1. Does Less Lung = More Heart? Nathaniel Marchetti, DO Temple University Philadelphia, PA

2. Cardiac Effects of COPD Why do we care about the heart in COPD? Why do we care about the heart in COPD? What does hyperinflation do to the heart? What does hyperinflation do to the heart? Effect of LVRS on cardiac function Effect of LVRS on cardiac function

3. N=5,887 Specific Causes of Death in the Lung Health Study at 14.5 yrs Anthonisen, et al AIM 2005

4. COPD Patients Are at Risk for a Range of Cardiovascular Diseases Curkendall, et al Annals Epidemiol 2006

5. Author Sample size Follow-up(yrs) Age (yrs) Relationship Hole,197715,4111544-64 Increased RR of 1.56 CV mortality with lowest quintile FEV 1 Ebi-Kryston,198817,7171040-64 Chronic phlegm associated with increased all cause & respiratory mortality Schunneman,20041,1952947 Increased RR of 2.11 in CV mortality with lowest quintile FEV 1 Persson,19861,4621238-60 PEF inversely proportional to AMI causing death Truelsen,200112,8781745-84 Stroke & stroke related mortality inversely related to FEV 1 % Hozawa,200513,8421345-64 HR of CV mortality inversely coupled to FEV 1 % predicted (Modified from McNee PATS 2008) Association of CV Mortality and FEV 1

6. Vascular Stiffness is Greater in COPD Patients with Worse Airflow Obstruction and More Systemic Inflammation FEV 1 CRP N=60 Eickhoff AJRCCM 2008

7. Vascular Stiffness Increases During AECOPD Marchetti, et al COPD 2011

8. Increased Risk of AMI and CVA Following AECOPD N=25,857 Risk AMI increased 2.27- fold 1-5 days post AECOPD Risk CVA increased 1.26- fold 1-49 days post AECOPD p=0.03 Donaldson et al, Chest 2010

9. Troponin T Elevation & Long-term Mortality after AECOPD cTnT < 0.01 μgL -1 cTnT 0.01-0.03 μgL -1 cTnT > 0.04 μgL -1 396 Hospitalized AECOPD patients who had measurements of cardiac - specific troponin (cTnT) Followed for median 1.9 yrs Elevated cTnT associated with increased all-cause mortality with a hazard ratio of 1.64 (95% CI 1.15-2.34) Brekke ERJ 2008

10. Risk of Death at 30 days Following Hospitalized AECOPD Variable OR (95% CI) p BMI 0.905 (0.83-0.99) 0.029 P a CO 2 1.041 (1.02-1.07) 0.002 NT-proBNP 9.241 (2.58-33.05) 0.001 Troponin T >0.03 5.115 (1.73-15.15) 0.003 Chang et al, Thorax 2011

11. Effect of Hyperinflation on the Heart

12. Effect of leg elevation on cardiac function o EDAI represents LVEDP o certain increase in preload resulted in more pronounced increase in SVI o patients on steeper portion of Starling curve suggesting an under filled LV o SWI/EDAI represents LV systolic function o No increase in LV EF Jorgenssen et al Anes & Anal, 2007

13. ? Under filled LV in Emphysema o Diminished preload o ? Lower intra-thoracic blood volume

14. Reduced Intrathoracic Blood Volume and Left and Right Ventricular Dimensions in Patients with Severe Emphysema Compared cardiac MRI of 13 severely emphysematous patients to 11 healthy controls Compared cardiac MRI of 13 severely emphysematous patients to 11 healthy controls Emphysema patients Emphysema patients FEV 1 24% FEV 1 24% TLC 139% TLC 139% RV 272% RV 272% Jorgenssen et al Chest, 2007

15. Lower LV end diastolic volume in emphysema subject Jorgenssen et al Chest, 2007

16. Cardiac Function Results o Emphysematous subjects had o Lower LV and RV end-diastolic volume index o Lower LV and RV ejection fraction o Lower SVI for LV and RV Jorgenssen et al Chest, 2007

17. Lower intra-thoracic blood volume Jorgenssen et al Chest, 2007 p = 0.001 P = 0.001

18. Percent Emphysema, Airflow Obstruction, and Impaired Left Ventricular Filling Sub study of Multi-Ethnic Study of Atherosclerosis (MESA) Sub study of Multi-Ethnic Study of Atherosclerosis (MESA) Measured LV structure and function with MRI in 2,816 patients Measured LV structure and function with MRI in 2,816 patients Measured extent of emphysema on CT (HU < -910) Measured extent of emphysema on CT (HU < -910) Included 70% of lung since they were cardiac CTs Included 70% of lung since they were cardiac CTs Spirometry Spirometry Barr, et al NEJM, 2010

19. Effect of percent emphysema on cardiac measurements Barr, et al NEJM, 2010 Increasing amounts of emphysema lead to decreased LV volumes but no change in EF

20. Effect of current smoking Mean Change in LVEDV for an increase in emphysema of 10% Current Smokers -9.2 mL Former Smokers -4.2 mL Never Smokers -2.6 mL Barr, et al NEJM, 2010

21. Correlation of LVEDV with Emphysema Barr, et al NEJM, 2010

22. Decreasing Cardiac Chamber Sizes and Associated Heart Dysfunction in COPD. Role of Hyperinflation 138 patients with GOLD I-IV disease 138 patients with GOLD I-IV disease Excluded patients with known cardiac disease Excluded patients with known cardiac disease Lung volumes and 6MWD Lung volumes and 6MWD ECHO parameters ECHO parameters Measured cardiac chamber size Measured cardiac chamber size Diastolic dysfunction Diastolic dysfunction Watz, et al Chest, 2010

23. Chamber size decreased with increasing GOLD stage Watz, et al Chest, 2010

24. Correlation of LVED diameter to IC/TLC Watz, et al Chest, 2010 r = 0.56, p < 0.001

25. IC/TLC was independent predictor of cardiac chamber size Watz, et al Chest, 2010

26. Effects of hyperinflation on the oxygen pulse as a marker of cardiac performance in COPD 87 COPD patients compared to 46 healthy controls 87 COPD patients compared to 46 healthy controls CPET CPET Measured O 2 pulse (VO 2 /HR) Measured O 2 pulse (VO 2 /HR) Dynamic hyperinflation (IC/TLC) Dynamic hyperinflation (IC/TLC) Vassaux, et al ERJ, 2008

27. Correlation of O 2 pulse with dynamic and static hyperinflation Peak O 2 pulse vs Static IC/TLCChange in O 2 pulse vs Change in IC Vassaux, et al ERJ, 2008 r = 0.95, p=0.001 r = -0.30, p<0.001

28. IC/TLC 25% Rest Peak Exercise Difference Vassaux, et al ERJ, 2008

29. Summary Patients with COPD seem to have diminished cardiac chamber size Patients with COPD seem to have diminished cardiac chamber size Have decreased intra-thoracic blood volume with under filled LV Have decreased intra-thoracic blood volume with under filled LV Appears to be related to hyperinflation Appears to be related to hyperinflation Occurs across GOLD stages Occurs across GOLD stages Can this be altered? Can this be altered?

30. Effect of LVRS on Cardiac Function

31. Extreme example

32. Effect of Bullectomy on Cardiac Function Marchetti, et al J Thorac Cardiovasc Surg 2008

33. Effects of LVRS on Left Ventricular Diastolic Filling and Dimensions in Patients With Severe Emphysema 10 patients that had LVRS with FEV 1 28% 10 patients that had LVRS with FEV 1 28% Controls = 10 lobectomy patients with FEV 1 84% Controls = 10 lobectomy patients with FEV 1 84% Performed TEE in OR and measured Performed TEE in OR and measured LV dimensions LV dimensions Mitral flow velocities as a marker of diastolic filling Mitral flow velocities as a marker of diastolic filling TEE done pre-operative but following induction of anesthesia TEE done pre-operative but following induction of anesthesia TEE repeated at end of case when chest closed TEE repeated at end of case when chest closed Jorgensen, et al Chest, 2003

34. Changes in Hemodynamics Jorgensen, et al Chest, 2003 LVRS subjects had an increase in CI, SVI, and SWI

35. Effect on Chamber Size Jorgensen, et al Chest, 2003 Improved end diastolic size in LVRS group No change in LVEDS = LV stiffness

36. Mitral Doppler Flow Following LVRS E A Pre LVRS Low E-max Low E/A ratio Post LVRS Improved E-wave Improved E/A ratio Jorgensen, et al Chest, 2003

37. Lung Deflation and Oxygen Pulse in COPD: Results from the NETT Randomized Trial 129 NETT patients that had CPET and arterial blood gas during exercise 129 NETT patients that had CPET and arterial blood gas during exercise 67 medical 67 medical 62 LVRS 62 LVRS Divided group in to “deflators” and “non- deflators” Divided group in to “deflators” and “non- deflators” Deflators defined as the change in RV/TLC by 75% of subjects Deflators defined as the change in RV/TLC by 75% of subjects Main outcome was % change in peak O 2 pulse from baseline to 6 months Main outcome was % change in peak O 2 pulse from baseline to 6 months Come, et al Respir Med 2012

38. % Change in O 2 pulse Come, et al Respir Med 2012 5215 47

39. Comparison of baseline to 6 months Come, et al Respir Med 2012 Changes in Sx deflators baseline to 6 months in A-line patients Changes in Sx deflators baseline to 6 months in all patients

40. Increased oxygen pulse after LVRS is associated with reduced dynamic hyperinflation 16 patients that had LVRS compared to 6 patients with medical therapy 16 patients that had LVRS compared to 6 patients with medical therapy CPET done baseline and 6 months CPET done baseline and 6 months O 2 pulse and pulse pressure were outcomes O 2 pulse and pulse pressure were outcomes Lammi, et al ERJ 2012 in press

41. Changes in O2 Pulse Lammi, et al ERJ 2012 in press

42. Correlations Between Hyperinflation and O 2 Pulse Lammi, et al ERJ 2012 in press

43. Conclusions LVRS improved non-invasive markers of stroke volume Increase in O 2 pulse after LVRS correlated with reductions in static and dynamic hyperinflation Strategies to reduce DH might improve exercise performance in part by ameliorating exercise- induced cardiac dysfunction Lammi, et al ERJ 2012 in press

44. Summary COPD can impair LV function and it is related to hyperinflation COPD can impair LV function and it is related to hyperinflation Leads to low end-diastolic pressures Leads to low end-diastolic pressures Decreased intra-thoracic blood volumes Decreased intra-thoracic blood volumes Small cardiac chamber size Small cardiac chamber size Reducing lung volumes theoretically will help with improving LV function Reducing lung volumes theoretically will help with improving LV function

45. Left Ventricular Function in Chronic Obstructive Lung Disease 15 patients with severe COPD (FEV 1 0.64L) 15 patients with severe COPD (FEV 1 0.64L) 7 had history of right heart failure 7 had history of right heart failure Had higher mean PA pressure Had higher mean PA pressure No difference in CO/CI in R heart failure patients No difference in CO/CI in R heart failure patients More hypercapnic and hypoxemic More hypercapnic and hypoxemic Baum et al NEJM, 1971

46. Abnormal LV function in 14/15 patients Baum et al NEJM, 1971

47. LVEDVI correlated with ITBV Jorgenssen et al Chest, 2007

48. Spirometric, CT and MRI findings Barr, et al NEJM, 2010

49. Vassaux, et al ERJ, 2008

50. Conclusions Increasing GOLD stage is associated with decreasing cardiac chamber size Increasing GOLD stage is associated with decreasing cardiac chamber size IC/TLC as a marker of hyperinflation best predicted chamber size IC/TLC as a marker of hyperinflation best predicted chamber size What happens during exertion when DH occurs? What happens during exertion when DH occurs?

51. Conclusions LVRS improved LV performance LVRS improved LV performance Increase end-diastolic area index Increase end-diastolic area index Improved LV filling Improved LV filling Basically improved preload Basically improved preload Could be related to increased intra thoracic blood volume due to decreased PEEP i Could be related to increased intra thoracic blood volume due to decreased PEEP i

52. Conclusion Cardiac performance compromised in severe emphysema Cardiac performance compromised in severe emphysema Due to correlation of ITBV and LVEDVI authors felt that intrathoracic hypovolemia contributed to LV dysfunction Due to correlation of ITBV and LVEDVI authors felt that intrathoracic hypovolemia contributed to LV dysfunction ? Secondary to increased thoracic pressures from hyperinflation (PEEP i ) ? Secondary to increased thoracic pressures from hyperinflation (PEEP i )