more

They studied in these three

elliptical

several groups.

more spherical, the left ventricular the ventricular volume index, rises, the percentage of akinesis and the ejection fraction falls. sistent left anterior descending

patient,

had

more

or

normal-shaped

parameters of ventricular As the ventricle becomes

end-diastolic and

and

the

pressure,

systolic

volume

dyskinesis

goes

up,

Those patients who had percoronary artery occlusion,

like

our

tion, and edly there

they studied exercise duration, a heart failure score, an activity index. The exercise duration was markdecreased, the heart failure score was higher, and was a lower activity scale in those with the larger,

spherical ventricles. A second investigation tients 11 to 31 days after ejection fractions less than either placebo or captopril and had angiography and baseline and 12 months,

increased duration

ventricles.

end-diastolic artery

pressure, wedge pressure decreased

The end-diastolic volume and diasignificantly in the controls, only

slightly in the captopril-treated was always longer in the treated

average being significantly higher. Very those patients with persistent left anterior nary artery occlusion, the increase over lar volume, which accompanied larger and dyskinesis at baseline in the controls, the treatment group. The treatment group est

baseline

dyskinesis

In addi-

by Pfeffer et al.22 studied 59 paa first anterior infarct who had 45%. They were randomized to 25 to 50 mg three times a day, hemodynamic measurements at as well as periodic exercise test-

ing. In the treated group, the pressure, and mean pulmonary

compared with controls. stolic area, which rose

spherical

actually

had

group. group,

Exercise with the

interestingly, in descending corotime in ventricuareas of akinesis did not occur in with the great-

a lower

ventricular

volume at 1 year than the nontreated group with the smaller degree of dyskinesis at baseline. So in those with persistent occlusion, the expected larger ventricular volumes did not occur in the captopril-treated group. Another drug that also appears to be beneficial is intravenous nitroglycerin.23 Jugdutt and co-workers23 gave intravenous

nitroglycerin

to a group

of patients

within

5 hours

of the onset of acute myocardial infarction and measured indices of infarct expansion with echocardiograms. They found less asynergy and higher ejection fractions in the nitroglycerin-treated group. Endocardial segment length increased in the control group, whereas there was no expansion in the nitroglycerin group. This improvement was most marked in anterior wall infarcts, but to a lesser degree, this also occurred in those who had inferior infarcts.

CLININICAL

THERAPEUTIC

CONFERENCE

IN THE

The

COMPROMISED

expansion

infarcted

index,

segment

MYOCARDIUM

which

to that

is the ratio

of the

of the length

noninfarcted

segment,

of the did

not increase in those treated with nitroglycerin. It appears that intravenous nitroglycerin is also an agent that we must consider as being effective in preventing infarct expansion. We have some very exciting information that we may be able to intervene early after myocardial infarction to prevent infarct expansion and subsequent ventricular dilatation and thereby improve the long-term survival of patients

who

have

suffered

myocardial

infarction.

There are two large clinical trials currently underway looking at this potential with the use of ACE inhibitors. One is the Survival and Ventricular Enlargement study study using captopril mentioned earlier.17 The other is the Salvage Of Left Ventricular Dysfunction after myocardial infarction using enalapril.*24 These studies should be reported within the next year or two, giving us bottom-line data on survival. It is premature to say that everybody should get ACE inhibitors immediately after myocardial infarction, but certainly this patient would be the type who might benefit, because he had a transmural anterior wall infarction. And, in this case, the end, or at least the intermediate, result was beneficial because there was not the increase in volume of his ventricle (at least until 1989) that you might have expected with this degree of infarction. Dr. Som berg: A very nice thorough presentation of this interesting field. It is very interesting to work with nitroglycerin. Maybe you would comment on beta-blockers in terms of infarct expansion. I wanted you to articulate again if your first line would be putting people on beta-blockers and if there is a good justification of ACE inhibitor at this time, because we know the ACE inhibitors may reduce expansion, but the beta-blockers do reduce mortality. Dr. Berkson: I think, at present, I would agree with that. The work of Dr. Jugdutt is really very interesting. I heard a recent presentation of his with a larger study group. He is giving the intravenous nitroglycerin within 4 to 5 hours of onset. He starts at 5 tg/minute and increases dosage at 5and 10-minute intervals. He says that at 5 zg you get the greatest effect on preload. As the dose increases, the effect is mainly on afterload, and of course, you have to be careful that you do not decrease coronary blood flow too much. He aims for a drop in mean blood pressure to 80 mm Hg in normotensives and a drop of about 30% in hypertensives, and he continues the infusion for about 24 to 48 hours. He also has compared captopril acutely with nitroglycerin and so it will be very interesting to see the long-range results of his studies. He does say that the in-hospital mortality

rate

is lower

in the

nitroglycerin-treated

group.

In terms of the beta-blockers, the Beta Blocker Heart Attack Trial study showed that the greatest benefit, a decrease in sudden death, occurred in the subgroup who had evidence of mild signs of failure at the time of the infarction. There have been more promising studies using betablockers in dilated cardiomyopathies. There is now a clinical trial going on in this regard. Also, the National Heart, Lung and Blood Institute is considering funding a study to evaluate the use of beta-blockers early on in people who

683

BERKSON

do not have severe degrees of myocardial dysfunction to see if we can prevent ventricular dilatation. At present. we have so many drugs to give our patients that is hard to decide what to do, but I believe that intravenous nitroglycerin at the time of myocardial infarction probably is a good idea if the patient is not hypotensive. In addition.

we

should

give

aspirin,

and beta-blockers as soon not have a contraindication. should include has a transmural

ing

ACE

adding

other

therapy,

as possible, if the patient does The long-term management aspirin, and if the patient

beta-blockers, anterior

inhibitors.

thrombolytic

infarct,

Down

one

the

might

road

we

consider

will

Is there

evidence

that

the

acting directly on the angiotensin system is it merely another way to reduce the Answer: I do not think we know the They do lower blood pressure, decrease

ACE

be

inhibitors

are

in heart per se. or blood pressure? exact mechanism. preload and after-

load, and lower wall stress. There is also some evidence that there are organ angiotensin systems operative. These drugs may have a much more localized effect than we thought. I do not think I can answer more definitively at present.

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Hammermeister

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#{149} J Clin Pharmacol

1992;32:680-684

Discussant David

M. Berkson,

From

the

MD

Department

of

Preventative Medicine, Medical School, and the Josephs Hospital, Chicago,

Community Health and Northwestern University Section of Cardiology, St. IL

The clinical Therapeutic conferences are held at the chicago cal School as part of the Medical Grand Rounds Program. The editor thanks cIBA-Geigy corporation for their educational for the support of this conference. The showed reduced

SOLVD

study

a beneficial effect EF and congestive

published

subsequent

of enalapril on survival heart failure.

to this

Medigrant

discussion

in patients

with