Olaf Forster

A Cathepsin D-Cleaved 16 kDa Form of Prolactin Mediates Postpartum Cardiomyopathy

Postpartum cardiomyopathy (PPCM) is a disease of unknown etiology and exposes women to high risk of mortality after delivery. Here, we show that female mice with a cardiomyocyte-specific deletion of stat3 develop PPCM. In these mice, cardiac cathepsin D (CD) expression and activity is enhanced and associated with the generation of a cleaved antiangiogenic and proapoptotic 16 kDa form of the nursing hormone prolactin. Treatment with bromocriptine, an inhibitor of prolactin secretion, prevents the development of PPCM, whereas forced myocardial generation of 16 kDa prolactin impairs the cardiac capillary network and function, thereby recapitulating the cardiac phenotype of PPCM. Myocardial STAT3 protein levels are reduced and serum levels of activated CD and 16 kDa prolactin are elevated in PPCM patients. Thus, a biologically active derivative of the pregnancy hormone prolactin mediates PPCM, implying that inhibition of prolactin release may represent a novel therapeutic strategy for PPCM.

Reversal of IFN-γ, oxLDL and prolactin serum levels correlate with clinical improvement in patients with peripartum cardiomyopathy

Peripartum cardiomyopathy (PPCM) is characterized by acute onset of heart failure of unknown aetiology. We aimed to identify mechanisms involved in initiation and progression of the disease.

Predictors of outcome in 176 South African patients with peripartum cardiomyopathy.

Objective Identify novel prognostic factors for patients with peripartum cardiomyopathy (PPCM). Design and setting Prospective cohort study conducted in a single tertiary care centre in South Africa. Patients 176 African women with newly diagnosed PPCM were studied. Interventions Clinical assessment, echocardiography and laboratory results were obtained at baseline and at 6 months. Main outcome measures Poor outcome was defined as the combined end point of death, left ventricular (LV) ejection fraction (LVEF) < 35%, or remaining in New York Heart Association (NYHA) functional class III/IV at 6 months. Complete LV recovery was defined as LVEF ≥55% at 6 months. Results Forty-five (26%) patients had a poor outcome. Multiple logistic regression analysis revealed that, after adjustment for age, NYHA functional class, LVEF and systolic blood pressure, increased left ventricular end systolic dimension (LVESD), lower body mass index (BMI) and lower total cholesterol at baseline were independent predictors of poor outcome (adjusted OR 1.09, 95% CI 1.04 to 1.15, p=0.001; OR 0.89, 95% CI 0.83 to 0.96, p=0.004, and OR 0.50, 95% CI 0.34 to 0.73, p=0.0004, respectively). Thirty (21%) of the 141 surviving patients with echocardiographic follow-up recovered LV function at 6 months. Multiple logistic regression analysis revealed that, after adjustment for NYHA functional class, LVEF and left ventricular end diastolic dimension, older age and smaller LVESD at baseline were predictors of LV recovery (OR 1.08, 95% CI 1.01 to 1.17, p=0.02 and OR 0.92, 95% CI 0.86 to 0.98, p=0.007, respectively). Conclusions This study suggests that increased LVESD, lower BMI and lower serum cholesterol at baseline may be independent predictors of poor outcome in patients with PPCM, while older age and smaller LVESD at baseline appear to be independently associated with a higher chance of LV recovery.

Long-term outcome of Peripartum cardiomyopathy in a population with high seropositivity for Human Immunodeficiency Virus

BACKGROUND Peripartum cardiomyopathy (PPCM) is a rare cardiomyopathy with a high risk of mortality. The present study assessed clinical outcome and mortality over a 2-year period in an African cohort of 80 PPCM patients. METHODS A prospective study over a 2-year period at a tertiary center, where 80 consecutive women presenting with PPCM were enrolled on first diagnosis. Patients obtained standard heart failure therapy. Detailed assessments included echocardiography, NYHA functional class, left ventricular ejection fraction (LVEF), mortality and serum levels for hemoglobin, CRP, IL-6, TNF-alpha, Fas/Apo-1, and T-cell count at each 6-month intervals for 24 months. RESULTS Baseline mean age was 30 ± 7 years; 38% were primigravidas and 34% were co-infected with HIV. NYHA functional class III-IV was present in 89% patients with a mean LVEF of 30 ± 9%. Four patients were lost to follow-up, 9 moved to remote areas, 7 were excluded due to subsequent pregnancy. The 2-year mortality rate was 28%. Eight of 80 (10%) died by 6 months. Mean LVEF of surviving patients was: 44 ± 11% at 6-months, 46 ± 13% at 12-months and 50 ± 14% at 24-months follow-up. Of the 69 patients still enrolled at 6 months 14 (20%) died over the remaining 18-month period, despite functional recovery. No statistically significant difference in LVEF and mortality was observed between PPCM patients with or without HIV co-infection. CONCLUSION The novel finding of this study is the continuous high mortality of PPCM patients occurring beyond 6 months independent of HIV infection and subsequent pregnancy. This finding strongly encourages the need for long-term clinical follow-up and management of women with PPCM.

Current issues in the diagnosis and management of peripartum cardiomyopathy

Peripartum cardiomyopathy is a form of heart failure that occurs in women within 1 month pre- and 5 months postdelivery. The syndrome carries a high mortality and predisposing factors are not known. The incidence and prevalence of peripartum cardiomyopathy appear to be increasing and this article aims to alert clinicians to consider a possible diagnosis of peripartum cardiomyopathy, outlines the current treatment options, and describes recent advances in the understanding of the pathophysiology of this condition.

MYOCARDIAL AUTOANTIBODIES AND THEIR CLINICAL SIGNIFICANCE

ABSTRACT A number of intracellular structural/nonstructural proteins and receptors expressed by cardiac myocytes have been identified as putative targets of autoimmune response in subsets of patients classified as those suffering from idiopathic dilated cardiomyopathy (IDCM). At present it is difficult to determine whether such antibodies are a primary or secondary phenomenon; however, it is becoming increasingly clear that the presence of such autoantibodies against cardiac tissues most likely does contribute to the pathogenic process. This view is supported by the results of immunoglobulin apheresis of dilated cardiomyopathy (DCM) patients, which appears to lead to significant improvement of cardiac function at least in a select group of such patients. The concept of “molecular mimicry” between proteins of infectious agents and cardiac tissue proteins and receptors appears to provide the most convincing evidence for an infectious etiology for at least a subgroup of DCM patients. Among the autoantigens, the alpha chain of cardiac myosin and the beta-1-adrenoreceptor seem to provide the most consistent data as targets of autoimmune responses. The data taken together clearly suggest that as previously suspected, human DCM is a complex heterogeneous disease and is likely a result of host genetics, cardiac tissue insult in the form of an infectious process or a cardiotoxic agent, a dysregulation of immune regulatory mechanisms, and metabolic/contractile abnormalities. How each of these interplays in different DCM patients at different stages of the disease process influences the complexity of the results one obtains in studying this heterogeneous disease. Murine models of coxsackie virus infection and experimental immunization of mice with cardiac myosin in inbred and various gene knockout strains of mice have provided important clues. Similarly, the fact that immunization of rodents with synthetic myosin peptides that resemble the peptides present on the outer membrane protein of Chlamidya and induce cardiac dysfunction adds to such models. Finally, the observation that mice that have targeted gene deletions for PD-1 within T cells and targeted gene deletions for the intracellular signaling molecule STAT-3 to cardiac tissue, both of which develop heart failure, provides yet other pieces to the puzzle of human-dilated cardiomyopathies. Attempts to identify which of these models serve as surrogates for which subset of DCM patient remain a future challenge. Identification of antibodies against cardiac myosin and the beta-1-adrenoreceptor protein may provide an initial means to segregate patients into those that present an autoimmune component and those that do not in efforts to identify groups of patients that could benefit best from therapies aimed at treating these patients for the autoimmune process.

Clinical profi ling of patients with peripartum cardiomyopathy and its value for translational research

Postpartum cardiomyopathy (PPCM) is a disease of unknown etiology and exposes women to high risk of mortality after delivery despite optimal medical therapy. Experimental data suggested that enhanced oxidative stress promotes the proteolytical processing of the lactation hormone prolactin into a biologically active derivative, the 16kDa prolactin, which appears to be a major cause for PPCM. We observed increased oxLDL levels in a subset of these PPCM patients, indicative of oxidative stress, enhanced Cathepsin D activity and substantial levels of the cleaved 16kDa form of prolactin. We therefore propose that the excessive generation of 16kDa prolactin mediates PPCM in humans and suggest that inhibition of prolactin release may represent a novel therapeutic strategy for PPCM.