ABSTRACT
Introduction: Peripartum cardiomyopathy (PPCM) is defined as a disorder of unknown aetiology that
occurs between one month antepartum and five months postpartum in women without pre-existing heart
disease. While the incidence of PPCM has been reported between 1: 2392 and 15000 live births in the USA,
the disease is ubiquitous on the African continent with an incidence ranging from 1: 100 to 1: 1000
deliveries. The mortality rate ranges between 15 and 40.7%, while 23 to 54% of patients recover completely.
Aim of this thesis was to describe the clinical profile of 100 PPCM patients, identify predictors of negative
outcome, analyze differences in kinetics of cardiac function biomarkers, pro-inflammatory cytokines,
markers of re-modeling and prolactin in cardiac function improvers versus non-improvers and investigate a
possible autoimmune component in the pathogenesis of PPCM.
Methods: We conducted a single centre, prospective study of 100 newly diagnosed patients meeting
diagnostic criteria for PPCM. All patients received standard anti-failure therapy with diuretics (furosemide,
aldactone), the β-blocker carvedilol, ACE-inhibitor perindopril and digoxin if indicated. Clinical assessment,
2-dimensional echocardiographic studies and blood analysis were systematically performed at time of
presentation, after six and twelve months of therapy.
Findings: Fifteen patients died within the follow-up period of six months and eight were not available for
full follow-up since they moved to remote areas. Patients who completed six months of treatment showed a
significant reduction of heart rate, left ventricular dimensions and significant improvement in
scintigraphically and echocardiographically derived values for left ventricular ejection fraction (p< 0.0001)
and NYHA functional class (p< 0.001). However, normalization of LVEF (>50%) was only observed in 18
(23%) of the patients. Baseline plasma levels of Fas/Apo-1 (OR = 3.56, CI 95% = 1.35–9.42) and NYHA FC
(OR = 2.67, CI 95% = 1.04–6.83) were independent predictors of death.extra-cellular loop (RAESDE and DEARRCY), while those from DCMO patients bind to epitopes on the
first (30%) and second extra-cellular loop (ARRCYND and PKCCDF). The β1-adrenoreceptor agonist-like
antibodies identified in PPCM patients are part of the IgG2 and IgG3 subclass, while those from DCMO
patients belong to the IgG2 subclass. Furthermore we demonstrated that β1-adrenoreceptor antibodies in
serum of PPCM patients prevented desensitization of the receptor. The β1-adrenoreceptor antibodies in
serum of PPCM patients were not detectable in serum of non PPCM peripartum controls and are different
from those found in patients with DCMO, suggesting that PPCM forms a distinct disease entity. We
demonstrated a positive correlation between the activity of the β1-adrenoreceptor antibodies and serum
expression levels of the marker of cardiac function NT-proBNP from baseline to twelve months (rs=0.58, 2-
tailed P=0.0228), 95% CI (0.10 to 0.84).
Investigating the cause for high prolactin expression levels in serum of PPCM patients, we identified a
STAT3 deficit in a PPCM mouse model. Significantly increased levels of cathepsin D cause the cleavage of the physiological 23-kDa form of prolactin into a 16-kDa form in PPCM patients, but not in non-PPCM
peripartum controls. This initiated another clinical study, investigating the effect of the prolactin-inhibitor
bromocriptine in addition to standard heart failure therapy in known PPCM patients, presenting with a
subsequent pregnancy. Comparison of clinical and echocardiographic data of these patients to others on
standard heart failure therapy demonstrated preservation or improvement of left ventricular dimensions and
systolic function as well as NYHA FC.
Conclusion:
While a wide range of parameters, reflecting cardiac dysfunction and pro-inflammatory immune activation,
were elevated in all PPCM patients at time of first presentation, indicating their involvement in the initiation
of the disease, we found significant differences over time between cardiac function improvers and nonimprovers
for ΔIFN-gamma (P=0.0181) serum levels, suggesting their role in disease progression.
Heightened IFN-gamma expression could indicate an ongoing T-cell mediated autoimmune response and an
insult to the cardiac muscle, resulting in fibrosis and inability to improve left ventricular systolic function.
Prolactin represents a stimulatory link between the neuroendocrine and immune systems, promoting proinflammatory
immune responses. Interestingly, we found significantly higher (P<0.0001) serum prolactin
levels in PPCM patients at time of first presentation than in peripartum controls, suggesting the hormone’s
role during the initial acute phase of PPCM. Several authors have described the induction of IFN-gamma by
prolactin. Disease progression and the ongoing autoimmune insult by beta1-adrenergic autoantibodies
appear to be driven by IFN-gamma. This pro-inflammatory cytokine remained high in PPCM nonimprovers,
decreased in improvers, was previously implicated in the development of autoimmune disease
and its suppression leads to desensitization of β-adrenoreceptors. Together with the β1-adrenoreceptor
autoantibodies that we have identified in PPCM patients and their demonstrated property to also prevent
desensitization of β1-adrenoreceptors, patients experience an adrenergic overdrive, leading to cardiac
myocyte insult.
10
While the pathogenesis of PPCM appears to be multifactorial, our task as scientists remains to find out, how
the monolith was erected. Specifically, it appears promising to investigate the effects of bromocriptine in
addition to standard heart failure therapy in a randomised, double-blinded clinical study. Although one could
argue that prolactin regulated expression of IFN-gamma and other cytokines may explain the gender-specific
differences in autoimmunity, it has been shown that elevated serum prolactin concentrations are associated
with accelerated autoimmune disease in both female and male mice. Possibly, prolactin does not only play a
role in the pathogenesis of PPCM, but also in other forms of cardiomyopathy, affecting males and females
alike. It would be interesting to study prolactin serum expression levels in male and female patients with
idiopathic DCMO. Clearly, further studies into the unfolding pathogenesis of PPCM are indicated.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/5011 |
| Date | 09 July 2008 |
| Creators | Forster, Olaf Alfred Edo Manfred |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 2826190 bytes, application/pdf, application/pdf |
Page generated in 0.0031 seconds