mariell jessup md, faha, facc, fesc professor of medicine university of pennsylvania philadelphia,...
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Asymptomatic Left Ventricular Dysfunction and Diabetes: Prevention and Timely Detection Disfunzione ventricolare sinistra asintomatica e diabete : come preveniria e come accorgersene . Mariell Jessup MD, FAHA, FACC, FESC Professor of Medicine University of Pennsylvania - PowerPoint PPT PresentationTRANSCRIPT
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