PERIPARTUM CARDIOMYOPATHY PPCM

1

• PERIPARTUM CARDIOMYOPATHY (PPCM)

2
Is there a Diagnostic Role for Plasma High
Sensitivity C-Reactive Protein in Peripartum
Cardiomyopathy (PPCM)?

• JAMES D. FETT, MD, MPHDepartment of Adult
  Medicine, Hôpital Albert Schweitzer,
  Deschapelles, Haiti
• J. BRUCE SUNDSTROM, PhD
• Department of Pathology Laboratory Medicine,
  Emory University School of Medicine, Atlanta, GA,
  USA
• AFTAB A. ANSARI, PhD
• Department of Pathology Laboratory Medicine,
  Emory University School of Medicine, Atlanta, GA,
  USA
• (No conflicts of interest or disclosures to
  declare)

3
Background/Introduction

• A high incidence of PPCM is found in the
  Artibonite River Valley of Haiti with 1 case of
  PPCM per 300 to 400 live births compared to USA
  incidence of 1 case per 3000 to 4000 live births.
  Fett, et al. Peripartum Cardiomyopathy in the
  Hospital Albert Schweitzer District of Haiti. Am
  J Obstet Gynecol 2002186-1005-10.
• Hypothesis PPCM involves an inflammatory process
  in the heart. Plasma high sensitivity C-Reactive
  Protein (CRP) is a marker of inflammation and
  proinflammatory cytokines and CRP may be a
  proinflammatory protein by itself. Therefore,
  newly diagnosed PPCM patients are expected to
  have an elevated plasma CRP. Ansari et al.
  Autoimmune Mechanisms as the Basis for Human
  Peripartum Cardiomyopathy. Clin Rev Allergy
  Immunol 200223301-24. Sliwa, Fett, Elkayam.
  Peripartum Cardiomyopathy. Lancet 2006368
  687-93.

4
AIM

• To demonstrate that PPCM patients have a
  significantly elevated plasma hs-CRP at diagnosis
  compared to normal mothers at the same stage
  peripartum.

5
Methodology Diagnostic Criteria for PPCM

• Onset heart failure (HF) during the last month of
  pregnancy to within 5 months postpartum
• Absence of preexisting heart disease
• Absence of other identifiable cause for HF (PPCM
  is a diagnosis of exclusion)
• Pearson et al. NIH Workshop on PPCM. JAMA
  20002831183-8.
• Demakis, Rahimtoola. Circulation 197144964-8.
• Additional criteria Echocardiographic evidence
  of left ventricular systolic dysfunction (EF
  lt45, /or FS lt30 , LVEDD LVIDd gt2.7 cm/M2)
• Hibbard, et al, Obstet Gynecol 199994311-16
• Documented sero-negative for Human
  Immunodeficiency Virus to avoid confusion with
  HIV-related DCM.

6
Methodology (continued)

• Setting Hôpital Albert Schweitzer (HAS)
  District, Artibonite River Valley, Haiti
• PPCM Patients
• Prospectively-identified
• PPCM Registry, 2000 - 2005.
• Meet all diagnostic criteria,
• Haitian Control Mothers
• Age and parity-matched
• Same stage peripartum as PPCM patients
  at diagnosis.
• Normal echocardiogram and heart exam

7
METHODOLOGY (continued)

• Plasma hs-CRP testing
• -Emory University School of Medicine, Dept.
  Pathology Laboratory Medicine by
• non-competitive capture ELISA
  immunoassay, (ALPCO, Windham, NH)
• Approved by HAS Ethics Committee, with written
  informed consent by all participants.

8
RESULTS Patient Characteristics

• Mean age 30.1 years, range 17 - 40 years
• Mean parity 4, range 1 - 9
• Mean left ventricular EF at diagnosis
• 23.9 , range 15 30
• Survival, 2 to 5 year follow-up
• 11/14 (78.6 )
• Left ventricular recovery (EF gt50 ), 2 to 5 year
  follow-up 7/14 (50 )
• Fett, et al. Five-year prospective study of the
  incidence and prognosis of peripartum
  cardiomyopathy at a single institution. Mayo
  Clin Proc 2005801602-1606.

9
RESULTS Plasma hs-CRP
Table I. Plasma high sensitivity-C-Reactive
Protein in Peripartum Cardiomyopathy and Control
Mothers, Deschapelles, Haiti
10
Results Graph I. Plasma hs-CRP
11
RESULTS (continued)

• Mean value plasma hs-CRP
• -survivors (n11), 259 mg/L
• -non-survivors (n 3), 38 mg/L
• (p 0.1021)
• -recovered LV systolic function (n 7) ,
  417 mg/L
• -non-recovered (n 7) , 27 mg/L
• (p 0.0039)
• Sensitivity and Specificity,using cut-off value
  of 10 mg/liter
• -sensitivity 93
• -specificity 100

12
Results Recovered vs Non-recovered PPCM patients
13
Discussion Other studies of plasma CRP in PPCM

• Mean plasma hs-CRP 201.2 mg/L in 12 PPCM
  patients at diagnosis vs 3.97 mg/L in 12 healthy
  controls, (P lt0.005), Deschapelles, Haiti. Ellis
  et al Inhibition of progenitor dendritic cell
  maturation by plasma from patients with
  peripartum cardiomyopathy role in
  pregnancy-associated heart disease. J Clin Devel
  Immunology 200512265-73.
• Mean plasma CRP 10.8 mg/L 100 PPCM patients at
  diagnosis vs 3.1 mg/L in 20 healthy controls, (P
  lt 0.01), Soweto, South Africa.
• Sliwa et al Peripartum cardiomyopathy
  inflammatory markers as predictors of outcome in
  100 prospectively studied patients. Eur Heart J
  200627441-6 (Note did not use high
  sensitivity CRP testused normal sensitivity
  Roche Diagnostics)

14
Discussion Related reports of plasma levels of
hs-CRP in excess of 10 mg/Liter at diagnosis

• Fulminant myocarditis, (n27mean CRP 70 mg/L)
• Kato et al. Circ J
  200468734-9.
• Parvovirus B19 myocarditis, (n24mean CRP 91
  mg/L)
• Kuhl et al.
  Circulation 2003108945-50.
• Lymphocytic myocarditis, (n31mean CRP
  survivors, 77.6
  mg/L, non-survivors 174 mg/L.
• Kaneko et al. Jpn.Heart J. 2000
  4141-7.
• Inflammatory cardiomyopathy, (n9mean CRP 91
  mg/L) Kashimoto et al. Int
  J Cardiol 200391173-8.
• Idiopathic dilated cardiomyopathy, (n188mean
  CRP survivors 49 mg/L non-survivors 105
  mg/L )
• Kaneko et al. Cardiology
  199991215-9.

15
Discussion What happens to plasma hs-CRP in
normal pregnancy?

• Few studies our study, normal controls
  postpartum same stage peripartum as PPCM patients
  at diagnosis
• -mean plasma hsCRP 5.1 mg/L, range 1.8 to
  9.9 mg/L
• Another study (Cardiophase hs-CRP, BN-II
  nephelometer,Dade Behring, Deerfield, IL, USA)
  
• -mean plasma hsCRP 7.3 mg/L in 37
  women at normal term pregnancy
• -mean plasma hsCRP 2.3 mg/L in 50
  age-matched healthy non-pregnant women
• Rovere-Querini P, et al. Plasma and tissue
  expression of the long pentraxin 3 during normal
  pregnancy and preeclampsia. Obstet Gynecol
  2006108148-55

16
Discussion Examples of potential diagnostic
utility of plasma hs-CRP

• Clinically normal Haitian mother, 28 y, g4, p4,
  plasma hs-CRP 14 mg/Liter echocardiogram showed
  systolic dysfunction (EF 45 , FS20). Follow-up
  echo 12 months, EF 52 .
• Clinically normal Haitian mother, 33y, g1p1,
  plasma hs-CRP 21.7 mg/Liter echocardiogram
  showed systolic dysfunction (EF 45 , FS 29 ).
  Follow-up echo 24 months, EF 55 .
• Fett et al. Unrecognized Peripartum
  Cardiomyopathy in Haitian Women. Int J Gynecol
  Obstet 200590161-166.

17
Discussion C-Reactive Protein in Myocardium

• C-reactive protein co-expresses with tumor
  necrosis factor-a in the myocardium in dilated
  cardiomyopathy. Satoh et al. Eur J Heart Fail
  20057748-54. (n41 DCM patients, 16 controls)
• Expression of CRP and TNF-a correlates with
  severity of cardiomyopathy.
• Myocardial levels do not correlate with serum
  levels of CRP.
• Lower levels of expression of CRP and TNF-a if
  treatment with spironolactone and ACE-I/ARB.

18
Conclusion

• Plasma hs-CRP has been shown to be
  significantly elevated in PPCM patients at
  diagnosis compared to control mothers at the same
  stage peripartum. Similar range of plasma hs-CRP
  elevation may be found in other cardiomyopathies.
  It is hoped that these findings may stimulate
  additional testing.

19
Discussion Addendum

• Plasma hs-CRP levels on 2 USA PPCM patients at
  diagnosis
• 1-Gravida 1, diagnosis _at_ term
  pregnancy, 157 mg/Liter
• 2- Gravida 2, para 2, diagnosis 5 days
  postpartum, 105 mg/Liter