Elkayam, Uri

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 In peripartum cardiomyopathy, the prevalence of focal myocardial damage detected by late gadolinium enhancement ( LGE ) cardiovascular magnetic resonance is important to elucidate mechanisms of myocardial injury and cardiac dysfunction. LGE equates irreversible myocardial injury, but LGE prevalence in peripartum cardiomyopathy is uncertain. Methods and Results Among 100 women enrolled within the Investigations of Pregnancy Associated Cardiomyopathy cohort, we recruited 40 women at 13 centers to undergo LGE cardiovascular magnetic resonance, enrolled within the first 13 weeks postpartum. Follow‐up scans occurred at 6 months postpartum, and death/transplant rates at 12 months. Baseline characteristics did not differ significantly in the parent cohort according to cardiovascular magnetic resonance enrollment except for mechanical circulatory support. LGE was noted only in 2 women (5%) at baseline. While left ventricular dysfunction with enlargement was prevalent at baseline cardiovascular magnetic resonance scans (eg, ejection fraction 38% [Q1–Q3 31–50%], end diastolic volume index=108 mL/m 2 [Q1–Q3 83–134 mL/m 2 ]), most women demonstrated significant improvements at 6 months, consistent with a low prevalence of LGE . LGE was not related to baseline clinical variables, ejection fraction, New York Heart Association heart failure class, or mortality. Neither of the 2 women who died exhibited LGE . LGE was inversely associated with persistent left ventricular ejection fraction at 6 months ( P =0.006). Conclusions Factors other than focal myocardial damage detectable by LGE explain the initial transient depressions in baseline left ventricular ejection fraction, yet focal myocardial damage may contribute to persistent myocardial dysfunction and hinder recovery in a small minority. Most women exhibit favorable changes in ventricular function over 6 months. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01085955.

Attenuation of endothelial-dependent coronary vasodilation has been reported in idiopathic dilated cardiomyopathy and anatomically normal coronaries; however, data are insufficient for understanding the incidence and extent of this finding. The response of conductance and resistance coronary arteries to endothelial stimulation with acetylcholine was examined in 25 patients. Coronary blood flow had a variable response to acetylcholine and suggested coronary endothelial dysfunction in approximately half of the patients. Abnormal endothelial dysfunction involved the large conductance epicardial coronary arteries and the small resistance vessels. Abnormal endothelial response of coronary blood flow to acetylcholine could not be predicted by demographic and hemodynamic data. Conclusions: Coronary artery endothelial function is heterogeneous in patients with idiopathic dilated cardiomyopathy. Endothelial dysfunction is present in approximately half of the cases and involves both resistance as well as conductance coronary blood vessels. Furthermore, coronary endothelial function cannot be predicted by demographic and hemo-dynamic parameters or left ventricular ejection fraction.