Mather, Paul

Peripartum cardiomyopathy (PPCM) is an idiopathic form of pregnancy-induced heart failure associated with preeclampsia. Circulating factors in late pregnancy are thought to contribute to both diseases, suggesting a common underlying pathophysiological process. However, what drives this process remains unclear. Using serum proteomics, we identified the senescence-associated secretory phenotype (SASP), a marker of cellular senescence associated with biological aging, as the most highly up-regulated pathway in young women with PPCM or preeclampsia. Placentas from women with preeclampsia displayed multiple markers of amplified senescence and tissue aging, as well as overall increased gene expression of 28 circulating proteins that contributed to SASP pathway enrichment in serum samples from patients with preeclampsia or PPCM. The most highly expressed placental SASP factor, activin A, was associated with cardiac dysfunction or heart failure severity in women with preeclampsia or PPCM. In a murine model of PPCM induced by cardiomyocyte-specific deletion of the gene encoding peroxisome proliferator–activated receptor γ coactivator-1α, inhibiting activin A signaling in the early postpartum period with a monoclonal antibody to the activin type II receptor improved heart function. In addition, attenuating placental senescence with the senolytic compound fisetin in late pregnancy improved cardiac function in these animals. These findings link senescence biology to cardiac dysfunction in pregnancy and help to elucidate the pathogenesis underlying cardiovascular diseases of pregnancy.

Introduction and hypothesis: Recent data have indicated an increase in the rate of early, confirmed pump thrombosis of the HeartMate II (HMII) left ventricular assist device. Factors related to this increase were not known, but one of the hypotheses was change in clinical management over time. The PREVENT ( PREVEN tion of Heartmate II Pump T hrombosis through Clinical Management) study was designed to evaluate the impact of clinical practices developed to reduce the risk of HMII pump thrombosis. Methods: PREVENT is a prospective, multi-center, single-arm, non-randomized study of up to 300 patients at up to 25 sites. Patient and pump management, including implant technique, anticoagulation, and pump settings are guided by protocol (Table 1). Primary endpoint is incidence of confirmed pump thrombosis at 3 months, with a total follow-up of 6 months. Presented here are the preliminary results from the first 100 subjects enrolled. Results: Median age was 61 years [25-79], 87% were male, and 79% were destination therapy. At implant, 9% were in INTERMACS Profile1, 68% Profiles 2-3, and 22% Profiles 4-7. Preliminary analysis of 90-day outcomes demonstrated an incidence of 1% for confirmed and 2% for suspected thrombosis with a 38% incidence of INTERMACS-defined bleeding. Adherence to the protocol recommendations was as follows: 91% of the pumps were anchored, 97% of the patients were bridged with heparin, median pump speed at 1 month was 9190 [range: 8400-10000], with 93% of the patients having a pump speed > 8600, and 78% of the patients having pump speeds > 9000. Median INR per patient was 2.2 [IQR: 2.0-2.4]. Overall Kaplan-Meier survival was 93%. Conclusions: Preliminary results are encouraging and suggest good adherence to the PREVENT protocol and low rates of pump thrombosis without a resultant increase in bleeding complications. Overall survival after HM II implantation remains excellent.

Background— Peripartum cardiomyopathy has variable disease progression and left ventricular (LV) recovery. We hypothesized that baseline right ventricular (RV) size and function are associated with LV recovery and outcome. Methods and Results— Investigations of Pregnancy-Associated Cardiomyopathy was a prospective 30-center study of 100 peripartum cardiomyopathy women with LV ejection fraction (LVEF) <45% within 13 weeks after delivery. Baseline RV function was assessed by echocardiographic end-diastolic area, end-systolic area, fractional area change, tricuspid annular plane excursion, and RV speckle-tracking longitudinal strain. LV recovery was defined as LVEF of ≥50% at 1 year, persistent severe LV dysfunction as LVEF of ≤35%, and major events as death, transplant, or LV assist device implantation. RV measurements were feasible for 90 of the 96 patients (94%) with echocardiograms available. Mean baseline LVEF was 36±9%. RV fractional area change was <35% in 38% of patients. Of 84 patients with 1-year follow-up data, 63 (75%) had LV recovery and 11 (13%) had LVEF of ≤35% or a major event (4 LV assist devices and 2 deaths). Tricuspid annular plane excursion and RV strain did not predict outcome. Baseline RV fractional area change by multivariable analysis was independently associated with subsequent LV recovery and clinical outcome. Conclusions— Peripartum cardiomyopathy patients had a high incidence of LV recovery, but a significant minority had persistent LV dysfunction or a major clinical event by 1 year. RV function per echocardiographic fractional area change at presentation was associated with subsequent LV recovery and clinical outcomes and thus is prognostically important.