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Update on Pulmonary Hypertension and Implications for Solid Organ Transplantation

Update on Pulmonary Hypertension and Implications for Solid Organ Transplantation . Ivan M. Robbins, M.D. Adult Pulmonary Hypertension Center Vanderbilt University. Pulmonary circulation. Low resistance, high compliance vascular bed Only organ to receive entire cardiac output (CO)

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Update on Pulmonary Hypertension and Implications for Solid Organ Transplantation

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  1. Update on Pulmonary Hypertension and Implications for Solid Organ Transplantation Ivan M. Robbins, M.D. Adult Pulmonary Hypertension Center Vanderbilt University

  2. Pulmonary circulation • Low resistance, high compliance vascular bed • Only organ to receive entire cardiac output (CO) • Changes in CO as well as pleural/alveolar pressure affect pulmonary blood flow • Different reactions compared to the systemic circulation • Normally in a state of mild vasodilation

  3. Vascular Pressure in Systemic and Pulmonary Circulations (mm Hg) 120/80, mean 93 25/8, mean 14 Systemic Circulation Pulmonary Circulation Arteries Arteries Right Atrium Mean >6 Left Atrium Mean 5 Lung Body SVR= 17.6 PVR= 1.8 Right Ventricle 25/2-5 Left Ventricle 120/5-10 Veins Veins

  4. Outline • Review classification of pulmonary hypertension (PH) • Pulmonary arterial hypertension (PAH) • Evaluation of PH and how to differentiate PAH from other forms of PH • PH and cardiac, renal and hepatic transplantation • Review PAH-approved therapy and treatment of non-Group 1 PH

  5. Dana Point Classification of Pulmonary Hypertension (PH) • 1) Pulmonary arterial hypertension • 2) Pulmonary hypertension due to left heart disease • 3) Pulmonary hypertension due to lung diseases and/or hypoxia • 4) Chronic Thromboembolic pulmonary hypertension (CTEPH) • 5) Pulmonary Hypertension with unclear and/or multifactorial mechanism

  6. Dana Point Classification of PAH, Group 1 • Idiopathic PAH (formerly primary pulmonary hypertension, PPH) • Heritable Drug/toxin induced • Associated with: • Connective tissue diseases • HIV infection • Portal hypertension • Systemic to pulmonary shunts • Schistosomiasis • Chronic hemolytic anemia

  7. WHO Group 2 PH • Pulmonary hypertension owing to left heart disease • Systolic dysfunction • Diastolic dysfunction • Valvular disease • Pulmonary venous obstruction

  8. PH with unclear or multifactorial mechanisms: Group 5 1.Hematologic disorders 2.Systemic disorders: vasculitis 3.Metabolic disorders 4.Others: chronic renal failure on dialysis

  9. Definitions • Definition of PH: • mPAP > 25 mm Hg at rest • Definition of PAH: • PWP < 15 • Normal LVEF • No left-sided valvular disease

  10. 100 80 Percentage Surviving 60 40 20 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Years of Follow-up PAH: A Disease of Decline & Deterioration IPAH NIH Registry Adapted from: D’Alonzo GE, Ann Int Med, 1991

  11. 100 90 80 None 70 60 Survival, % 50 Lung Involvement (without PHT) 40 30 PHT 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Years From Diagnosis of PHT Outcome of Scleroderma Patients with Pulmonary Hypertension is worse than IPAH Koh et al, BrJ Rheumatol, 1996

  12. IPAH NIH Registry • 187 patients followed over 7 years • Extensive evaluation to R/O secondary causes • mPAP-60mmHg, CI-2.3 l/min, PVRI-26 U • Mean age at Dx: 36, almost 2:1 female:male • Mean duration of symptoms before Dx: 2 years Rich, Ann Intern Med, 1987 • ~Two cases per 1,000,000

  13. PAH is a rare disease • Incidence of IPAH: ~1-2 cases/million per year • Prevalence: 5,000 patients? • Prevalence of PAH: 30,000 patients? • ~50 million Americans have systemic hypertension • 61% of American adults are overweight • 27% are obese (BMI>30) • 16% of Americans have diabetes • 22% have hyperlipidemia

  14. PAH is rare in patients >65 yo referred to our PH center Pugh et al, submitted, 2012

  15. Genetic Predisposition Proliferation Other Risk Factors Thrombosis Altered Pathways and Mediators Vasoconstriction Pathogenesis of PAH 2012:An Integrated View Vascular Remodeling Inflammation

  16. PH - History • History of smoking • ETOH/recreational drug use • Systemic hypertension • Cyanosis/murmur as a child • Joint/musculoskeletal pain • Raynaud’s Syndrome • FH of unexplained early cardiopulmonary disease • Previous DVT, PE or family hx of thromboembolic dz • Use of appetite suppressant drugs

  17. PH- Symptoms • DOE • Fatigue, weakness • Chest pain • LE or abdominal swelling • Syncope • Not typical of PAH: orthopnea

  18. Evaluation for PH • ECG • Chest x-ray • V/Q scan or contrasted spiral CT (+/- angiogram) • PFTs • Exercise oximetry • Echocardiogram • Right heart catheterization w/vasodilator testing • Labs: CBC, CMP, INR, ANA, HIV, TFTs

  19. Clues to causes of PH other than PAH • Dilated LA on echo or on CT angiogram • Hx of systemic vascular disease • LVH, LAE, no evidence of RVH or RAD on ECG • Orthopnea • Crackles, clubbing • Development of pulmonary edema with pulmonary vasodilators • Think of disorders affecting pulmonary veins

  20. PH - Radiographic studies • CXR: -large proximal PA with peripheral tapering (pruning) -cardiomegaly due to enlarged RA, RV -pleural effusion is uncommon • CT: -PA >aorta -cardiomegaly, enlarged RV -pericardial effusion

  21. CXR in PAH

  22. CXR in Eisenmenger Syndrome

  23. Mitral Stenosis

  24. Enlarged main PA on CTStandard view Coronal view A PA

  25. PAH Perf Vent CTEPH Perf Vent Ventilation Perfusion Lung Scan

  26. Evaluation for Chronic Thromboembolic PH (CTEPH) • V/Q scan remains the best screening tool • CT angiogram is excellent for acute, proximal PE but can miss CTEPH • Gold standard for diagnosis is pulmonary angiogram • Safe procedure even in patients with marked PH • Mortality in 2 large studies: 0/547 and 2/202* PE No PE Tanariu, N. et al, J Nucl Med, 2007 *Hofman LV, et al, AJR, 2004 Pitton MB, et al, AJR, 2007

  27. CTEPH: Pulmonary Angiography • Confirms diagnosis of CTEPH in patients with PH • Assess thrombus accessibility • Distinct angiographic patterns • “Web” narrowing • Poststenotic dilatation • Proximal occlusion • “Pouch” defects

  28. Organized Clot Removed at Surgery

  29. Pulmonary Function tests • No characteristic changes • Mandatory to screen for significant restrictive or obstructive lung disease • Diffusing capacity often significantly reduced in patients with scleroderma (<50%)

  30. RV, RA Enlargement on Echocardiogram RV LV RA LA Normal PH

  31. CTEPH, 0.6% Lung disease/ PAH, 2.3% Sleep-related hypoventilation, Unknown, 6.8% 9.7% Congenital heart disease, 1.9% Left heart disease, 78.7% PH by Echo ≠ PAH • Single echo lab / Australian community of 160,000 • ~10% of patients had est. sPAP>40 mm Hg • Only 2.3% with PAH after full evaluation N=483 of 4579 patients with echo PASP >40 mm Hg. Gabby E. Am J Respir Crit Care Med. 2007;175:A713.

  32. Overestimation Accurate Underestimation 60 40 20 0 Echo estimate of PAP often inaccurate in advanced lung disease • Cohort: 374 lung txp pts • Echo 24–48 h prior to RHC • Prevalence of PH: 25% • Echo frequently leads to over-diagnosis of PH in patients with advanced lung disease % of studies PH (-) PH (+) Arcasoy SM et al. Am J Respir Crit Care Med. 2003;167:735-740.

  33. Right Heart Catheterization • Gold standard for diagnosis of PH • Crucial for determining cause of PH, i.e. pre- vs post-capillary process • Required prior to initiating therapy for PAH • Acute vasodilator testing should be performed at time of RHC in patients with PAH

  34. Other Helpful Diagnostic Tests(Determined by patient’s history) • High resolution chest CT • Cardiopulmonary exercise study • Polysomnography • Arterial blood Gas • Hepatitis serologies • Left heart catheterization, evaluation of coronary arteries

  35. PH and Cardiac Transplantation • ISHLT guidelines: • no absolute cutoffs for PH that prohibits transplant1 • Relative contraindication: PVR>5 or PVRI>6 or TPG >16-20 • Increased risk of RHF and death if sPAP >60 mm Hg and one of the above • If PVR to <2.5 with vasodilator but patient becomes hypotensive, persistent high risk (3.8% vs 27.5% 3 month mortality2 1. Mehra, M. et al, J Heart Lung Transplant, 2006 2. Costard-Jackle, et al, JACC, 1992

  36. Causes of RV failure after cardiac transplantation in patients with PH • Smaller mass than LV, less able to adapt to increased afterload • Low coronary blood flow/unit mass, less cooling, perhaps less cardioplegia • TR results from annular distortion during implantation and from increased afterload

  37. PH in ESRD • Prevalence up 48% on echo reported in literature1-4 • Only 10-14% had est. sPAP>45-50 mm Hg1 • Largest study: 500 pts, 68 (13%) on PD • Mean sPAP: 47±9 mm Hg, range: 35-75 mm Hg • 5.9% incidence in PD patients • Longer duration of dialysis in PH pts, 51 vs 30 months • Patients with PH had: • Higher CO1-3 • Worse survival1,3 1. Yigla et al, Chest, 2003 2. Nakhoul, et al Nehrol Dial Transplant, 2005 3. Issa et al, Transplantation, 2008 4. Bozbas et al, Transplanat Proc, 2009 5. Hemnes et al, Nephrol Seminar, 2010

  38. PH is a risk factor for decreased survival in hemodialysis patients Yigla, et al Kidney International, 2009

  39. Problems with studies of PH in ESRD • No direct hemodynamic measurements • All studies are estimated pressure by echo • PH generally defined as est. sPAP>35 mm Hg • Volume status of patients not reported • RV function is reported in only one study • No measurement of PWP or PVR • Many studies involve small numbers of patients • No prospective studies

  40. Echocardiographic findings in ESRD patients undergoing transplant Bozbas et al, Transplantation Proceedings, 2009

  41. PH is a associated with decreased survival after renal transplant • Retrospective analysis of 215/472 renal txp pts who had echo and est. RVSP obtainable1 • 48% on no HD prior to txp, only 10 on PD • Mean RVSP 34±10 mm Hg, range 21-71 • RVSP <35 mm Hg in 68%, 35-50 mm Hg in 22%, >50 mm Hg in 10% (22 pts) • Time on HD significantly related to development of PH independent of other risk factors 1.Issa et al, Transplantation, 2008

  42. Summary • Pulmonary hypertension being recognized more frequently in patients with ESRD • LV dysfunction and fluid overload are the primary factors contributing to clinically significant PH in patients on HD • Although PH is associated with worse outcome, patients are not dying of rh failure • PH, as with other disorders, is associated with worse outcome

  43. PH in patients with portal hypertension • All patients must be screened for PH • Portopulmonary HTN: • mPAP> 25 mm Hg • PVR> 3 units • PWP <15 mm Hg Krowka, MJ Semin Respir Crit Care Med, 2012

  44. Portopulmonary hypertension • ~5% of pts in a large epidmiological study of PAH • Occurs in 5.3-8.5% of liver transplant candidates • Outcome is poor untreated: 14% and 4% in 2 uncontrolled studies • Death can occur due to RH failure or liver dz • Treated, survival is improved: 40-68% 5 yr survival • Can obtain MELD exception if hemodynamic improvement with PAH therapy

  45. Implications for liver transplantation • Higher risk with mPAP>35 mm Hg • Up to 36% post-tx in-hospital mortality due to: • Acute RH failure during reperfusion of liver • Frequent need for enormous amount of blood products • Mild PH with normal PVR generally resolves after transplant • Effect of Tx in pts with mPAP>35 mm Hg with increased PVR is unpredictable

  46. Treatment of Pulmonary Hypertension

  47. Treatment of non PAH-pulmonary hypertension • Pulmonary Venous Hypertension: • Treat heart failure with afterload reduction • Systolic or diastolic • MV or AV disease • Replace the valve • Pulmonary vein stenosis • Pulmonary vein stenting

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