Asymptomatic Left Ventricular Dysfunction and Diabetes:

Prevention and Timely DetectionDisfunzione ventricolare sinistra asintomatica e diabete:

come preveniria e come accorgersene.

Mariell Jessup MD, FAHA, FACC, FESC

Professor of Medicine

University of Pennsylvania

Philadelphia, Pennsylvania

Disclosure: I have no conflicts with respect to this lecture

A Case

• 50 year old woman commercial designer– No past medical history except well controlled DM– Meds: Multivitamin daily– Non-smoker, social alcohol– No family history of cardiac disease– Travels world-wide, plays tennis, squash and runs

15 miles weekly

• While on business trip – automobile accident – fracture of right leg – now needs orthopedic procedure

Pre-Op Clearance – 7/01• ECG – Left bundle branch block pattern.

– Prior ECG from 1984 – normal

• ECHO: LVEF = 20%, normal wall thickness, mild mitral regurgitation

• Cath – RA = 8, PA = 32/12 mean 22, PCW = 12, CI = 2.1 l/min/m2

– Normal coronaries

• Normal labs, including thyroid etc.

• Normal physical exam, – (BP 130/70, HR 70)

Back to the case• Medications – First visit 7/01

– Started lisinopril 10 mg daily

• Medications – 4 weeks later– carvedilol 3.125 mg twice daily

• Medications over next 6 months– carvedilol titrated to 25 mg twice daily

• Visit 2/4/02 – Feels “great”, leg healed, back to exercise and traveling

Follow-up ECHO 2/02

• LVEF improved to ~ 30%

• Plan :Continue ACEI and beta blocker

• Follow-up in 6 months

Bad Phone Call – 4/1/02• She was driving in Florida on business– stopped at

light – witnessed to lose consciousness – falls onto horn – causes accident as car rolls into intersection

• First responders nearby

• Ventricular fibrillation – cardioverted to sinus tachycardia with 2 shocks

• Admitted – comatose/intubated for 3 days – recovers completely over 6 weeks

• ICD implanted/Returned home

What is Stage B?

Left ventricular remodeling has occurred but the patient never has experienced signs or symptoms of heart failure

“pre-clinical” heart failure

ACC/AHA Heart Failure Guidelines - 2005

Stages of CHF — ACC/AHA Guidelines 2005

A High-risk patients

Hypertension, diabetes, coronary disease, family history, cardiotoxic drugs

BStructural heart disease

LVH, MI, low LVEF, dilatation, valvular disease

C Prior, current symptoms

D

Refractory

22%

34%

11.8%

0.2%

Ammar et al. Circulation 2007;1151 563

Who are the Stage B patients?• Post myocardial infarction

– Patients with an acute MI– Patients with a history of MI but normal LVEF

• LV remodeling– Left ventricular hypertrophy– Low LV ejection fraction

• Asymptomatic valvular heart disease• Undiagnosed, asymptomatic congenital heart

disease

How many people?• Up to 4 times the number of symptomatic heart

failure patients (stage C and D combined) may have asymptomatic left ventricular dysfunction1

• Large public health burden

• Potentially prevent progression to symptomatic heart failure and death

1Frigerio M, AJC 2004

Framingham Study: Prevalence

Age Group Men(n = 1860)

Women(n= 2397)

40 – 59 years 2.1 % 0.5 %

60 – 69 years 7.2 % 0.8 %

70 – 79 years 11.3 % 1.0 %

80+ years 14.3 % 1.9 %

Pooled 6.0 % 0.8 %

Wang TJ et al. Circulation. 2003;108:977-982.

Framingham: Summary

• 3% prevalence in general adult population, similar to overt heart failure

• Increases considerably with age

• Predominantly men – (confirmed in several studies)

• 50% with history of MI

Wang TJ et al. Circulation. 2003;108:977-982

Other Studies• 2042 randomly selected men and women >45

years old – 65% of subjects with low ejection fractions were

asymptomatic1

• 7.7% of elderly have LV dysfunction– only 48% diagnosed2

• 3 to 5 % of general population has asymptomatic LV dysfunction3

1Rodeheffer. J Card Fail 2002; 8:S253-257.2Morgan. BMJ 1999;318:368-72.3McDonagh. Heart 2002; 88(Suppl II):ii12-ii14.

Framingham Study: Heart Failure Morbidity

Wang TJ et al. Circulation. 2003;108:977-982.

EF > 50%

EF 40 to 50%

EF < 40%

Framingham Study - Mortality

Wang TJ et al. Circulation. 2003;108:977-982.

Moderate-to-severe ALVD (EF <40%)

0 2 4 6 8 10 12

0.0

0.2

0.4

0.6

0.8

1.0

Su

rviv

al

Years

P<.0001

No ALVD (EF >50%) and noHF history

Mild ALVD (EF 40% to 50%)

Systolic HF (EF 50%)

Screening for Stage B

1. Has the effectiveness of the program been demonstrated in a randomized trial?

2. Are efficacious treatments available?

3. Does the burden of suffering warrant screening?

4. Is there a good screening test?

5. Does the program reach those who could benefit?

6. Can the health system cope with the program?

7. Do persons with positive screenings comply

with advice and interventions?

FHS: Framingham Heart Study

ABC: the Health ABC study

CHS: Cardiovascular Health study

The Treatment• Limited evidence in this population• Extrapolate from the vast symptomatic heart

failure literature…..• Goals

– Prevent progression to symptomatic disease– Prevent death– Maintain an excellent quality of life– “Do no harm”

The argument for ACE inhibitors• They work for symptomatic HF: Stage C

– Reduce morbidity– Reduce mortality– Improve quality of life– Promote “positive” remodeling of the ventricle

• The data for “asymptomatic” HF: Stage B– SOLVD-Prevention– SAVE– TRACE

4228 asymptomatic pts with LVEF < 35% (mean EF 28%)>30% s/p MI greater than 3 months

Randomized to enalapril vs placeboMean follow-up 37 months

Results:No difference in mortality in enalapril group (8% “trend”)Significant decrease in new onset HF, hospitalizations in enalapril group

SOLVD-Prevention

SOLVD investigators. NEJM 1992;327:685-691

SOLVD Investigators. N Engl J Med 1992;327:685

42 48

Placebo (n=2117)

Enalapril (n=2111)

50

40

30

20

10

00 6 12 18 24 30 36

Months

*Mortality

(%)

All-Cause Mortality

SOLVD-Prevention

*P=0.30 enalapril vs placebo

SOLVD Long Term Follow-up

• 12 year follow-up of SOLVD-Prevention

–14% reduction in mortality

Prevention Trial

Jong et al. Lancet 2003;361:1843

0 2 4 6 8 10 12

Car

diac

Mor

tali

ty

Years

The SAVE Trial• 2231 patients 3 days s/p MI without heart failure

and EF < 40%• Randomized to captopril or placebo and

followed for an average of 3.5 years• Re-assessment of EF: fell > 9% in placebo• Captopril – 19% reduction in all cause mortality

and 22% reduction in heart failure hospitalization

Pfeffer MA, et. al., NEJM 1992;327:669-677.

SAVE RemodelingNumber of patients that developed LV dilatation in the SAVE

study of captopril versus placebo after acute MI

80 -70 -60 -50 -40 -30 -20 -10 -

1 year 2 year

Time Post-MI

Placebo

Captopril

Sutton, et al. Circulation 1997;96:3294-9

Sutton M, et. al., Circulation 1997, 96:3294-9

TRACE

• 1749 patients with MI and EF < 35%– 41% had no heart failure– Followed for 50 months

• In the asymptomatic group: 30% reduction in mortality in trandolapril

Kober L, NEJM 1995;333:1670-76.

The argument for beta-blockers

• Alter the natural history of cardiovascular disease by influencing neurohormonal pathways

• Like ACE inhibitors, beta-blockers have been shown to improve survival, improve remodeling and decrease hospitalizations in patients with symptomatic systolic heart failure

• Most effective when initiated early in disease state but may also impact survival in patients with advanced disease

• Underutilized in most disease states – Fear of side-effects (especially in asymptomatic pts)– Lack of understanding of pathophysiology of disease

SOLVD - Prevention

• Plasma norepinepherine levels were strongly associated with progression to symptomatic heart failure

• This supports the concept that even in the absence of symptoms the adrenergic system is activated and can lead to negative remodeling

ACEI

ß BLOCKER

Yes

No

n=2231 YES No

13.3%

19.5%

24.3%

27.7%

SAVE

Circulation 1995;92:3132

Beta blocker and mortality in SAVE

The best survival occurred with a

combination of beta-blockers and

ACE inhibitors

CAPRICORN• Acute myocardial infarction within 21 days• Received all “adjuvent” therapies for MI• LV ejection fraction 40%• Receiving ACE inhibitor 48 h

• 1,023 patients had no heart failure – “Stage B” – (about 50% of the total were asymptomatic)

The CAPRICORN Investigators. Lancet. 2001;357:1385–1390.

CAPRICORN: Reduced Mortality in Stage B Post MI

¯31%Risk Reduction

(3%, 53%)

Pro

po

rtio

n A

live

Carvedilol(n=504)

Placebo(n=519)

0

1.00

0.90

0.70

0.60

0.80

Years

0 0.5 1 1.5 2 2.5

Sudden Death(Low EF) Primary Prevention Trials

MADIT 1

MUSTT

MADIT 2

DEFINITE

SCDHEFT