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Mariell Jessup MD, FAHA, FACC, FESC Professor of Medicine University of Pennsylvania Philadelphia, Pennsylvania

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

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Mariell Jessup MD, FAHA, FACC, FESC Professor of Medicine University of Pennsylvania Philadelphia, Pennsylvania

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  1. Asymptomatic Left Ventricular Dysfunction and Diabetes:Prevention and Timely DetectionDisfunzioneventricolaresinistraasintomatica 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

  2. 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

  3. 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)

  4. 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

  5. Follow-up ECHO 2/02 • LVEF improved to ~ 30% • Plan :Continue ACEI and beta blocker • Follow-up in 6 months

  6. 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

  7. 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

  8. ACC/AHA Heart Failure Guidelines - 2005

  9. Stages of CHF — ACC/AHA Guidelines 2005 D Refractory Ammar et al. Circulation 2007;1151 563 0.2% C Prior, current symptoms 11.8% B Structural heart disease LVH, MI, low LVEF, dilatation, valvular disease 34% A High-risk patients Hypertension, diabetes, coronary disease, family history, cardiotoxic drugs 22%

  10. 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

  11. 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

  12. Framingham Study: Prevalence Wang TJ et al. Circulation. 2003;108:977-982.

  13. 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

  14. 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.

  15. Framingham Study: Heart Failure Morbidity EF > 50% EF 40 to 50% EF < 40% Wang TJ et al. Circulation. 2003;108:977-982.

  16. Framingham Study - Mortality 1.0 0.8 No ALVD (EF >50%) and noHF history 0.6 Survival 0.4 Mild ALVD (EF 40% to 50%) P<.0001 0.2 Moderate-to-severe ALVD (EF <40%) Systolic HF (EF 50%) 0.0 0 2 4 6 8 10 12 Years Wang TJ et al. Circulation. 2003;108:977-982.

  17. 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?

  18. FHS: Framingham Heart Study ABC: the Health ABC study CHS: Cardiovascular Health study

  19. 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”

  20. 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

  21. SOLVD-Prevention 4228 asymptomatic pts with LVEF < 35% (mean EF 28%) >30% s/p MI greater than 3 months Randomized to enalapril vs placebo Mean 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 investigators. NEJM 1992;327:685-691

  22. SOLVD-Prevention All-Cause Mortality *P=0.30 enalapril vs placebo 50 Placebo (n=2117) 40 * Mortality (%) 30 Enalapril (n=2111) 20 10 0 0 6 42 12 18 24 30 48 36 Months SOLVD Investigators. N Engl J Med 1992;327:685

  23. SOLVD Long Term Follow-up • 12 year follow-up of SOLVD-Prevention • 14% reduction in mortality Prevention Trial Cardiac Mortality 0 2 4 6 8 10 12 Years Jong et al. Lancet 2003;361:1843

  24. 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.

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

  26. 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.

  27. 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

  28. 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

  29. Beta blocker and mortality in SAVE The best survival occurred with a combination of beta-blockers and ACE inhibitors ß BLOCKER n=2231 YES No Yes 13.3% 24.3% ACEI No 19.5% 27.7% SAVE Circulation 1995;92:3132

  30. 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.

  31. Risk Reduction • 31% (3%, 53%) CAPRICORN: Reduced Mortality in Stage B Post MI 1.00 Carvedilol(n=504) 0.90 Placebo(n=519) 0.80 Proportion Alive 0.70 0.60 0 0 0.5 1 1.5 2 2.5 Years

  32. Sudden Death(Low EF) Primary Prevention Trials MADIT 1 MUSTT MADIT 2 DEFINITE SCDHEFT

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