Rasmusson, Kismet

Abstract Background Multimorbidity and functional limitation are associated with poor outcomes in heart failure (HF). However, the individual and combined effect of these on health‐related quality of life in patients with HF is not well understood. Methods Patients aged ≥30 years with two or more HF diagnostic codes and one or more HF‐related prescription drugs from four U.S. institutions were mailed a survey to measure patient‐centric factors including functional status (activities of daily living [ADLs]) and health‐related quality of life (PROMIS‐29 Health Profile). Patients with HF from January 1, 2013 to February 1, 2018 were included. Multimorbidity was defined as ≥2 non‐cardiovascular comorbidities; functional limitation as any limitation in at least one of eight ADLs. Patients were categorized into four groups by multimorbidity (Yes/No) and functional limitation (Yes/No). We dichotomized the PROMIS‐29 sub‐scale scores at the median and calculated odd ratios for the four multimorbidity/functional limitation groups. Results A total of 3330 patients with HF returned the survey (response rate 31%); 3020 completed the questions of interest and were retained. Among these patients (45% female; mean age 73 [standard deviation: 12] years), 29% had neither multimorbidity nor functional limitation, 24% had multimorbidity only, 22% had functional limitation only, and 25% had both. After adjustment, having functional limitation only was associated with higher anxiety (odds ratio [OR]: 3.44, 95% confidence interval [CI]: 2.66–4.45), depression (OR: 3.11, 95% CI: 2.39–4.06), and fatigue (OR: 4.19, 95% CI: 3.25–5.40); worse sleep (OR: 2.14, 95% CI: 1.69–2.72) and pain (OR: 6.73, 95% CI: 5.15–8.78); and greater difficulty with social activities (OR: 9.40, 95% CI: 7.19–12.28) compared with having neither. Results were similar for having both multimorbidity and functional limitation. Conclusion Patients with only functional limitation have similar poor health‐related quality of life scores as those with both multimorbidity and functional limitation, underscoring the important role that physical functioning plays in the well‐being of patients with HF.

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.