Pulmonary Hypertension and Congestive Heart Failure Stephen L. Rennyson MD August 11, 2011

Pulmonary Hypertension Mean Pulmonary Artery Pressure (mPAP) > 25 mmHg

WHO Classification of Pulmonary Hypertension 1. Pulmonary Arterial Hypertension 2. Left Heart Disease 3. Chronic Hypoxemia 5. Miscelaneous 4. Thromboembolic -Sarcoid, fibrosing mediastinitis

Relationship of CHF and PH Passive Congestion (Elevated PCWP) Increased LVEDP (PCWP) Pre - Capillary vs Post - Capillary PH

Group 2 PH Comprises 1/2 of all PH Systolic and Diastolic Dysfunction Leads to RV dysfunction Difficult to treat -- Cardio-Renal Syndrome Independently associated with worse outcomes

Group 2 PH RVSP RVSP Independent predictor of mortality Congestive Heart Failure Volume 17, Issue 4, pages 189-198, 21 JUL 2011 DOI: 10.1111/j.1751-7133.2011.00234.x Independent predictor of mortality

Survival after Cardiac Transplantation Elevated PAP and Low RV function Group 1 indicates normal pulmonary artery pressure/preserved right ventricular ejection fraction (n=73); group 2, normal pulmonary artery pressure/low right ventricular ejection fraction (n=68); group 3, high pulmonary artery pressure/preserved right ventricular ejection fraction (n=21); and group 4, high pulmonary artery pressure/low right ventricular ejection fraction (n=215). Voelkel N F et al. Circulation 2006;114:1883-1891

Cardiac Catheterization

Hemodynamic Assessment Right Heart Catheterization RA, RV, PAP, PCWP Thermodilution and Fick End Expiration -- Best approximate of atmospheric pressure

Transpulmonary Gradient (TPG) Change in pressure across the pulmonary circulation mPA - PCWP Normal TPG < 10 mmHg

Pulmonary Vascular Resistance Resistance to flow that must be overcome to push blood through the system Ohms Law: mPA - PCWP Cardiac Output Normal Values of < = to 1.5 Wood Units

PH due to CHF Pre Capillary PH Post Capillary PH mPA > 25 mmHg PCWP < 15 mmHg CO normal Post Capillary PH mPA > 25 mmHg PCWP > 15 mmHg CO normal or low

Post Capillary PH out of proportion Use of TPG and PVR TPG > 10-12 mmHg PVR > 1.5 wood units

PH out of proportion Active or Reactive PH Passive PH Elevated mPA beyond PCWP TPG> 10-12 Passive PH Elevated mPA solely attributed to PCWP TPG < 10-12 Tx Based on Traditional CHF management Tx Based on Traditional CHF management ??

Reactive PH Longstanding Advanced Heart Failure Chronic Venous hypertension Mediated by Endothelin Pulmonary Vascular Remodeling Elastic Fibers Intimal Fibrosis Medial Hypertrophy Changes -- Indistinguishable from PAH

Pulmonary Remodeling Does not normalize with traditional CHF treatments “Fixed” Pulmonary Arteriopathy Ultimately RV Failure

ISHLT guidelines -- Vasodilator Challenge Reactive Changes Vasodilator Challenge Inhaled NO, IV epoprostenol, milrinone, nitroprusside, nitroglycerin, dobutamine . . . ISHLT guidelines -- Vasodilator Challenge mPA > 50 mmHg AND TPG > 15 mmHG OR PVR > 3 Wood Units

Vasodilator Challenge VCU/MCV -- NO challenge Reactive Changes with Fixed PH: --Persistent PVR >=2.5 WU or --PVR < 2.5 WU secondary to SBP <85 mmHg

Right Ventricular Failure RV Hypertrophy RV Dilation Flattening of Interventricular Septum -- D Shaped LV RA Enlargement Tricuspid Regurgitation

Right Ventricular Evaluation Transthoracic Echocardiography Qualitative Quantitative Tricuspid Annular Peak Systolic Excursion (TAPSE) -- > M-mode Tissue Doppler First Pass (RVEF) MRI

TAPSE American Journal of Respiratory and Critical Care Medicine Vol 174. pp. 1034-1041, (2006)

TAPSE (< 1.8 cm) American Journal of Respiratory and Critical Care Medicine Vol 174. pp. 1034-1041, (2006)

TAPSE (< 1.8 cm) American Journal of Respiratory and Critical Care Medicine Vol 174. pp. 1034-1041, (2006)

TAPSE (< 1.8 cm) American Journal of Respiratory and Critical Care Medicine Vol 174. pp. 1034-1041, (2006)

Medical Management Flolan Sildenafil Bosentan / Darusentan Prostacyclin Bosentan / Darusentan Moraes D L et al. Circulation 2000;102:1718-1723

Role for pulmonary vasodilators? Prostanoids -- FIRST Trial -- Flolan Endothelial Receptor Antagonists REACH and ENABLE trials -- Bosentan Phosphodiesterase Inhibitors -- Sildenafil

Flolan International Randomized Survival Trial FIRST Flolan International Randomized Survival Trial 471 patients class III/IV Improved Hemodynamics Increased CI / Decreased PVR and PCWP Exercise Tolerance and QOL No Change Increased Mortality Contraindicated Am Heart J 1997;134:44-54

Research of Endothelin Antagonists in Chronic Heart Failure REACH Research of Endothelin Antagonists in Chronic Heart Failure 370 Patients High dose Bosentan vs Placebo Trial Stopped Early Increase in early CHF exacerbations Elevated Transaminase Levels

ENABLE 1600 Patients Bosentan (lower dose) vs Placebo Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure 1600 Patients Bosentan (lower dose) vs Placebo Increased CHF exacerbations

Phosphodiesterase Inhibitors

Sildenafil No large scale clinical trials Acute Hemodynamic Trials Long Term Hemodynamics Quality of Life Trials

Acute Hemodynamic Changes 11 patients Right Heart Cath Inhaled NO (80 ppm) Sildenafil (50 mg) NO/Sildenafil combination Lepore JJ, Maroo A, Bigatello LM, et al. Chest. 2005;127:1647-1653

Duration of Effect NO Alone NO and Sildenafil Lepore JJ, Maroo A, Bigatello LM, et al. Chest. 2005;127:1647-1653

Acute Changes Lepore JJ, Maroo A, Bigatello LM, et al. Chest. 2005;127:1647-1653

Chronic Therapy 34 patients, 12 week trial Sildenafil vs Placebo (75 titrated to 150 mg/day) Class II-IV NYHA CHF, (iCMO and NiCMO) Hemodynamic and Qualitative measurements Lewis G D et al. Circulation 2007;116:1555-1562

Quantitative Analysis Lewis G D et al. Circulation 2007;116:1555-1562

Quantitative Analysis Lewis G D et al. Circulation 2007;116:1555-1562

Qualitative Analysis Lewis G D et al. Circulation 2007;116:1555-1562

Sildenafil Improved first pass RVEF Improved NYHA class in over 50% of Sildenafil and 13% in placebo Conclusions Improvements in both quantitative and qualitative measurements in CHF patients with PH Lewis G D et al. Circulation 2007;116:1555-1562

PH and Cardiac Transplantation TPG and PVR Increased mortality Barrier to successful transplantation ISHLT guidelines -- Vasodilator Challenge mPA > 50 mmHg AND TPG > 15 mmHG OR PVR > 3 Wood Units

Sildenafil in Class IV CHF Pre-Transplant Case Series of 6 patients awaiting transplant All had TPG > 15 mmHg Jabbour A et al. Eur J Heart Fail 2007;9:674-677

TPG Jabbour A et al. Eur J Heart Fail 2007;9:674-677

PVR Jabbour A et al. Eur J Heart Fail 2007;9:674-677

Sildenafil in addition to vasodilator challenge enabled sufficient decrease in PVR and TPG to enable transplantation Jabbour A et al. Eur J Heart Fail 2007;9:674-677

Mechanical Support

Kavarana M. N. et al.; Ann Thorac Surg 2002;73:745-750 Pulsatile LVAD Retrospective Analysis of 69 LVAD patients No significant difference in pre-LVAD hemodynamics 30% Developed RV dysfunction (21/69) Prolonged inotropic support, longer HD, Increased transfusions, mortality RVAD needed post-operative 1 patient Kavarana M. N. et al.; Ann Thorac Surg 2002;73:745-750

Kavarana M. N. et al.; Ann Thorac Surg 2002;73:745-750 Peri-Operative Kavarana M. N. et al.; Ann Thorac Surg 2002;73:745-750

Kavarana M. N. et al.; Ann Thorac Surg 2002;73:745-750 Transplantation Kavarana M. N. et al.; Ann Thorac Surg 2002;73:745-750

Continuous Flow HM-II 40 LVAD patients -- Single Center Pre and Post LVAD implant Hemodynamics Echocardiographic indices

Continuous Flow HM-II Pre-LVAD Post-LVAD PCWP 24.5 12.9 TPG 12.7 9.4 mean mean PCWP 24.5 12.9 TPG 12.7 9.4 PVR 3.7 2.1 C.I. 1.9 2.5 All p-values < .001

Continuous Flow HM-II RV failure after LVAD >14 days inotropic support or RVAD 5% (2/40) At 6 Months 37/40 alive or transplanted

Continuous Flow HM-II RV failure can be treated effectively with continuous flow left ventricular assist devices Bridge to transplant patients

Biventricular Support (TAH) -- Syncardia An option for severe bi-ventricular failure with significant Reactive PH Effective Bridge to transplantation

Pulmonary Circulation After TAH Single center retrospective study (VCU/MCV) 40+ patients Evaluation of hemodynamics pre and post TAH Pulsatile mechanism vs Continuous Flow of LVAD

Pulmonary Hypertension secondary to CHF (Systolic and Diastolic) Chronic post-capillary PH Pulmonary Vascular Remodeling RV dysfunction Passive PH TPG < 12 mmHg Reactive PH TPG > 12 mmHg Traditional Medical Therapy Advanced Treatment Options ACEi / ARB/ Aldosterone Antagonists Beta Blockade / Diuretic CRT Sildenafil ?? LVAD vs TAH