Atrial dysfunction and chronotropic incompetence

Transcription

1 Pathophysiology of heart failure with preserved ejection fraction Atrial dysfunction and chronotropic incompetence Vojtech Melenovsky IKEM, Prague, Czech Republic DECLARATION OF CONFLICT OF INTEREST : None

2 Extraventricular mechanisms considerably contribute to HFpEF pathophysiology Atrial factors left atrial abnormalities imparment of LA contractile and reservoir function right atrial abnormalities impaired chronotropic response of sinus node to exercise

3 Left atrial function The main purpose of LA is to modulate left ventricular filling reservoir stores blood during ventricular systole conduit passive chanel from PV into LV when MV open pump actively boosts LV filling at end-diastole Sagel PS, Anesthesiology 2003

4 LA booster instantaneously optimizes LV filling Atrial pressure boost LVEDP, mmhg controls r = 0,42 Pressure at the onset of A contraction Frank-Starling mechanism operates in LA sinus rhythm LV hypertrophy, normal EF mean LA pressure, mmhg In LVH, LVEDP >> mean LA pressure atrial fibrillation by 5-10 mmhg, thanks to LA boost LVEDP mean LA press. LVEDP mean LA press. AF onset - mean LA pressure, LVEDP (worse filling) cardiac output by 30% Braunwald E, Circ. 1961; 23:

5 LA contractile impairment in HFpEF LA contractility on exercise Increased LA volume discriminates HFpEF from asymptomatic H/LVH Reduced LA active emptying in HFpEF Decreased LA contractile reserve increased afterload (handgrip) Melenovsky V, JACC 2007; 49:

6 LA dysfunction and exercise intolerance in HFpEF Cardiopulmonary exercise testing (treadmill, Bruce protocol) LA function assessment at rest and during exercise (exercise echo with TDI), n=50, n=15, n=30 no difference in Am at rest, but diminished LA contractile reserve at exercise in HFpEF exercise LA systolic function predicts exercise capacity Tan YT, Heart 2010; 96:

7 LA function by speckle-tracking echocardiography HFpEF LA expansion Asymptomatic LVDD LA expansion LA systole LA systole LA function parameter HFpEF (n=119) asymptomatic LV DD (n=301) LA volume index > 24 m/m2 78% 20 % < total LAEF<50% / active LAEF<35% 31% / 26% 6% / 9% < p Low LA strain rate during LA systole LA systolic dysfunction Low LA strain rate during LA expansion LA diastolic dysfunction 65% 30% < % 1% < LA in HFpEF contraction - LA systolic dysfunction expansion - increased LA stiffness Morris DA, JASE 2011; 24:

8 Areas with decreased LA strain correspond to LA wall fibrosis LA strain velocity vector imaging MR imaging of LA Gd late-enhancement Kuppahally SS, Circ. Imaging 2010; 3:

9 Consequences of increased LA stiffness impairment of reservoir function Circulation model with high / low LA compliance pressure bumps in LA and PV large pressure V waves in PAWP tracings in the absence of mitral regurgitation - PAWP, pulmonary congestion - pulmonary vascular resistance - PV ectopy Mehta S, Am H J 1991; 122: reduced cardiac output less effective LV filling Suga H, Circ Res, 1974;35(1):39-43

10 Loss of LA function is more ominous in HFpEF than in HF EF CHARM program n=7599 pts with CHF with low or preserved (>40%) EF, candesartan / placebo, f-u: 28 mo. Hazard ratios of CV events according to EF and presence of AFib In HFpEF, AF was associated with almost 2x higher relative risk of most major CV outcomes, compared to HFrEF Olsson LG, JACC 2006; 47:

11 ... role of chronotropic incompetence

12 Heart rate response to exercise Maximal HR declines with age Chronotropic incompetence HR max < 80% of age-predicted HR max (220-age) or < 80% of heart rate reserve = observed HR change (max-rest) / predicted HR change Mortality according to achievement of target HR Tanaka H, JACC 2001 Chronotropic incompetence risk of coronary artery disease sudden cardiac death Framingham Heart Study Lauer MS, Circ. 1996

13 Chronotropic incompetence in HF is frequent (20-40% in general HF population) prevalence not affected by age or HF etiology, but mostly by the stage HF % 72% HF EF, n=278 CI: HR max < 80% predicted HR max 23% Jorde UP. Eur J of HF 2008, 10: in HFpEF, chronotropic incompetence affects 25-30% patients Brubaker PH, Circ. 2011; 123:

14 HR response limits exercise capacity in HFpEF Heart rate (bpm) Peak VO 2 ml/min/kg 25 Cardiac output Stroke Volume r=0.60 P= (ml/min) r=0.08 p= (ml) advanced HFpEF Con-LVH matched age, gender, Hy, DM, LVH, BMI; bicycle CPX study, radionucl. ventriculography physiologic increase in SV (and EDV) is only minimal Peak VO 2 ml/min/kg Heart Rate r=0.66 p< Con-LVH HFpEF CO response is strongly dependent on HR response atenuated HR response is a limiting factor of exercise capacity in HFpEF (bpm) s Borlaug B, Circulation 2006, 114:

15 Chronotropic incompetence in HFpEF healthy controls hypertensive cont. HFpEF no HR-afecting medication allowed Phan TT, Circ. Heart Fail. 2010; 3: 29-34

16 autonomic dysfunction abnormal vagal tone Mechanisms of CI in HF diminished sinus node responsiveness to norepinephrine Controls NYHA III NYHA I NYHA II NYHA IV β-receptor desensitisation and downregulation plasma norepinephrine (pg/ml) Colucci WS, Circ. 1989; 80:314-23

17 Mechanisms of CI in HF Medication (BB, digoxin, amiodarone) can contribute to CI Exercise heart rate reserve, % patients with HF EF, n=237 BB no BB Witte K, Heart 2006, 92: in mild HF: CI more frequent in BB+ patients in advanced HF: CI is more due to intrinsic sinus node disease

18 Sinus node disease Mechanisms of CI in HF CHF patients without SVTs and controls EP sudy of sinus node, CARTO activation map of RA Sinus node sinoatrial conduction, conduction heterogeneity in RA intrinsic sinus node rate, SN cell loss Fibrosis in sinus node and right atrium similar process that affect also LA rate-adaptive atrial pacing strategies might help Sanders P, Circ. 2004; 110:

19 Conclusions in HFpEF, onset of LA contractile dysfunction is responsible for transition from asymptomatic disease to clinical heart failure; Increased LA stiffness and impaired LA reservoir function may contribute to hemodynamic worsening and HF complications LA strain imaging or MRI may help to identify LA fibrosis Chronotropic incompetence is present in 1/3 of patients in HFpEF and contributes to exercise intolerance; rate-adaptive pacing may help To tackle all these atrial factors, fibrotic atrial remodelling should be targetted

20 Thank you for attention

21 HFpEF and betablockers OPTIMIZE-HF registry patients with CHF hospitalisation (aver. age 80y), without previous BB, BB therapy iniciated in 49%, 1y follow-up EF LK < 40% (n=3001) Betablocker therapy: HR 0.77 ( ) EF LK 40% (n=4153) Betablocker therapy: HR ( ) No effect of chronic BB therapy on mortality in HFpEF Hernandez AF, JACC 2009; 53:

22 AF is associated more with new-onset HFpEF than HFrEF Framingham Heart Study: Clinical characteristics at the first HF episode, comparison HFrEF vs HFpEF patients with AF at the day of HF onset, were 2.5 x likely to have preserved EF loss of LA systolic function, rather than tachycardia, is a precipitator specific for HFpEF Lee DS, Circ. 2009; 119:

23 In healthy older subjects, excercise cardiac output is maintained despite HR response BLSA study, 61 healthy volunteers (25-79years) HR EDV old old Rodeheffer RJ, Circ. 1984: 69: In healthy older subjects, increase in EDV (SV) during Ex. compensates for HR response Ex. response of stiff heart depends more on HR

24 In general population, advanced diastolic dysfunction is ~ 5x more frequent than symptomatic HFpEF (1-2%) Redfield MM, JAMA 2003; 289, Bursi F, JAMA 2006; 296: Extraventricular mechanisms likely contribute to HFpEF patophysiology Atrial factors left atrial abnormalities imparment of LA contractile and reservoir function right atrial abnormalities impaired chronotropic response of sinus node to exercise

25 What is chronotropic incompetence? HR max < 80% of age-predicted HR max (220-age) or < 80% of heart rate reserve (HRR) observed HR change (max rest) / predicted HR change (max-rest) Chronotropic incompetence mortality according to achievement of target HR risk of coronary disease and sudden death Framingham Heart Study Lauer, MS, Circ. 1996;93:

26 Maximal HR declines with age Heart rate response to exercise BLSA study, 61 healthy volunteers (25-79years) HR old Tanaka H, JACC 2001 EDV old Exercise CO response in healthy older subjects is maintained by: increasing EDV and stroke volume, that compensates diminished heart rate stiff hearts depend more on HR response Rodeheffer RJ, Circ. 1984: 69:203-13

27 LA enlargement = a marker of left-sided heart disease max LA volume (derived from A4C-A2C planimetry) is more informative than LA diameter in PLAX LA dilatation due to LA volume ovlerload - exercise - MiR - shunt LA pressure overload hypertension - AoS, MiS - heart failure - diastolic dysfunction In older subjects with normal EF, LA volume predicts HF LAVI > 40 ml/m 2 Tsang TS, AJC 2002; 90: severe diastolic dysfunction Takemoto Y, AJC 2005 LAVI > 32 ml/m 2-97% higher risk of HF