mariell jessup md, faha, facc, fesc professor of medicine university of pennsylvania philadelphia,...

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, FESCProfessor of Medicine

University of PennsylvaniaPhiladelphia, 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 10 120.0

0.2

0.4

0.6

0.8

1.0

Surv

ival

Years

P<.0001

No ALVD (EF >50%) and noHF history

Mild ALVD (EF 40% to 50%)

Systolic HF (EF 50%)

Screening for Stage B1. 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

talit

y

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%)

Prop

ortio

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 1MUSTT

MADIT 2DEFINITESCDHEFT