Molecular mechanisms of peripartum cardiomyopathy: A vascular/hormonal hypothesis

Bello, Natalie A.; Arany, Zoltàn

doi:10.1016/j.tcm.2015.01.004

Cited by 71 publications

(47 citation statements)

References 54 publications

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“…4,5,30,31 What predisposes the development of this disease in only a small subgroup of women in this context remains unclear. We identified a potential genetic predisposition to peripartum cardiomyopathy in approximately 15% of women in our study, owing to truncating variants primarily affecting TTN .…”

Section: Discussionmentioning

confidence: 99%

Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies

et al. 2016

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BACKGROUND Peripartum cardiomyopathy shares some clinical features with idiopathic dilated cardiomyopathy, a disorder caused by mutations in more than 40 genes, including TTN, which encodes the sarcomere protein titin. METHODS In 172 women with peripartum cardiomyopathy, we sequenced 43 genes with variants that have been associated with dilated cardiomyopathy. We compared the prevalence of different variant types (nonsense, frameshift, and splicing) in these women with the prevalence of such variants in persons with dilated cardiomyopathy and with population controls. RESULTS We identified 26 distinct, rare truncating variants in eight genes among women with peripartum cardiomyopathy. The prevalence of truncating variants (26 in 172 [15%]) was significantly higher than that in a reference population of 60,706 persons (4.7%, P = 1.3×10−7) but was similar to that in a cohort of patients with dilated cardiomyopathy (55 of 332 patients [17%], P = 0.81). Two thirds of identified truncating variants were in TTN, as seen in 10% of the patients and in 1.4% of the reference population (P = 2.7×10−10); almost all TTN variants were located in the titin A-band. Seven of the TTN truncating variants were previously reported in patients with idiopathic dilated cardiomyopathy. In a clinically well-characterized cohort of 83 women with peripartum cardiomyopathy, the presence of TTN truncating variants was significantly correlated with a lower ejection fraction at 1-year follow-up (P = 0.005). CONCLUSIONS The distribution of truncating variants in a large series of women with peripartum cardiomyopathy was remarkably similar to that found in patients with idiopathic dilated cardiomyopathy. TTN truncating variants were the most prevalent genetic predisposition in each disorder.

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Section: Discussionmentioning

confidence: 99%

Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies

et al. 2016

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“…For example, peripartum cardiomyopathy (PPCM), diagnosed by the onset of heart failure in late gestation or immediately postpartum, is a disease of unknown etiology 35, 36 . One model for PPCM is the cardiac PPARγ coactivator (PGC)-1α-null mouse, which develops heart failure during late pregnancy and has vascular insufficiency and metabolic deficiency.…”

Section: Discussionmentioning

confidence: 99%

PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy

Liu

Rowe

Yang

et al. 2017

Circulation Research

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Rationale Pregnancy profoundly alters maternal physiology. The heart hypertrophies during pregnancy, but its metabolic adaptations are not well understood. Objective To determine the mechanisms underlying cardiac substrate use during pregnancy. Methods and Results We use here 13C-glucose, 13C-lactate, and 13C-fatty acid tracing analyses to show that hearts in late pregnant mice increase fatty acid uptake and oxidation into the tricarboxylic acid (TCA) cycle, while reducing glucose and lactate oxidation. Mitochondrial quantity, morphology, and function do not appear altered. Insulin signaling appears intact, and the abundance and localization of the major fatty acid and glucose transporters, CD36 and GLUT4, are also unchanged. Rather, we find that the pregnancy hormone progesterone induces pyruvate dehydrogenase kinase (PDK)-4 in cardiomyocytes, and that elevated PDK4 levels in late pregnancy lead to inhibition of pyruvate dehydrogenase (PDH) and pyruvate flux into the TCA cycle. Blocking PDK4 reverses the metabolic changes seen in hearts in late pregnancy. Conclusions Taken together, these data indicate that the hormonal environment of late pregnancy promotes metabolic remodeling in the heart at the level of PDH, rather than at the level of insulin signaling.

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“…4 This 16-kDa prolactin upregulates miR-146a and exerts a toxic effect on the endothelium and on cardiomyocytes and together with a soluble sFlt1, which decreases the proangiogenic VEGF and placental growth factor levels, lead to impaired vascular and cardiac function and subsequently heart failure in late pregnancy and postpartum. [5][6][7][8] The prolactin hypothesis has been developed from studies on mice. Treatment of STAT3 cardiac knockout mice with bromocriptine thus blocked prolactin production in these 20 reported the largest series in which Cathepsin D has been measured.…”

Section: Angiogenic Imbalance In Post-ppcm Women With LV Recoverymentioning

confidence: 99%

“…5,6 Recently, the 2-hit hypothesis was proposed: one hit is the late-gestational hormonal changes with vasotoxic effects, including sFlt1 and prolactin, and the second hit is a predisposed inability to resist this insult in some women, probably because of some baseline altered endothelial function. 7,8 In addition, a progressive increase in the number of circulating endothelial progenitor cells (EPCs) during pregnancy in healthy women has been found in most studies, 9,10 but no data exist on women with PPCM.…”

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confidence: 99%

Angiogenic Imbalance and Residual Myocardial Injury in Recovered Peripartum Cardiomyopathy Patients

Goland

Weinstein

Zalik

et al. 2016

Circ: Heart Failure

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Background-Recent studies suggest that angiogenic imbalance during pregnancy may lead to acute peripartum cardiomyopathy (PPCM). We propose that angiogenic imbalance and residual cardiac dysfunction may exist even after recovery from PPCM. Methods and Results-Twenty-nine women at least 12 months after presentation with PPCM, who exhibited recovery of left ventricular (LV) ejection fraction (≥50%), were included in the study (mean age 35±6 years, LV ejection fraction 61.0±3.9%). The number of circulating endothelial progenitor cells (EPCs) and plasma levels of proangiogenic vascular endothelial growth factor and of soluble vascular endothelial growth factor receptor Flt1 (sFlt1) Conclusions-Higher concentration of sFlt1 with concomitant decreased circulating endothelial progenitor cell levels along with inappropriate attenuated vascular endothelial growth factor levels may imply an angiogenic imbalance that exists even after recovery and may thus predispose to PPCM. In addition, tissue Doppler imaging and 2D strain were able to identify residual myocardial injury in post-PPCM women with apparent recovery of LV systolic function. Both angiogenic imbalance and residual myocardial injury may play an important role in the recurrence of LV dysfunction during subsequent pregnancies. (Circ Heart Fail. 2016;9:e003349.

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Molecular mechanisms of peripartum cardiomyopathy: A vascular/hormonal hypothesis

Cited by 71 publications

References 54 publications

Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies

Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies

PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy

Angiogenic Imbalance and Residual Myocardial Injury in Recovered Peripartum Cardiomyopathy Patients

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