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
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