Sheppard, Richard

Introduction: IL2 soluble receptor (IL2Rs) and neopterin (NPT) are peripheral markers of T cell and monocyte activation investigated extensively in auto-immune disorders. We assessed these biomarkers in subjects with non ischemic cardiomyopathy of recent onset (ROCM) from the IMAC2 (Intervention in Myocarditis and Acute Cardiomyopathy) registry. We compared the degree of cellular activation in peripartum cardiomyopathy (PPCM) with that evident in non-peripartum women and men with ROCM. Methods: 130 subjects were investigated: 96 subjects with ROCM including 37 women with PPCM (group 3), 27 non-peripartum women (group 2) and 32 men (group 1), and 34 controls without cardiac disease (CTL). All subjects with ROCM had serum obtained at entry and an assessment of LVEF by transthoracic echocardiography. LVEF was reassessed 6 months after enrollment. Results: The ROCM cohort (n=96, 64F/32M, mean age 30±6) had a mean LVEF at baseline of 0.24±0.08 which increased to 0.43±0.13 at 6 months. For controls (mean age 45±6, 24F/10M) the mean LVEF was 0.58±0.10. Both IL2Rs and NPT were markedly elevated in ROCM subjects compared to controls (IL2Rs: ROCM=1411±671, CTL=970±329 pg/ml, p<0.001; NPT: ROCM=9.2±5.6, CTL=6.2±3.1 nmol/l, p=0.003). Increased NYHA class was associated with higher serum levels for both NPT (p=0.013) and IL2Rs (p=0.009). No differences were evident in subjects with PPCM versus men and women with ROCM for either IL2Rs (group 1/2/3 =1524±504/1531±904/1225±566 pg/ml, p=0.10) or NPT (group 1/2/3=9.4±6.5 /9.3±5.8 /8.9±4.7 nmol/l, p=0.92). IL2Rs levels were lower in black subjects: blacks (n=25) IL2Rs=1123±496; whites (n=71) 1513±698, p=0.012. Levels of IL2Rs and NPT did not predict the degree of recovery at 6 months, although there was a nonsignificant trend towards more recovery with lower IL2Rs levels. Conclusions: Marked elevation of IL2Rs and NPT, biomarkers of cellular immune activation, are evident in subjects with ROMC. The degree of activation in subjects with PPCM appears similar to that seen in men and non-peripartum women with ROCM, suggesting similar inflammatory pathogenesis for these syndromes of acute heart failure. The relationship of cellular activation to myocardial injury and recovery in ROCM should be further investigated.

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.

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.