Kociol, Robb D.

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— Congestion is a primary driver of symptoms in patients with acute heart failure, and relief of congestion is a critical goal of therapy. Monitoring of response to therapy through the assessment of daily weights and net fluid loss is the current standard of care, yet the relationship between commonly used markers of decongestion and both patient reported symptom relief and clinical outcomes are unknown. Methods and Results— We performed a retrospective analysis of the randomized clinical trial, Diuretic Optimization Strategy Evaluation in Acute Heart Failure (DOSE-AHF), enrolling patients hospitalized with a diagnosis of acute decompensated heart failure. We assessed the relationship among 3 markers of decongestion at 72 hours—weight loss, net fluid loss, and percent reduction in serum N terminal B-type natriuretic peptide (NT-proBNP) level—and relief of symptoms as defined by the dyspnea visual analog scale area under the curve. We also determined the relationship between each marker of decongestion and 60-day clinical outcomes defined as time to death, first rehospitalization or emergency department visit. Mean age was 66 years, mean ejection fraction was 35%, and 27% had ejection fraction ≥50%. Of the 3 measures of decongestion assessed, only percent reduction in NT-proBNP was significantly associated with symptom relief ( r =0.13; P =0.04). There was no correlation between either weight loss or net fluid loss and symptom relief, ( r =0.04; P =0.54 and r =0.07; P =0.27, respectively). Favorable changes in each of the 3 markers of decongestion were associated with improvement in time to death, rehospitalization, or emergency department visit at 60 days (weight: hazard ratio, 0.91; 95% confidence interval, 0.85–0.97 per 4 lbs; weight lost; fluid hazard ratio, 0.94; 95% confidence interval, 0.90–0.99 per 1000 mL fluid loss; NT-proBNP hazard ratio, 0.95; 95% confidence interval, 0.91–0.99 per 10% reduction). These associations were unchanged after multivariable adjustment with the exception that percent reduction in NT-proBNP was no longer a significant predictor (hazard ratio, 0.97; 95% confidence interval, 0.93–1.02). The rates of death, HF hospitalization, or emergency department visit at 60 days for patients with 0, 1, 2, and 3 markers of decongestion (above the median) were 67%, 64%, 46%, and 38%, respectively (log rank P value=0.05). Figure. Relationship between number of markers of decongestion above median* and time to 60-day risk of emergency department (ED) visit, rehospitalization, or death. *Median net fluid loss, 3.8 L; median net weight loss, 6.5 lbs; median percent reduction in N terminal B-type natriuretic peptide 24.3%. Conclusions— Weight loss, fluid loss, and NT-proBNP reduction at 72 hours are poorly correlated with dyspnea relief. However, favorable improvements in each of the 3 markers were associated with improved clinical outcomes at 60 days. These data suggest the need for ongoing research to understand the relationships among symptom relief, congestion, and outcomes in patients with acute decompensated heart failure. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00577135.