Race, hypertensive disorders of pregnancy and outcomes in peripartum cardiomyopathy.

BACKGROUND: Black women with peripartum cardiomyopathy (PPCM) have a higher prevalence of hypertensive disorders of pregnancy (HDP) and worse clinical outcomes compared with non-Black women. We examined the impact of HDP on myocardial recovery in Black women with PPCM. METHODS: A total of 100 women were enrolled into the Investigation in Pregnancy Associated Cardiomyopathy (IPAC) study. Left ventricular ejection fraction (LVEF) was assessed by echocardiography at entry, 6, and 12-months post-partum (PP). Women were followed for 12 months postpartum and outcomes including persistent cardiomyopathy (LVEF ≤35%), left ventricular assist device, (LVAD), cardiac transplantation, or death were examined in subsets based on race and the presence of HDP. RESULTS: Black women with HDP were more likely to present earlier compared to Black women without HDP (days PP HDP: 34 ± 21 vs 54 ± 27 days, P = .03). There was no difference in LVEF at study entry for Black women based on HDP, but better recovery with HDP at 6 (HDP: 52 ± 11% vs no HDP: 40 ± 14%, P = .03) and 12-months (HDP:53 ± 10% vs no HDP:40 ± 16%, P = .02). At 12-months, Black women overall had a lower LVEF than non-Black women (P < .001), driven by less recovery in Black women without HDP compared to non-Black women (P < .001). In contrast, Black women with HDP had a similar LVEF at 12 months compared to non-Black women (P = .56). CONCLUSIONS: In women with PPCM, poorer outcomes evident in Black women were driven by women without a history of HDP. In Black women, a history of HDP was associated with earlier presentation and recovery which was comparable to non-Black women.

Circulating T-Cell Subsets, Monocytes, and Natural Killer Cells in Peripartum Cardiomyopathy: Results From the Multicenter IPAC Study.

OBJECTIVE: The aim of this work was to evaluate the hypothesis that the distribution of circulating immune cell subsets, or their activation state, is significantly different between peripartum cardiomyopathy (PPCM) and healthy postpartum (HP) women. BACKGROUND: PPCM is a major cause of maternal morbidity and mortality, and an immune-mediated etiology has been hypothesized. Cellular immunity, altered in pregnancy and the peripartum period, has been proposed to play a role in PPCM pathogenesis. METHODS: The Investigation of Pregnancy-Associated Cardiomyopathy (IPAC) study enrolled 100 women presenting with a left ventricular ejection fraction of <0.45 within 2 months of delivery. Peripheral T-cell subsets, natural killer (NK) cells, and cellular activation markers were assessed by flow cytometry in PPCM women early (<6 wk), 2 months, and 6 months postpartum and compared with those of HP women and women with non-pregnancy-associated recent-onset cardiomyopathy (ROCM). RESULTS: Entry NK cell levels (CD3-CD56+CD16+; reported as % of CD3- cells) were significantly (P < .0003) reduced in PPCM (6.6 ± 4.9% of CD3- cells) compared to HP (11.9 ± 5%). Of T-cell subtypes, CD3+CD4-CD8-CD38+ cells differed significantly (P < .004) between PPCM (24.5 ± 12.5% of CD3+CD4-CD8- cells) and HP (12.5 ± 6.4%). PPCM patients demonstrated a rapid recovery of NK and CD3+CD4-CD8-CD38+ cell levels. However, black women had a delayed recovery of NK cells. A similar reduction of NK cells was observed in women with ROCM. CONCLUSIONS: Compared with HP control women, early postpartum PPCM women show significantly reduced NK cells, and higher CD3+CD4-CD8-CD38+ cells, which both normalize over time postpartum. The mechanistic role of NK cells and "double negative" (CD4-CD8-) T regulatory cells in PPCM requires further investigation.

Proinflammatory TH17 cytokine activation, disease severity and outcomes in peripartum cardiomyopathy.

BACKGROUND: Immune dysregulation is implicated in the development and clinical outcomes of peripartum cardiomyopathy (PPCM). METHODS AND RESULTS: 98 women with PPCM were enrolled and followed for 1 year postpartum (PP). LVEF was assessed at entry, 6-, and 12-months PP by echocardiography. Serum levels of soluble interleukin (IL)-2 receptor (sIL2R), IL-2, IL-4, IL-17, IL-22, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were measured by ELISA at entry. Cytokine levels were compared between women with PPCM by NYHA class. Outcomes including myocardial recovery and event-free survival were compared by cytokine tertiles. For cytokines found to impact survival outcomes, parameters indicative of disease severity including baseline LVEF, medications, and use of inotropic and mechanical support were analyzed. Levels of proinflammatory cytokines including IL-17, IL-22, and sIL2R, were elevated in higher NYHA classes at baseline. Subjects with higher IL-22 levels were more likely to require inotropic or mechanical support. Higher levels of TNF-α and IL-22 were associated with poorer event-free survival. Higher TNF-α levels were associated with lower mean LVEF at entry and 12 months. In contrast, higher levels of immune-regulatory cytokines such as IL-4 and IL-2 were associated with higher LVEF during follow up. CONCLUSION: Proinflammatory cytokines IL-22 and TNF-α were associated with adverse event-free survival. IL-17 and IL-22 were associated with more severe disease. In contrast, higher levels of IL-2 and IL-4 corresponded with higher subsequent LVEF. Increased production of TH17 type cytokines in PPCM correlated with worse disease and outcomes, while an increased immune-regulatory response seems to be protective.

Recovery from severe heart failure following peripartum cardiomyopathy.

OBJECTIVES: Traditional concepts surrounding peripartum cardiomyopathy (PPCM) hold that if recovery does not occur within 6 months of diagnosis, it is unlikely to happen. The purpose of the study was to determine the length of time required for recovery of left ventricular systolic function. METHODS: Patients were identified from the Hôpital Albert Schweitzer PPCM Registry over the period 2000-2008. Echocardiography was carried out at diagnosis and every 6 months thereafter. Recovery of systolic heart function was defined as left ventricular ejection fraction greater than 0.50. RESULTS: Thirty-two out of 116 (27.6%) PPCM patients reached recovery levels, with 75% of patients taking over 12 months to recover. Shortest time to recovery was 3 months and longest time to recovery was 48 months. CONCLUSION: Recovery of left ventricular systolic function in PPCM patients often requires longer than 6-12 months following diagnosis. It is important to continue effective treatment and follow-up for a sufficient period to assure maximum benefit.

Global Left Ventricular Strain at Presentation Is Associated with Subsequent Recovery in Patients with Peripartum Cardiomyopathy.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is a serious complication of pregnancy associated with variable degrees of left ventricular (LV) recovery. The aim of this study was to test the hypothesis that global LV strain at presentation has prognostic value in patients with PPCM. METHODS: One hundred patients with PPCM aged 30 ± 6 years were enrolled in the multicenter Investigation in Pregnancy Associated Cardiomyopathy study along with 21 normal female control subjects. Speckle-tracking global longitudinal strain (GLS) and global circumferential strain (GCS) analysis was performed. The predefined primary combined outcome variable was death, transplantation, LV assist device implantation, or evidence of persistent LV dysfunction (LV ejection fraction [LVEF] < 50%) at 1 year. RESULTS: GLS measurement was feasible in 110 subjects: 89 of 90 patients with PPCM (99%) with echocardiographic data and all 21 control subjects. Of 84 patients (94%) with 1-year follow-up, 21 (25%) had unfavorable primary outcomes: four LV assist device placements, two deaths, and 15 patients with persistent LV dysfunction. GLS at presentation with a cutoff of 10.6% (absolute value) was specifically associated with the subsequent primary outcome with 75% sensitivity and 95% specificity. GCS at presentation with a cutoff of 10.1% was associated with the primary outcome with 78% sensitivity and 84% specificity. GLS and GCS remained significantly associated with outcomes after adjusting for LVEF (GLS odds ratio, 2.07; P < .001; GCS odds ratio, 1.37; P = .005). GLS was significantly additive to LVEF (C statistic = 0.76-0.91, net reclassification improvement = 1.32, P < .001). CONCLUSIONS: GLS and GCS in patients with PPCM at presentation were associated with subsequent clinical outcomes, including death, LV assist device implantation, and evidence of persistent LV dysfunction. Strain measures may add prognostic information over LVEF for risk stratification.

Breastfeeding, Cellular Immune Activation, and Myocardial Recovery in Peripartum Cardiomyopathy.

The etiology of peripartum cardiomyopathy remains unknown. One hypothesis is that an increase in the 16-kDa form of prolactin is pathogenic and suggests that breastfeeding may worsen peripartum cardiomyopathy by increasing prolactin, while bromocriptine, which blocks prolactin release, may be therapeutic. An autoimmune etiology has also been proposed. The authors investigated the impact of breastfeeding on cellular immunity and myocardial recovery for women with peripartum cardiomyopathy in the IPAC (Investigations in Pregnancy Associated Cardiomyopathy) study. Women who breastfed had elevated prolactin, and prolactin levels correlated with elevations in CD8+ T cells. However, despite elevated prolactin and cytotoxic T cell subsets, myocardial recovery was not impaired in breastfeeding women.

Peripartum cardiomyopathy.

Peripartum cardiomyopathy (PPCM) is a disorder in which initial left ventricular systolic dysfunction and symptoms of heart failure occur between the late stages of pregnancy and the early postpartum period. It is common in some countries and rare in others. The causes and pathogenesis are poorly understood. Molecular markers of an inflammatory process are found in most patients. Clinical presentation includes usual signs and symptoms of heart failure, and unusual presentations relating to thromboembolism. Clinicians should consider PPCM in any peripartum patient with unexplained disease. Conventional heart failure treatment includes use of diuretics, beta blockers, and angiotensin-converting enzyme inhibitors. Effective treatment reduces mortality rates and increases the number of women who fully recover left ventricular systolic function. Outcomes for subsequent pregnancy after PPCM are better in women who have first fully recovered heart function. Areas for future research include immune system dysfunction, the role of viruses, non-conventional treatments such as immunosuppression, immunoadsorption, apheresis, antiviral treatment, suppression of proinflammatory cytokines, and strategies for control and prevention.

Brief communication: Outcomes of subsequent pregnancy after peripartum cardiomyopathy: a case series from Haiti.

BACKGROUND: Maternal risks with pregnancies after an index diagnosis of peripartum cardiomyopathy (PPCM) are inadequately understood. OBJECTIVE: To describe the clinical outcomes of subsequent pregnancy in Haitian women with PPCM. DESIGN: Prospectively identified cases from a defined population base, 2000-2005. SETTING: Hôpital Albert Schweitzer, Deschapelles, Haiti. PATIENTS: 15 patients with PPCM and subsequent pregnancies among 99 prospectively identified patients with PPCM. MEASUREMENTS: Clinical and echocardiographic parameters. RESULTS: Fifteen women with PPCM had 16 subsequent pregnancies after the index pregnancies. Eight of these patients experienced worsening heart failure; of these, 1 died and 1 regained normal left ventricular systolic function. Seven patients tolerated pregnancy without worsening heart failure, and ventricular function recovered in these patients within 30 months after the subsequent pregnancy. LIMITATIONS: The results may not apply to non-Haitian women, and power was insufficient to identify factors that might predict recovery (n = 15). CONCLUSIONS: Half of the women with subsequent pregnancy after PPCM experienced worsening heart failure and long-term systolic dysfunction, while the other half experienced no deterioration and regained normal left ventricular systolic function.

Myocardial Damage Detected by Late Gadolinium Enhancement Cardiac Magnetic Resonance Is Uncommon in Peripartum Cardiomyopathy.

BACKGROUND: In peripartum cardiomyopathy, the prevalence of focal myocardial damage detected by late gadolinium enhancement (LGE) cardiovascular magnetic resonance is important to elucidate mechanisms of myocardial injury and cardiac dysfunction. LGE equates irreversible myocardial injury, but LGE prevalence in peripartum cardiomyopathy is uncertain. METHODS AND RESULTS: Among 100 women enrolled within the Investigations of Pregnancy Associated Cardiomyopathy cohort, we recruited 40 women at 13 centers to undergo LGE cardiovascular magnetic resonance, enrolled within the first 13 weeks postpartum. Follow-up scans occurred at 6 months postpartum, and death/transplant rates at 12 months. Baseline characteristics did not differ significantly in the parent cohort according to cardiovascular magnetic resonance enrollment except for mechanical circulatory support. LGE was noted only in 2 women (5%) at baseline. While left ventricular dysfunction with enlargement was prevalent at baseline cardiovascular magnetic resonance scans (eg, ejection fraction 38% [Q1-Q3 31-50%], end diastolic volume index=108 mL/m2 [Q1-Q3 83-134 mL/m2]), most women demonstrated significant improvements at 6 months, consistent with a low prevalence of LGE. LGE was not related to baseline clinical variables, ejection fraction, New York Heart Association heart failure class, or mortality. Neither of the 2 women who died exhibited LGE. LGE was inversely associated with persistent left ventricular ejection fraction at 6 months (P=0.006). CONCLUSIONS: Factors other than focal myocardial damage detectable by LGE explain the initial transient depressions in baseline left ventricular ejection fraction, yet focal myocardial damage may contribute to persistent myocardial dysfunction and hinder recovery in a small minority. Most women exhibit favorable changes in ventricular function over 6 months. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01085955.

Inflammation and virus in dilated cardiomyopathy as indicated by endomyocardial biopsy.

Polymerase chain reaction (PCR) testing of "quick-freeze" endomyocardial biopsy tissue for identification of evidence of viral presence is an important new tool in the investigation of unexplained dilated cardiomyopathy patients; and particularly those who are not improving with conventional treatment. Alternate therapeutic measures, including anti-viral treatment and immunosuppressive therapy, offer promise in contributing to left ventricular systolic function improvement. It is important to include PCR testing for a broad spectrum of cardiotropic viruses prior to the application of immunosuppressive therapy.

The crystal structure of human angiogenin in complex with an antitumor neutralizing antibody.

The murine monoclonal antibody 26-2F neutralizes the angiogenic and ribonucleolytic activities of human angiogenin (ANG) and is highly effective in preventing the establishment and metastatic dissemination of human tumors in athymic mice. Here we report a 2.0 A resolution crystal structure for the complex of ANG with the Fab fragment of 26-2F that reveals the detailed interactions between ANG and the complementarity-determining regions (CDRs) of the antibody. Surprisingly, Fab binding induces a dramatic conformational change in the cell binding region of ANG at the opposite end of the molecule from the combining site; crosslinking experiments indicate that this rearrangement also occurs in solution. The ANG-Fab complex structure should be invaluable for designing maximally humanized versions of 26-2F for potential clinical use.

Peripartum cardiomyopathy: challenges in diagnosis and management.

INTRODUCTION: Peripartum cardiomyopathy (PPCM) is one of the leading causes of maternal mortality all over the world. Fortunately, some of the most important answers to the "PPCM puzzle" are emerging: AREAS COVERED: This is an update that includes current and recent research results. These developments hold promise to importantly decrease mortality from PPCM and increase recovery rates. Expert commentary: Increasing risks for the development and severity of PPCM include a genetic predisposition and the presence of any form of hypertension in pregnancy. Earlier recognition/diagnosis of PPCM confers greater opportunity for full recovery. Important biomarkers have the potential to help to recognize PPCM earlier and to provide better treatment. "Follow the Guidelines" is good advice for the best opportunity to achieve full recovery. These include the use of diuretics, BB, ACEI/ARB in tolerable dosages. Phasing out specific treatments appears to be safe for some; but the process must be individualized.

GNB3 C825T Polymorphism and Myocardial Recovery in Peripartum Cardiomyopathy: Results of the Multicenter Investigations of Pregnancy-Associated Cardiomyopathy Study.

BACKGROUND: Black women are at greater risk for peripartum cardiomyopathy (PPCM). The guanine nucleotide-binding proteins ß-3 subunit (GNB3) has a polymorphism C825T. The GNB3 TT genotype more prevalent in blacks is associated with poorer outcomes. We evaluated GNB3 genotype and myocardial recovery in PPCM. METHODS AND RESULTS: A total of 97 women with PPCM were enrolled and genotyped for the GNB3 T/C polymorphism. Left ventricular ejection fraction (LVEF) was assessed by echocardiography at entry, 6 and 12 months postpartum. LVEF over time in subjects with the GNB3 TT genotype was compared with those with the C allele overall and in black and white subsets. The cohort was 30% black, age 30+6, LVEF 0.34+0.10 at entry 31+25 days postpartum. The % GNB3 genotype for TT/CT/CC=23/41/36 and differed markedly by race (blacks=52/38/10 versus whites=10/44/46, P<0.001). In subjects with the TT genotype, LVEF at entry was lower (TT=0.31+0.09; CT+CC=0.35+0.09, P=0.054) and this difference increased at 6 (TT=0.45+0.15; CT+CC=0.53+0.08, P=0.002) and 12 months (TT=0.45+0.15; CT+CC=0.56+0.07, P<0.001.). The difference in LVEF at 12 months by genotype was most pronounced in blacks (12 months LVEF for GNB3 TT=0.39+0.16; versus CT+CC=0.53+0.09, P=0.02) but evident in whites (TT=0.50++0.11; CT+CC=0.56+0.06, P=0.04). CONCLUSIONS: The GNB3 TT genotype was associated with lower LVEF at 6 and 12 months in women with PPCM, and this was particularly evident in blacks. Racial differences in the prevalence and impact of GNB3 TT may contribute to poorer outcomes in black women with PPCM.

Relaxin-2 and Soluble Flt1 Levels in Peripartum Cardiomyopathy: Results of the Multicenter IPAC Study.

OBJECTIVES: This study explored the association of vascular hormones with myocardial recovery and clinical outcomes in peripartum cardiomyopathy (PPCM). BACKGROUND: PPCM is an uncommon disorder with unknown etiology. Angiogenic imbalance may contribute to its pathophysiology. METHODS: In 98 women with newly diagnosed PPCM enrolled in the Investigation in Pregnancy Associated Cardiomyopathy study, serum was obtained at baseline for analysis of relaxin-2, prolactin, soluble fms-like tyrosine kinase 1 (sFlt1), and vascular endothelial growth factor (VEGF). Left ventricular ejection fraction (LVEF) was assessed by echocardiography at baseline and 2, 6, and 12 months. RESULTS: Mean age was 30 ± 6 years, with a baseline of LVEF 0.35 ± 0.09. Relaxin-2, prolactin, and sFlt1 were elevated in women presenting early post-partum, but decreased rapidly and were correlated inversely with time from delivery to presentation. In tertile analysis, higher relaxin-2 was associated with smaller left ventricular systolic diameter (p = 0.006) and higher LVEF at 2 months (p = 0.01). This was particularly evident in women presenting soon after delivery (p = 0.02). No relationship was evident for myocardial recovery and prolactin, sFlt1 or VEGF levels. sFlt1 levels were higher in women with higher New York Heart Association functional class (p = 0.01) and adverse clinical events (p = 0.004). CONCLUSIONS: In women with newly diagnosed PPCM, higher relaxin-2 levels soon after delivery were associated with myocardial recovery at 2 months. In contrast, higher sFlt1 levels correlated with more severe symptoms and major adverse clinical events. Vascular mediators may contribute to the development of PPCM and influence subsequent myocardial recovery. (Investigation in Pregnancy Associate Cardiomyopathy [IPAC]; NCT01085955).

Impact of pregnancy-related heart failure on humoral immunity: clinical relevance of G3-subclass immunoglobulins in peripartum cardiomyopathy.

BACKGROUND: The impact and clinical relevance of pregnancy-related heart failure (HF) on humoral immunity are not known. Heart failure is often characterized by immunoglobulins (Ig) that differ in subclass profile with etiology. Subclass immunoglobulins differ in the biologic information they confer in disease. Therefore, given that progressive gestation is associated with immunologic incompetence, we sought to study the relative impact of pregnancy-related onset of HF on humoral immunity. METHODS: Immunoglobulins (class G and subclasses G1, G2, G3) against cardiac myosin were evaluated in 47 patients with peripartum cardiomyopathy (PPCM) from different global regions: South Africa (n = 15), Mozambique (n = 9), and Haiti (n = 23) and compared with healthy mothers and patients with idiopathic dilated cardiomyopathy (DCM). C-reactive protein, tumor necrosis factor-alpha, and Fas-Apo-1 were also studied in PPCMs. RESULTS: All PPCM groups were similar in Ig profiles. The immunoglobulins, frequencies and reactivities, were markedly and nonselectively raised in PPCM patients compared with DCM. Immunoglobulin frequencies in PPCMs, Haiti: G1 58%, G2 66%, G3 54%; Mozambique: G1 77%, G2 66%, G3 66%; and South Africa: G1 47%, G2 53%, G3 53%, were higher compared with DCMs from South Africa (n = 24): G1 8%, G2 8%, G3 21%, or the United Kingdom (n = 68): G1 10%, G2 8.8%, G3 22% (P < .0001). Hence, unlike the selective up-regulation of immunoglobulins of the G3 subclass (IgG3s) in DCM, class G and all subclass immunoglobulins were raised in PPCM. Of the serological variables, IgG3s (immunoglobulins with proinflammatory characteristics) discriminated NYHA functional status at diagnosis. IgG3-positive patients were in a higher NYHA class at initial presentation (P < .05). CONCLUSIONS: Immunoglobulin subclass profiles in patients with HF differ with etiology. Unlike DCM, the impact of pregnancy-related HF on humoral immunity is not subclass-restricted. However, raised levels of IgG3s may be of prognostic value in clinical PPCM.