One hundred cases of
peripartum Cardiomyopathy... and counting: what is going on?
Fett JD, Dowell DL, Carraway RD, Sundstrom JB, Ansari AA.
Related Articles, Links
One hundred cases of peripartum cardiomyopathy... and counting: what is going on?
Int J Cardiol. 2004 Dec;97(3):571-3. No abstract available.
James D. Fett, MD
JD Fett, MD, H˘pital Albert Schweitzer, Deschapelles, Haiti
DL Dowell, MD, H˘pital Albert Schweitzer, Deschapelles, Haiti
RD Carraway, MD, H˘pital Albert Schweitzer, Deschapelles, Haiti
JB Sundstrom, PhD, Emory University School of Medicine, Atlanta, GA, USA
AA Ansari, PhD, Emory University School of Medicine, Atlanta, GA, USA
100 CASES OF PERIPARTUM CARDIOMYOPATHY.
AND COUNTING: What's going on?
We have previously documented a high-incidence area of peripartum cardiomyopathy
(PPCM).1 Since initiating the PPCM Registry at Hospital Albert Schweitzer(HAS) on 1
Feb 2000, 108 new PPCM cases have been registered. This translates into an
incidence of approximately 1 case per 300 live births in a district of 258,000
population, several times the estimated incidence in the United States.2
Murphy,3 in his chapter on PPCM in MYOCARDITIS: From Bench to Bedside, suggests
this high incidence in Haiti may be attributed to multiple possible etiologies, such
as human immunodeficiency virus, sickle cell disease, hookworm disease with severe
anemia, and tuberculosis. However, all of those diseases and a long list of others
have been to the best of our ability specifically ruled out, since PPCM is by
definition a diagnosis of exclusion.4 As such, there must always be room for
periodic reassessment if new clinical information becomes available.
During the first year of the HAS PPCM Project over 50 % of new PPCM cases were first
diagnosed in women following their 5th or higher pregnancy and fewer than 10 % in
primiparas. While the grand multiparas continue to constitute over one-third of the
new cases, in the third year of the project, one-third of new PPCM cases have been
in primiparas, three of whom died shortly after admission to hospital in 2003, with
severe congestive heart failure (CHF).
In the HAS setting of high volume workload and limited resources cardiac
catheterization and endomyocardial biopsy are not available. However, cardiac
tissue exam from autopsy has demonstrated an inflammatory infiltrate in 1 of the 3
primiparas mentioned above. This infiltrate, on immunohistochemical staining,
consisted of mononuclear cells, including T-lymphocytes (CD8) and
monocyte/macrophage lineage cells (CD68). The second primipara's cardiac tissue at
autopsy showed non-specific changes in the myocardium similar to those that may be
seen in dilated cardiomyopathy of various etiologies, including PPCM. The third
primipara's cardiac tissue at autopsy, in addition to the non-specific changes,
showed areas of interstitial fibrosis (possible resolving or resolved myocarditis5).
This is certainly compatible with the focal nature and stage of disease of
myocarditis (and/or inflammatory cardiomyopathy) reported in PPCM.6
Lacking biopsy potential at HAS and because a focal myocarditis in PPCM may not even
be found in limited autopsy tissue, we have attempted to identify peripheral blood
markers of an inflammatory process. In the HAS setting the most promising test
identified to-date is the high-sensitivity C-Reactive Protein (hs-CRP), demonstrated
to be an indicator of activation of proinflammatory cytokines.7 In early testing
(Unpublished, in preparation) 22 Haitian PPCM mothers have been found to have
markedly increased mean hs-CRP plasma levels compared to 14 Haitian non-PPCM control
mothers at the same stage postpartum (144.3 mg/L vs 5.2 mg/L, p=0.0003). Thirty-two
Haitian PPCM mothers have also been found, as expected with stage III and IV NYHA
Classification CHF, to have markedly elevated mean B-type Natriuretic Peptide
(pro-BNP) plasma levels compared to 22 non-PPCM control Haitian mothers (1096.5
pg/ml vs 204.2 pg/ml, p=<0.00009). Once again, limited resources with lack of
adequate cold storage have hampered our investigation since we would like to also
measure proinflammatory cytokines Tumor Necrosis Factor-alpha (TNF-a), Interleukin-1
(IL-1) and Interleukin-6 (IL-6), all of which may prove useful targets for potential
new immunomodulatory treatments.8,9,10
One might expect that nutritional deficiencies could play a role in the development
of PPCM in this impoverished setting; however we have not demonstrated either a
macro-nutrient deficiency (protein and iron) or a micro-nutrient deficiency (Vitamin
A, Vitamin B-12, Vitamin C, Vitamin E, B-Carotene, Selenium) in Haitian PPCM
patients or controls.11 Also in field epidemiology case-control studies we have not
found any geographic distribution, cultural practices, customs, or activities which
distinguish PPCM mothers from non-PPCM control mothers.12 It is certainly possible
that unidentified nutritional deficiencies and/or environmental toxins/infectious
agents could be playing a role in a process involving an aberrant immune response to
as yet unidentified antigen(s).
It is possible that PPCM has an autoimmune component, but this is not yet certain.
Nonetheless, we have found plasma autoantibodies (AAB's) in more than half of 30
Haitian PPCM mothers tested to-date.11,13,14,15 The targets of such autoantibodies
include human cardiac myosin heavy chain (200 Kd), putative cardiac transaldolase
(37 Kd), putative cardiac myosin light chain (27 Kd), and yet-unidentified 25 and 33
Kd cardiac proteins. It is uncertain if these AAB's are merely secondary
epiphenomena or if they could be directly contributing to cardiomyocyte injury. In
the latter case they would be enticing targets for potential immunomodulatory
treatments. There is evidence that these and/or other identified or unidentified
AAB's may correlate with severity of cardiac dysfunction16 and that removal may be
associated with clinical improvement in dilated cardiomyopathy.17
Some non-PPCM Haitian control mothers have also been found to have plasma AAB's,
elevated hs-CRP, abnormal or borderline echocardiograms (in one returning later to
normal), but normal BNP (i.e. not in left ventricular failure). Does this mean that
they have developing or latent, sub-clinical PPCM? We do not know, but this is a
subject of current study. It is highly important for us to define a non-invasive
methodology that can predict the onset of human PPCM so that preventive measures can
be instituted. This is one of the goals of our research efforts.
In treatment we have learned that an ACE-inhibitor is our most valuable medication,
not only because of its direct beneficial effects on the heart but also because of
its potential benefit to interrupt the chain of events in the pathobiology of
PPCM.18 More effective treatments are urgently needed
This meticulous identification and characterization of PPCM diagnosis-of-exclusion
patients in one high-incidence area through a PPCM Registry continues to be the
focus of multiple ongoing studies. Whether this growing body of evidence will shed
light on PPCM in the USA and other resource-abundant countries remains to be seen.
Although incomplete, at the very least our study suggests that it may be prudent to
investigate plasma/serum levels of hs-CRP, TNF-a, IL-1, IL-6, and cardiac-specific
autoantibodies in PPCM patients wherever in the world these patients appear. It
also suggests that endomyocardial biopsy in settings where it can be accomplished
may have an increasingly important role in those PPCM mothers who are not improving
in the early phase of disease.20 This is particularly the case with newer
immunomodulatory treatments on the horizon.
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