PCN RESEARCH OVERVIEW

Peripartum Cardiomyopathy Network (PCN): Research and the IPAC study

The Peripartum Cardiomyopathy Network (PCN), was established in 2009 as a multi-center network of 30 sites across North America dedicated to clinical care of women with peripartum cardiomyopathy (PPCM) and the development of research designed to investigate the disorder and determine the best treatments to improve outcomes. The network completed the previous Investigation of Pregnancy Associated Cardiomyopathy (IPAC) study, which evaluated the clinical and biologic predictors of in a cardiac recovery for women newly diagnosed with PPCM. The co-directors of the Peripartum Cardiomyopathy Network for IPAC were Dr. Dennis McNamara, Principal Investigator of the IPAC and Dr. James D. Fett, former medical director of the Albert Schweitzer Hospital in Haiti and a leader internationally in clinical investigations in peripartum cardiomyopathy for more than two decades.

The PCN network consists of physicians, nurse practitioners, and nurses dedicated to caring for women with peripartum cardiomyopathy. While the IPAC study was supported by the National Heart Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH), the network itself is not fiscally supported by any agency but the members are connected by a commitment to improving care for women with PPCM.

Understanding PPCM and the Results from IPAC:

The PCN enrolled 100 women at 30 sites over two years and completed follow up for the IPAC study in September of 2013. This study investigated clinical, demographic, biomarker and genetic predictors of outcomes for women with PPCM. Since 2015 the IPAC study has resulted in 12 publications from 11 different first authors representing 7 different institutions.

Race and Outcomes:

It has long been realized that Black women are at greater risk of PPCM, and that their clinical outcomes are poor. The initial publication of clinical outcomes in IPAC evaluated the impact of race on outcomes in PPCM (McNamara, 2015). Black women made up 30% of the IPAC cohort and presented with more severe cardiomyopathy, and had less recovery of cardiac function than White women in subsequent follow up. The reason for this difference remains unknown, however Black women also presented much later than non-Black women, suggesting that access to care may contribute to the poorer outcomes in Black women.

Genetics

Investigators continue to evaluate whether genetic background contributes to the risk of PPCM and how genetics impacts the potential for recovery. Several studies from IPAC addressed the role of genetics in PPCM. Dr. Zoltan Arany of the University of Pennsylvania addressed how mutations of a gene called titin (TTN) important in cardiac function may increase the risk of PPCM in a cohort of over 170 women including the women in IPAC (Ware, 2016). Ten percent of women with PPCM in this study had mutations in titin nearly 10 times greater than the general population. Dr Arany demonstrated in a subsequent study that while titin mutations increased the risk of this disorder, women with titin mutations were just as likely to recover (Goli, 2021). In a separate analysis, Dr. Richard Sheppard from McGill University reported that a variant of a gene important in blood pressure regulation (GNB3) more common in Black was associated with less recovery in the IPAC cohort regardless of race (Sheppard, 2016).

Biomarkers:

The analysis of biomarkers provides clues to the development of PPCM. In an investigation from IPAC of the impact of vascular biomarkers Dr. Julie Damp of Vanderbilt University reported that elevations in sFlt1, a biomarker previously linked to preeclampsia, were associated with poor outcomes in IPAC (Damp, 2016). In contrast, elevation in a naturally occurring hormone, relaxin, appeared to be protective. Subsequent reports have also addressed the role of systemic inflammation in determining the overall severity of PPCM including both studies of cellular activation (McTiernan, 2018) and the cytokine response (Koczo, 2021). Maternal obesity in IPAC was associated with less recovery of cardiac function, potentially mediated though a hormone leptin secreted by adipose cells and associated with an increased risk of heart failure(Davis, 2018).

Clinical Testing and Predicting Outcomes:

IPAC has provided the opportunity to evaluate innovative ways to use routine clinical testing. Most women with PPCM are evaluated and followed by echocardiograms which addresses the severity of the cardiomyopathy by assessment of the left ventricular ejection fraction (LVEF), and the degree of cardiac enlargement or remodeling. In addition, the prognostic information provided by echo can be increased through assessment of right ventricular function (Blauwet, 2016), and Global Longitudinal Strain (Sugahara, 2019). Cardiac magnetic resonance imaging (cMR) plays an increasing role in evaluation of omen with PPCM. Reports from IPAC suggest that signs of cardiac inflammation or scarring are surprisingly uncommon in women presenting with PPCM (Schelbert, 2017). Even routine electrocardiograms (ECG) can provide additional prognostic information (Honigberg, 2019).

Breastfeeding:

Due to concerns that elevations in the hormone prolactin necessary for breastfeeding may contribute to the development of PPCM, whether breastfeeding itself will adversely impact recovery from PPCM remains controversial. In the IPAC study, 15% of women continued to breastfeed and there was no evidence that this impacted recovery. (Koczo, 2019). For women with PPCM who are well compensated, it appears that breastfeeding is safe and presented no hazards to their eventual cardiac recovery.

Peripartum Cardiomyopathy Network (PCN) for Clinical care and Clinical Research:

PCN is first and foremost a network of physicians, nurses, and nurse practitioners dedicated to caring for women with PPCM. Clinical research has plays an important role in determining how to improve care in the future, and given the rare nature of this disorder the collaboration of the multiple sites of the PCN has been essential aspect in this goal The productivity of the IPAC during IPAC, the first multicenter prospective study of PPCM in North America, demonstrates the potential power of this collaborative network to address important issues in the pathogenesis of PPCM and subsequent therapy.

References of IPAC publications

  1. McNamara DM, Elkayam U, Alharethi R, et al for the IPAC Investigators. Clinical Outcomes for Peripartum Cardiomyopathy in North America: Results of the Investigations of Pregnancy Associated Cardiomyopathy (IPAC) study. JACC, 2015;66:905-14.
  2. Ware JS, Li, J, Mazaika E, Yasso CM, et al for the IMAC and IPAC Investigators. Shared Genetic Etiology of Peripartum and Dilated Cardiomyopathies. New England Journal of Medicine, 2016 Jan 21;374(3):233-41. (*contributed equally to the work.)
  3. Sheppard R, Hsich E, Damp J, et al for the IPAC Investigators. GNB3 C825T Polymorphism and Myocardial Recovery in Peripartum Cardiomyopathy: Results of the Multicenter Investigations of Pregnancy-Associated Cardiomyopathy Study. Circ Heart Fail. 2016 Mar;9(3):e002683. [Epub ahead of print]
  4. Damp J, Givertz MM, Semigran M, et al for the IPAC Investigators. Relaxin-2 and Soluble Flt1 Levels in Peripartum Cardiomyopathy: Results of the Multicenter IPAC Study. JACC Heart Fail. 2016 May;4(5):380-8.
  5. Blauwet LA, Delgado-Montero A, Ryo K et al for IPAC Investigators. Right Ventricular Function in Peripartum Cardiomyopathy at Presentation Is Associated With Subsequent Left Ventricular Recovery and Clinical Outcomes. Circ Heart Fail. 2016 May;9(5).
  6. Schelbert EB, Elkayam U, Cooper LT, et al for the Investigations of Pregnancy Associated Cardiomyopathy (IPAC) Investigators. Myocardial Damage Detected by Late Gadolinium Enhancement Cardiac Magnetic Resonance Is Uncommon in Peripartum Cardiomyopathy. J Am Heart Assoc. 2017 Apr 3;6(4). pii: e005472. doi: 10.1161/JAHA.117.005472.
  7. McTiernan CF, Morel P, Cooper LT, et al for the IPAC Investigators. Circulating T Cell Subsets, Monocytes, and Natural Killer Cells in Peripartum Cardiomyopathy: Results From the Multicenter IPAC Study. J Card Fail. 2018 Jan;24(1):33-42.
  8. Davis EM, Ewald G, Givertz MM, et al for the IPAC Investigators. Maternal Obesity Affects Cardiac Remodeling and Recovery in Women with Peripartum Cardiomyopathy. Am J Perinatol. 2018 Sep 5. doi: 10.1055/s-0038-1669439.
  9. Honigberg MC, Elkayam U, Rajagopalan N, et al for the IPAC Investigators. Electrocardiographic findings in peripartum cardiomyopathy. Clin Cardiol. 2019 May;42(5):524-529. doi: 10.1002/clc.23171. Epub 2019 Mar 29.
  10. Koczo A, Marino A, Jeyabalan A, et al for the IPAC Investigators. Breastfeeding, Cellular Immune Activation and Myocardial Recovery in Peripartum Cardiomyopathy (PPCM). J Am Coll Cardiol -Basic Translational Science. 2019 Jun 24;4(3):291-300.
  11. Sugahara M, Kagiyama N, Hasselberg NE, Blauwet LA, Briller J, Cooper L, Fett JD, Hsich E, Wells G, McNamara D, Gorcsan J 3rd; IPAC Investigators. Global Left Ventricular Strain at Presentation Is Associated with Subsequent Recovery in Patients with Peripartum Cardiomyopathy. J Am Soc Echocardiography. 2019 Sep 25. pii: S0894-7317(19)30876-4. doi: 10.1016/j.echo.2019.07.018. [Epub ahead of print]
  12. Koczo A, Marino A, Rocco J, Ewald G, Givertz MM, Rajagopalan N, Bozkurt B, Elkayam U, Cooper LT, Fett J, McTiernan CF, Morel PA, Hanley-Yanez K, McNamara DM; IPAC Investigators. Proinflammatory TH17 cytokine activation, disease severity and outcomes in peripartum cardiomyopathy. Int J Cardiol. 2021 Sep 15;339:93-98. doi: 10.1016/j.ijcard.2021.06.022. Epub 2021 Jul
  13. Goli R, Li J, Brandimarto J, Levine LD, Riis V, McAfee Q, DePalma S, Haghighi A, Seidman JG, Seidman CE, Jacoby D, Macones G, Judge DP, Rana S, Margulies KB, Cappola TP, Alharethi R, Damp J, Hsich E, Elkayam U, Sheppard R, Alexis JD, Boehmer J, Kamiya C, Gustafsson F, Damm P, Ersbøll AS, Goland S, Hilfiker-Kleiner D, McNamara DM; IMAC-2 and IPAC Investigators; Arany Z. Genetic and Phenotypic Landscape of Peripartum Cardiomyopathy. Circulation. 2021 May 11;143(19):1852-1862. doi: 10.1161/CIRCULATIONAHA.120.052395. Epub 2021 Apr 20.

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