Angiogenic imbalance and residual myocardial dysfunction in women with Peripartum Cardiomyopathy and left ventricular function recovery

Transcription

1 Angiogenic imbalance and residual myocardial dysfunction in women with Peripartum Cardiomyopathy and left ventricular function recovery Sorel Goland¹, Adi Zalik¹, Jan Mark Weinstein³, Liaz Zilberman¹, Rafael Kupershtein², Michael Arad²,Tuvia Ben Gal*, Jacob George¹ ¹Kaplan Medical Center, Rehovot ²Sheba Medical Center, ³Soroka Medical Center, *Rabin Medical center, Israel

2 Peripartum Cardiomyopathy (PPCM) Occurs toward the end of pregnancy or in the first postpartum months in previously healthy women. Heart failure due to LV systolic dysfunction (LVEF<45%) Recent research suggests that PPCM is a vascular disease, triggered by late-gestational hormonal changes Elkayam U. J Am Coll Cardiol. 2011; 58: Bello NA, Arany Z. Trends Cardiovasc Med Hilfiker-Kleiner D et al.cell. 2007;128: Patten IS et al. Nature. 2012;485:

3 Two-hit hypothesis : a new concept of pathophysiology of PPCM 1. A predisposed inability to resist this insult in some women (genetic predisposition? some baseline altered endothelial function?) 2. The late-gestational hormonal changes with vasotoxic effects, including sflt1 and prolactin ('angiogenic imbalance' ) Bello NA, Arany Z. Trends Cardiovasc Med. 2015;25:

4 LV function recovery (LVEF 50%) in PPCM The rates of LV recovery differ among the studies ~ 50% recovery of LV function in the US ~70% in the IPAC registry ~35% in South Africa, Haiti and Turkey Worsening of LV function during subsequent pregnancy (SSP) can occur in 20% Rare cases of spontaneous deterioration of LV function Goland S, Elkayam U. J Card Fail. 2011; 17: Fett JD et al Int J Gynaecol Obstet. 2009;104: Blauwet LA et al. Heart. 2013;99(5): McNamara D et al. J Am Coll Cardiol. 2015;66(8):

5 What are the possible reasons for deterioration of LV function Is our definition of LV recovery inappropriate? Should we use a cut-off of 55% or 60% for complete recovery? Should we use Dobutamine stress echo? The lack of contractile reserve on DSE has been showed to predict recurrence of LV dysfunction in SSP Can we use better echo techniques? Two recent developments enable a more accurate assessment of cardiac function: tissue Doppler imaging and myocardial strain are sensitive to assess subtle changes in the myocardium Lampert MB et al, AJOG 1997 ;176: Fett JD World J Cardiol. 2014; 26; 6(3):

6 Hypothesis Recent studies suggest that angiogenic imbalance during pregnancy may lead to acute PPCM We propose that angiogenic imbalance and residual cardiac dysfunction may exist even after recovery from PPCM.

7 Aim To evaluate plasma concentrations of proand anti-angiogenic factors in post-ppcm women with LV recovery To assess possible residual myocardial dysfunction using sensitive echo techniques

8 Potential contributing factors to possible residual 'angiogenic imbalance' Pro-angiogenic vascular endothelial growth factor (VEGF) plays a key role in circulating endothelial progenitor cells (EPC s) recruitment, enhancing mobilization EPCs play a critical role in endothelial homeostasis with ability to repair endothelial injury. An anti-angiogenic factor sflt-1 (mostly released by placenta) neutralizes circulating VEGF Flt1 is elevated PPCM, pre-eclampsia, atherosclerosis, CKD, DM, ANCA-associated vasculitis

9 Methods Post- PPCM women with LV recovery ( 50%) at least 12 months after clinical presentation Plasma levels VEGF and sflt1 were measured using ELISA (enzyme-linked immunosorbent assay). The number of circulating endothelial progenitor cells (EPCs) (CD34+ and CD34/KDR+) were quantified by flow cytometry All patients underwent comprehensive cardiac function assessment including TDI and 2D strain echocardiography All measures where compared to age-,parity- and time- (from last pregnancy) matched controls Stress echo was planned to assess normal LV response to exercise

10 Results 41 women post-ppcm 29 pts with LV function recovery and appropriate echo quality were included mean age 29±7 years LVEF 61.0±3.9% follow-up (mean 32 months, months) 20 pts underwent stress echo and showed good LV contractile response (increase 5% LVEF)

11 Clinical characteristics of PPCM patients at the time of diagnosis The mean LVEF at diagnosis of PPCM 33.2±11.1%. Diagnosis postpartum in 77%. Mean parity was 2.3±1.2 Twin pregnancies 15%. Gestational hypertension 17% Pre-eclampsia 17%

12 Results: comparison of echo measurements between the post-ppcm and control groups Post- PPCM Matched controls EF (%) 61.0± ± LVEDd (mm) 45.1± ± LA area (cm2) 15.6± ± PAP (mm Hg) 22.8± ± E (cm/sec) 74.5± ± DT (sec) 179.8± ± E' septal (cm/sec) 9.9± ± S septal 7.6± ± S RV 11.4± ±

13 Results: comparison 2D strain values between the post-ppcm and control groups LG Strain% Apical circ Strain%

14 Results: comparison of sflt1 and VEGF between the post-ppcm and control groups Flt1 VEGF/Flt1 VEGF

15 Results: comparison of EPC s (CD34+/KDR+) between the post PPCM and control groups Box plots of Ln-CD34+/KDR+ of PPCM and control groups. The band at the middle of each box plot represents the median, the bottom and top of the boxes represent the 25th and 75th percentiles

16 Summary A higher concentration of sflt1 with attenuated production of VEGF along with concomitant decrease in circulating EPCs in post-ppcm women suggesting that 'angiogenic imbalance' exists even after recovery from PPCM. TDI and 2D strain were able to identify residual myocardial injury in post-ppcm women with apparent recovery of LV systolic function.

17 Conclusions Both 'angiogenic imbalance' and residual myocardial injury may play an important role in the recurrence of LV dysfunction during SSP Our finding of altered endothelial function, especially increased sflt1, which persists even after recovery from PPCM, may potentially offer an opportunity to identify women prone to develop relapse in SSP and are at risk for cardiovascular events in the future. Our results have to be tested in a larger population of post-ppcm women.

18 Limitations The main of our study is a small number of patients; however, taking in account the rarity of the disease, our numbers are similar to many studies on PPCM. Despite the relatively small number of patients, we had optimally matched controls and underwent comprehensive echocardiographic assessment. The delay in time from the presentation to the study recruitment (1-5 years), however, no pts had SPP after PPCM

19 Thank you!

20 Results: comparison of endothelial function measures between the post PPCM and control groups