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1 I have nothing to disclose.

2 ESC Congress, München, 2012 Pulmonary Circulation and the Right and Left Ventricles Left Ventricle in Pulmonary Hypertension Robert Naeije Erasme University Hospital Brussels, Belgium

3 PH can be a cause of left ventricular failure Woman aged 58, with 2 yr history of dyspnea-fatigue symptomatology, more recent onset of edema Admitted with clinical RVF Work-up excluded lung or heart disease, and CTEPH Diagnosis is IPAH NYHA III, 6MWD 320 m

4 Ppa 62 mmhg Pra 18 mmhg Ppw 24 mmhg Q 1.6 L/min/m 2

5 Treatment with iv dobutamine and furosemide Before diuretics, Ppw 24 mmhg After diuretics, Ppw 13 mmhg

6 Diagnosis Diastolic left ventricular failure caused by leftward bowing of the septum during diastole, decreased LV chamber size, compliance and contractility This is called a «reverse Bernheim effect» after the report by Bernheim et al in 1910 of RV failure in a patient with aortic stenosis Bernheim P De l asystolie veineuse dans l hypertrophie du cœur gauche par sténose concomitante du ventricule droit Rev Med 1910;39:

7 Pathophysiology of LV failure in PH Pulmonary hypertension Increased afterload Increased contractlity Increased EDV Homeometric adaptation (Anrep) to preserve RV-arterial coupling Heterometric adaptation (Starling) to preserve flow output, causes altered ventricular interaction

8 From preserved RV-arterial coupling to ventricular interaction Male Age 25 Years mpap = 56 mmhg Female Age 24 Years mpap = 53 mmhg SV = 90 ml, 6MWD = 500 m SV = 30 ml, 6MWD = 300 m V Noordegraaf, VUMC

9 Preserved RV-arterial coupling: SV/ESV > 1.5 to 2 Altered ventricular interaction From M Overbeek

10 Ventricular interdependence In 1910, Bernheim postulated that LV hypertrophy and dilatation could compress the RV and diminish RV function Rev Med 1910;39:785 In 1914, Henderson and Prince show on an isolated cat heart preparation that pressure and volume loading of one ventricle decreased the output and function of the contralateral ventricle Heart 1914;5:217 In 1956, Dexter describes a «reverse Berheim effect» in patients with ASD Br Heart J 1956;23:365

11 Definition of ventricular interdependence Ventricular interdependence is defined as the forces that are transmitted from one ventricle to the other ventricle through the myocardium and pericardium, independent of neural, humoral or circulatory effects Ventricular interdependence is diastolic and systolic Santamore and Dell Italia, Progr Cardiovasc Dis 1998;40:289

12 Diastolic interaction

13 Diastolic interaction: increased EDV decreases the other ventricle s compliance

14 Effects of chronic RV pressure overload on LV diastolic function Lazar et al, AJC 1993;72: pts with various causes of PH (27 IPAH) of variable severity, RHC, radionuclide angiography showing RVEF < 30 % in 24 pts, normal LVEF in all RVEF was inversely correlated to PAWP and directly to LV peak filling rate

15 Systolic interaction

16 Systolic interaction: changes in contractility affects the other ventricle s contractility Rapid withdrawal of blood from the LV using a LV assist device: a decrease in LVP causes an immediate decrease in RVP and flow output Woodward et al: Isolated ventricular systolic interaction during transient reductions in LVP Circ Res 1992;70:944

17 Aortic constriction improves RV function which has been altered as a consequence of pulmonary banding Belenkie I et al. Circulation 1995;92: Copyright American Heart Association

18 RV pressure segment length and pressure-diameter loops during severe pulmonary artery (PAC) and aortic constriction (AOC) Copyright American Heart Association Belenkie I et al. Circulation 1995;92:

19 Asynchrony

20 High altitude-induced right heart failure Huez S, Faoro V, Vachiery JL, Martinot JB, Naeije R, Circulation 2007;115: Sagama Mt, 4500 m Bolivia, 2006

21 Interventricular mechanical asynchrony in PAH Marcus et al, JACC 2008;51:750

22 Ventricular geometry, strain, and rotational mechanics in PH Puwanant et al, Circulation 2010;121:259 Altered LV torsion as a function of PASP and EI

23 Chronic LV underfilling

24 RV failure following chronic pressure overload is associated with a reduction in LV mass Hardziyenka et al, JACC 2011;57: patients with CTEPH before and after PEA CTEPH was associated with decreased peak LV filling rate, LVEF and LV free wall mass 18 rats with MCT-PH and RVF MCT-PH was associated with decreased LV filling velocity, free LV wall mass and smaller LV free wall myocytes Increased expression of ANP and reduced expressions of -MHC and SERCA 2, in both RV and LV

25 The shrinking LV in chronic RV pressure overload Hardziyenka et al, JACC 2011;57:921

26 Electrophysiologic remodeling of the LV in pressure overload-induced RV failure Hardziyenka et al, JACC 2012;59: rats with MCT-PH RVF and 16 patients with CTEPH The LV of rats with MCT-RVF exhibited electrophysiological remodeling, with longer AP and ERPs, and slower longitudinal conduction velocity AP/ERP prolongation agreed with reduced Kcnip2 expression (encodes the repolarizing K channel subunit KChiP2) Expressions of other K, Na and Ca channels unchanged Impulse transmission was hampered by decreased cell length and width, and impaired cell to cell transmission The LV of patients with CTEPH also exhibited AP prolongation and conduction slowing

27 Electrophysiologic remodeling of the LV in pressure overload-induced RV failure Hardziyenka et al, JACC 2012;59:2193

28 Pathobiology of LV underfilling: extended paracrine effects?

29 Number of extravascular (MO, x40) Relative mrna expression (IL-1 beta : ABL1) IL-6/IL-10 ratio (mrna expression) Relative mrna expression (MCP-1 : ABL1) Persistent RV failure on acute PA banding Dewachter et al. Crit Care Med Interleukin-1 beta * Right Ventricle * Left Ventricle Pro-inflammatory IL-6/IL-10 ratio MCP * Right Ventricle * Left Ventricle * Right Ventricle * Left Ventricle Macrophages/mm * * SHAM Pulmonary artery Constriction (PAC) 0 Right Ventricle Left Ventricle

30 RV failure on chronic aorta-pulmonary shunting Rondelet, Dewachter et al. Eur Heart J Relative mrna expression ( gene : HPRT) Relative mrna expression * * * * RV LV RV LV RV LV RV LV IL - 1 IL - 1 b IL - 6 IL month SHAM 6-month SHUNT

31 Clinical implications Acute RV failure: importance of RV contractility (dobutamine), limitation of RV volume (diuretics, RAP < 12 mmhg always desirable) and LV systolic function and BP (catecholamines, norepinephrine) Chronic LV unloading, dyssynchrony and atrophic remodeling is largely restored by effective decrease in RV afterload (PEA, lung transplantation) Resynchronization by RV pacing, investigation of LVF therapies with favorable biological effects (bblockers) are curently investigated

32 Conclusions The LV is abnormal in severe PH because of negative diastolic and systolic interactions, chronic underfilling, altered geometry and electrophysiological remodeling The pathobiology of LV failure on PH requires further studies, as current data do not allow to discern the direct effects of underfilling from extended RV paracrine signaling