Rationale and Design for the Peripartum Cardiomyopathy in Nigeria (PEACE) Registry.

Introduction

The first descriptions of the association between cardiac failure and the puerperium were made by Rudolf Virchow and Charles Porak separately in 1880 [1,2]. In 1937, Gouley et al described the clinical and pathological features of a severe and fatal type of heart failure (HF) in seven pregnant women in the last months of pregnancy, which persisted after delivery [3]. Hull and Hidden then described 80 postpartum patients with similar clinical features in New Orleans in 1938, and called it ‘Postpartal HF’ [4]. However it was in 1971 that Demakis et al first described the diagnostic criteria of the disease and called it peripartum cardiomyopathy (PPCM) [5,6]. Since then, the definition of PPCM has undergone several modifications but the most recent was by the HF Association of the European Society of Cardiology (ESC) Working Group on PPCM [7].

Epidemiology

The true incidence or prevalence of PPCM is unknown. However PPCM is rare in some parts of the world and more common in others [8,9]. Recent studies suggest an estimated incidence of 1 case per 299 live births in Haiti, one case per 1000 live births in South Africa, and 1 case per 2289 - 4000 live births in the USA [10–13]. The reasons for this variation in incidence between and within countries remain unknown, but probably reflect an overestimation of the disorder in earlier studies that relied upon clinical criteria alone for the diagnosis. Northern Nigeria seems to be one of the “hot spots” of PPCM in the world. The disease was recently described as the most prevalent type of cardiomyopathy in Kano, Nigeria, found in 55 out of 1296 patients (4.2%) referred for echocardiography over a period of 7 months, representing 52.4% of all cardiomyopathies [14]. However, PPCM seems less common among other ethnic groups in Nigeria for reasons that are not yet clear.

PPCM has been associated with several risk factors over the years, but there is significant inconsistency between studies of their association with the disease. The suggested risk factors include increased age, gravidity or parity, African origin, toxaemia or hypertension of pregnancy, use of tocolytics, twin pregnancy, obesity and low socioeconomic status [15–17–20].

The aetiology and pathogenesis of PPCM are unknown, but several hypotheses have been proposed over the years. Although a possible role of genetic susceptibility has been suggested, its role in the aetiology of PPCM is still weak [21]. In a small study in Kano, sisters of PPCM patients were systematically screened with echocardiogram for possible cardiac abnormalities to support the familial theory of the disease, but none was found [22]. Most of the hypotheses were on non-genetic factors such as selenium deficiency, myocarditis, autoimmunity including the possible role of systemic lupus erythematosus, vasculo-hormonal abnormalities and increased hemodynamic burden of pregnancy [7,23]. The Hausa-Fulani tribe of northern Nigeria was described 4 decades ago to have a high incidence (1:100) of a form of HF seen among women shortly after delivery; the postpartum cardiac failure (PPCF) [24,25]. This was probably related to some local Hausa-Fulani customs in the immediate postpartum period, such as frequent ingestion of a thick pap made with millet and rich in dry lake salt (“Kunun Kanwa” in Hausa language), twice-daily hot baths and lying on heated mud beds by the breastfeeding mothers [24]. However, it is important to appreciate that PPCF was actually defined by its authors as mainly “a high-output HF with well preserved ventricular function”, which is different from what we know today as PPCM [24]. In addition, these practices were recently not found to be risk factors for PPCM in northern Nigeria [20].

Selenium deficiency hypothesis

In Kano, it was observed that among women referred for echocardiography, PPCM almost always occurred in women with low income [17]. The most plausible explanation for this observation would be poor nutrition predisposing the poor women to the disease, although the confounding effect of other risk/aetiological factors associated with poverty cannot be dismissed. Malnutrition had been suspected to play a role in the aetiopathogenesis of PPCM, but the occurrence of the disease in well-nourished patients had put this theory to doubt [24]. Cenac et al had reported selenium deficiency in 35 women with PPCM in Niger Republic[9]. However, a similar study among 18 PPCM patients in Haiti didn’t corroborate the findings[9,11.] In a more recent study in Kano, Nigeria, Karaye et al reported significantly lower serum selenium in PPCM patients than in controls, and patients had higher prevalence (76.9%) of critically low serum selenium (<70µg/L) than controls (22.0%) (p < 0.001) [20].

Epidemiologic studies showed that low selenium levels in the soil and in local foodstuffs correlated with low selenium levels in whole-blood and hair samples, and treatment with sodium selenite prevented Keshan disease and mitigated the clinical manifestations in patients with the disease [19,26]. Owing to the importance of many selenoproteins in attenuating oxidant stress in a variety of cellular compartments, one can readily conclude that selenium deficiency promotes oxidant stress and injury, which may also potentiate the oxidant injury of other contributing pathogenic factors, including viral and other infections [27,28]. Therefore in spite of the observations by Fett et al, it is still conceivable that selenium deficiency is related to PPCM, at least in some parts of the world, such as the Sahel regions of Africa [20,29]. Although selenium supplementation has been used safely in Keshan disease and for other indications in pregnant women with beneficial effects, it has not been previously systematically used to treat PPCM [19,30,31].

Hemodynamic burden of pregnancy hypothesis

Several hemodynamic changes such as peripheral vasodilatation, increase in blood volume and cardiac output occur between the 1st and 2nd trimesters of pregnancy, and patients with known preexisting structural cardiac diseases typically present with clinical HF at this time[32,33]. In striking contrast, PPCM overwhelmingly presents during the postpartum period, and factors that modify the stresses of vaginal delivery such as caesarian section do not appear to modify the risk of developing the disease [33].

Pregnancy seems to affect cardiac structure and function, even if uneventful. Melchiorre et al found that by the end of uneventful pregnancy, significant LV diastolic dysfunction and impaired myocardial relaxation were evident in 17.9% and 28.4% of women, respectively, whereas myocardial contractility was preserved [34]. There was full recovery of the cardiac dysfunction at 1 year postpartum [34].

Outcomes

LV function recovery and mortality rates for PPCM vary widely across the globe due to several reasons; likely a reflection of the standard of medical care in various Countries [35–39]. Mortality rates as high as 24.2% at 6 months and 47.4% at 1 year of follow-up have been reported in Kano, Nigeria, but much lower rates of 13.0% over 6 months in South Africa, 15.3% over 2 years in Haiti and 28.0% over 5 years in USA, have also been reported [35–39]. In addition, the majority of the deaths seem to occur within 6 months of a PPCM diagnosis [35–39]. Although some researchers didn’t identify any predictors of mortality, others inconsistently reported younger age at diagnosis, lower body mass index (BMI) and some echocardiographic variables as independent predictors of mortality [35–39].

LV reverse remodelling (LVRR) was recently shown to involve both LV systolic and diastolic functions, and maximum improvement seems to occur within the first 6 months of PPCM diagnosis [38–40]. In our cohort, 47.1% satisfied the criteria for LVRR while 29.4% recovered LV systolic function at 1 year follow-up [38]. Blauwet et al found older age and smaller LV end-systolic dimension (LVESD) to be significant predictors of LV recovery among PPCM patients in South Africa [35]. In addition, “electrical remodelling” in the form of shortening of previously broad QRS duration, which is suggestive of improved LV function, has also been reported among PPCM patients [41].

Right ventricular (RV) systolic and diastolic dysfunction (RVSD and RVDD respectively) have been recently studied in PPCM, suggesting that the disease is bi-ventricular in nature[39,42,43]. Karaye et al recently reported a prevalence of RVSD of 71.1% of the patients at baseline, which fell to 36.4% at 6 months and 18.8% at 1 year [39]. Karaye et al also found RVDD in 69.8%, and combined RVSD and RVDD in 58.1% of PPCM patients [44]. In this study, Selenium deficiency was the only variable that significantly determined RVDD, being related to impaired RV relaxation in late diastole [44].

Hypotheses

The aetiology of PPCM is multifactorial, and we hypothesised that in our setting, the impact of selenium deficiency on hemodynamic effects of pregnancy on cardiac function is probably of significant importance. We also hypothesised that selenium supplementation using oral Sodium Selenite 200 µg/day for 3 months, will be safe, and could correct the selenium deficiency in affected subjects and improve the LV systolic function.

The primary aim of the present study is to describe the burden and demographic, social and clinical characteristics, ventricular remodelling and survival of PPCM in Nigeria. In the first substudy, we aim to describe the prevalence of selenium deficiency and its relationship with cardiac function in apparently healthy pregnant women in Nigeria (control group). In the second substudy, we aim to determine the relationship between selenium deficiency, oxidative stress and PPCM, and the impact of sodium selenite supplementation on LVRR, change in New York Heart Association (NYHA) functional class and survival, in an open-label randomised trial.

Methods

Study design

The main Registry is a prospective, national, multicentre longitudinal study, being conducted in centres in Nigeria. It is expected that PPCM subjects will be recruited in 36 registered tertiary and secondary level healthcare centres in Nigeria that have Doppler echocardiography facility. Fourteen centres have started recruiting patients on 5th June 2017, and the remaining 22 centres are expected to join soon.

The sub-studies are being carried out in only 4 centres in 2 cities (Kano and Ile-Ife) in Nigeria, because of the logistics of biomarker assays. The first sub-study is also a longitudinal study in which apparently healthy pregnant women at 28-38 weeks of gestation and attending antenatal clinic (ANC) are being recruited, evaluated and followed up till 6-8 weeks postpartum.

The second sub-study is an open-label randomised trial in which oral Sodium Selenite (by NaturesWay®) 200 µg/day for 3 months will be offered to PPCM patients with selenium deficiency and LVEF<45% at 6 months postpartum. The randomisation is being carried out by simple balloting at the laboratories of the participating centres by the lead Chemical Pathologist who is blinded to the patients’ identities and clinical characteristics, after measuring the biomarkers of the patients and confirming their selenium deficiency status.

Sample size estimation for the sub-study

The minimum sample size for the sub-study was estimated at 32, using 2-sided significance level of 95%, a power of 80% and prevalence of selenium deficiency among apparently healthy postpartum women of 22% and among untreated PPCM patients of 76.9%.[20] However, we shall recruit into the sub-studies 200 PPCM subjects and randomise them to treatment and control groups, and 120 apparently healthy pregnant subjects who have satisfied the inclusion criteria.

Inclusion criteria

  1. Confirmed diagnosis of PPCM

  2. PPCM patients with HF symptoms at the time of recruitment (for new patients only)

  3. Asymptomatic pregnant women attending antenatal clinic (ANC) (Control group)

  4. Sub-study: Open-label randomised Trial: Non-pregnant PPCM patients with all of the following: LVEF <45% at 6 months postpartum AND selenium deficiency

  5. Written informed consent

Exclusion criteria

  1. Asymptomatic PPCM patients at the time of recruitment (for new patients only)

  2. Patients being followed up for PPCM who have LVEF ≥45% at recruitment

  3. Pregnant women with any medical condition other than PPCM

  4. Subjects who are considered not likely to attend follow up reviews regularly, because of lack of patient’s and close relative’s phone numbers, or long distance from the study centre, etc.

  5. Refusal or withdrawal of consent

Qualified PPCM subjects that are being followed up by the centres are to be recruited regardless of the presence of symptoms.

Diagnosis of PPCM

PPCM will be defined according to the recommendations of the HF Association of ESC Working Group on PPCM [7]. The LV may not be dilated but the LVEF should be <45%. It is a diagnosis of exclusion. HF will be defined as a syndrome in which patients have the following features: symptoms of HF, typically shortness of breath at rest or during exertion, and/or fatigue; signs of fluid retention such as pulmonary congestion or ankle swelling; and objective evidence of an abnormality of the structure or function of the heart at rest [45].

Data collection

E-mails were sent to the e-mail group of the Nigerian Cardiac Society to invite all centres to join the Registry. Centres that have facilities to assay the biomarkers for the sub-study were invited to join it. A Study Protocol was provided to each of the sites to guide investigators to consistently complete the CRFs and send to the Registry Coordinator through the site’s Principal Investigator (PI). At the study sites, physicians and obstetricians are being approached and requested to consecutively refer all patients with suspected PPCM to the investigators, for further evaluation. In addition, apparently healthy pregnant women attending the antenatal clinic are being consecutively referred to the investigators for evaluation and follow up at no cost. The study would be explained to the subjects, and they would then be interviewed, clinically evaluated and recruited consecutively after applying the inclusion and exclusion criteria. Demographic data, relevant aspects of history and physical signs, results of investigations, medications, co-morbid conditions, and complications would be recorded in a detailed questionnaire.

Enrolment visit

At this visit, each subject will have a 12-lead ECG and transthoracic echocardiogram at rest at the study centres according to standard recommendations [46,47]. Other baseline investigations recommended for the management of patients with PPCM would be carried out at the laboratories of the study centres, including complete blood counts and serum urea, electrolytes and creatinine [7]. For the study centres that have facilities to join the sub-study, the serum selenium and glutathione peroxidise (GPO) will be assayed according to standard criteria [48–50]. Abnormal values of the biomarkers will be defined as serum selenium <70µg/L and GPO >470U/L.

Follow-up visits

Patients will be reviewed every 3 months for 18 months, and investigations will be repeated every 6 months. Patients and subjects will be contacted by telephone and reminded of their follow-up appointment. Data will be recorded in the study questionnaire.

Subjects in the treatment arm of the randomised open-label trial will be given sodium selenite 200µg tablets to take daily for 3 months. One month supply of the drug will be supplied to each patient at a time, and all the patients in the sub-study will be reviewed monthly for the 3 months and then every 3 months. Both arms will continue to receive best medical treatment according standard recommendations [7,45]. Patients’ compliance with the selenium treatment will be ensured by using both pill counts and checking selenium and GPO serum levels at the completion of the 3 months treatment. ECG and echocardiography will be carried out at baseline, and then every 6 months till the completion of the study, at 12-18 months of follow up. All adverse events relating to the supplementation will be recorded and sent to the Registry Coordinator for forwarding to the appropriate local authority. The following details will be expected for each patient reporting an adverse event following the selenium supplementation: name, age, hospital number, address, type of adverse event, date and time of the event, the intervention needed to treat the event, and the outcome of the intervention. The patients’ journey from enrolment to the end of the study is summarised in Figure 1.

Cardiac function assessment

Standard echocardiographic recordings would be obtained, and LVRR would be defined as the presence of both absolute increase in LVEF ≥10.0% and decrease in LV end-diastolic dimension indexed to body surface area (LVEDDi) ≤33.0mm/m2, while recovered LV systolic function as LVEF ≥55%, during the follow-up.[40,46] Echocardiographers will be blinded to the subjects’ study/treatment group.

LV diastolic function (LVDD) would be defined and graded using trans-mitral flow and LV myocardial TDI velocities at the mitral (septal) annular level as follows:[46]

Normal LV diastolic function: E:A ratio 1-2, deceleration time (DT) 160-230 milliseconds(ms) and E/e’ <8.

Grade I LVDD (impaired myocardial relaxation): E:A <1.0 and DT >240ms.

Grade II LVDD (pseudonormalised pattern): E:A 1-1.5, DT 160-230ms, e’ <7cm/s and E/e’ >15.0.

Grade III LVDD (restrictive filling): E:A >2.0, DT <160ms, e’ <7cm/s and E/e’ >15.0.

Figure 1

Flow of subjects

Legend: GPO, glutathione peroxidise; LVEF, left ventricular ejection fraction.

icfj.2017.12.12-g001.jpg

Laboratory methods - Specimen collection and processing

Five millilitres (5ml) of blood is being collected from the study participants for the biomarkers assays. Blood specimen will be obtained using a prominent vein (antecubital fossa is the preferred site), and minimal tourniquet time is recommended (<2mins). Skin is cleansed with alcohol swab and the site allowed to dry before venepuncture. Serum separator tube (clot and gel) bottles are used for all samples. Blood is allowed to clot for 30 minutes at 25°c, centrifuged at 3000rpm for 15 minutes, and then the serum transferred into a plain tube and frozen until analysis. Avoid repeated freeze-thaw cycles, and ensure prompt separation of cells from serum. The labelled serum samples are sent to the laboratory immediately and analysis is recommended as soon as possible although the serum is stable for one month at -80°c. GPO will be assayed using the Sandwich ELISA technique while Serum selenium would be measured using the Inductive Coupled Plasma Mass Spectrometry method.

Ethics

Informed consent shall be obtained from all recruited subjects and a consent form signed. Ethical approval for the study has been or is being sought from the Ethical Research Committees of all the participating centres before the commencement of the study, and the research shall conform to the ethical guidelines of the Declaration of Helsinki; on the principles for medical research involving human subjects [51].

Statistical analysis

Continuous variables would be explored for the presence of skewness. Proportions, medians with interquartile ranges and means with standard deviations will be used to summarise patients’ characteristics, as appropriate. Chi-square, Fisher’s exact probability, Student’s t and Mann-Whitney tests will be used to compare categorical and continuous variables, as appropriate. Regression be models will used to determine predictors of survival and LVRR, and results will be expressed as Odds ratio (OR) with 95% confidence intervals (95%CI). Survival analysis will be conducted using Kaplan-Meier curves and Log rank test obtained for survival and LVRR indices between patients treated and not-treated with selenium. The statistical analysis will be carried out using SPSS version 17.0 software. Two-sided p-value <0.05 will be considered as minimum level of statistical significance.

Discussion

This will be the largest systematic evaluation of PPCM in Nigeria, which will describe the burden and demographic, social and clinical characteristics and treatment of the disease. The study will also describe the ventricular remodelling and outcomes of PPCM, the relationship between selenium deficiency, oxidative stress and PPCM, the prevalence of selenium deficiency and its relationship with cardiac function in apparently healthy pregnant women, and the impact of sodium selenite supplementation on cardiac function among PPCM patients, in Nigeria. This information will assist in better understanding and in developing large-scale clinical trials and interventions for this seemingly deadly disease.

We recently observed that in Kano, Nigeria, a majority of PPCM patients who achieved LVRR did so at 6 months followup and the development was not significantly associated with the use of angiotensin-aldosterone receptor antagonists and beta-blockers [38]. For the present open-label randomised selenium trial, we therefore decided to enrol only patients with LVEF <45% and selenium deficiency at 6 months postpartum so as to fully appreciate the impact of selenium replacement on LV remodelling, independent of the natural course of the disease.

The available literature on PPCM is limited in several ways. Although Nigeria probably has the highest burden of PPCM in the world, much of the epidemiology of the disease is yet to be described in a comprehensive national study. Secondly, the studies that have described the outcomes of PPCM in Nigeria and elsewhere are still few, and have significant differences in objectives, methodology and follow-up periods. However, the relevance of this information on the management of affected patients and control of the disease cannot be over-emphasised. In addition, the relationship between selenium deficiency and PPCM seems to be relevant, and if proven, could potentially lead to a cure of the disease. However, the 2 studies that suggested the relevance of selenium deficiency in PPCM were singlecentred and involved only small number of patients. Therefore, the results need to be further substantiated. Finally, the data on cardiac function during pregnancy in Nigeria is limited, and its relationship with selenium deficiency has not yet been described. The results of this study could be very relevant in preventing the disease, and perhaps add to the armamentarium for treating it.

Limitations

The present study has several limitations. Most importantly PEACE Registry has very limited funding in spite of all our efforts. In fact we are relying on personal funds and donations from philanthropists. The ideal study design for the first sub-study is a randomised double-blind placebo-controlled trial, but our desire for the ideal was barred by the limited funding. We also had to limit the sample size of the sub-study because of the funding challenge. It is our sincere hope that the results of PEACE Registry will open the doors of more funding for us to search for more answers for PPCM.

Conclusions

This will be the largest systematic evaluation of PPCM in Nigeria, and it is hoped that the information will assist in developing locally applicable treatment guidelines and policies for the disease.

Declarations of interest

The authors declare no conflict of interest

Acknowledgements

The authors are most grateful to the sponsors of PEACE Registry: Dantata Group of Companies, Ammasco International Ltd and Fortune Oil Mills Nigeria Ltd. We are also very grateful to Professor Rasaaq Adebayo and Drs Hadiza Saidu, Naser Ishaq, Mohammed A Talle and Balarabe S Amin for their thoughtful suggestions on the Study Protocol. The authors agree to abide by the requirements of the “Statement of publishing ethics of the International Cardiovasular Forum Journal [52].

References

1. 

Virchow R Sitzing der Berliner Geburtshilflisher Gersellskhalt, cited by Porak, C. De l’influence réciproque de la grossesse et des maladies du Coeur, thesis, Paris. 1880;

2. 

Porak C De l’influence réciproque de la grossesse et des maladies du Coeur, thesis, Paris. 1880;

3. 

Gouley BA, McMillan TM, Bellet S Idiopathic myocardial degeneration associated with pregnancy and especially the puerperium. Am J Med Sci 1937; 19: 185–199

4. 

Hull E, Hidden E Postpartal heart failure. South Med J 1938; 31: 265–270

5. 

Demakis JG, Rahimtoola SH Peripartum cardiomyopathy. Circulation 1971; 44: 964–968

6. 

Demakis JG, Rahimtoola SH, Sutton GC, et alNatural course of Peripartum cardiomyopathy. Circulation 1971; 44: 1053–1061

7. 

Sliwa K, Hilfiker-Kleiner D, Petrie MC, et alHeart Failure Association of the European Society of Cardiology Working Group on Peripartum Cardiomyopathy. Current state of knowledge on aetiology, diagnosis, management, and therapy of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Working Group on peripartum cardiomyopathy. Eur J Heart Fail 2010; 128767–778 doi:10.1093/eurjhf/hfq120

8. 

Ferriere M, Sacrez A, Bouhour JB, et alCardiomyopathy in the peripartum period: current aspects. A multicenter study. 11 cases. Arch Mal Coeur Vaiss 1990; 83101563–1569

9. 

Cénac A, Djibo A Postpartum cardiac failure in Sudanese-Sahelian Africa: clinical prevalence in western Niger. Am J Trop Med Hyg 1998; 58: 319323

10. 

Pearson GD, Veille JC, Rahimtoola S, et alPeripartum cardiomyopathy: National Heart, Lung, and Blood Institute and Office of Rare Diseases (National Institutes of Health) workshop recommendations and review. JAMA 2000; 283: 1183–1188

11. 

Fett JD, Christie LG, Carraway RD, et alFive-year prospective study of the incidence and prognosis of peripartum cardiomyopathy at a single institution. Mayo Proceed 2005; 80: 1602–1606

12. 

Desai D, Moodley J, Naidoo D Peripartum cardiomyopathy: experiences at King Edward VIII Hospital, Durban, South Africa and a review of the literature. Trop Doct 1995; 25: 118–123

13. 

Mielniczuk LM, Williams K, Davis DR, et alFrequency of peripartum cardiomyopathy. Am J Cardiol 2006; 97: 1765–1768 doi:10.1016/j.amjcard.2006.01.039

14. 

Karaye KM, Sa’idu H, Habib AG Peripartum and other cardiomyopathies in a Nigerian adult population. Int J Cardiol 2011; 1472342–343 doi:10.1016/j.ijcard.2011.01.004

15. 

Sliwa K, Fett J, Elkayam U Peripartum cardiomyopathy. Lancet 2006; 368: 687–693 doi:10.1016/S0140-6736(06)69253-2

16. 

Abboud J, Murad Y, Chen-Scarabelli C, et alPeripartum cardiomyopathy: a comprehensive review. Int J Cardiol 2007; 12: 1183295–303 doi:10.1016/j.ijcard.2006.08.005

17. 

Karaye KM, Sani MU The Impact of Income on the Echocardiographic Pattern of Heart Diseases in Kano, Nigeria. Niger J Med 2008; 173350–355

18. 

Elkayam U, Akhter MW, Singh H, et alPregnancy-associated cardiomyopathy: clinical characteristics and a comparison between early and late presentation. Circulation 2005; 111: 2050–2055 doi:10.1161/01.CIR.0000162478.36652.7E

19. 

Keshan Disease Research Group of the Chinese Academy of Medical Sciences, Beijing. Epidemiologic studies on the etiologic relationship of selenium and Keshan disease. Chin Med J (Engl.) 1979; 92: 477–482

20. 

araye KM, Yahaya IA, Lindmark K, et alSerum Selenium and Ceruloplasmin in Nigerians with Peripartum Cardiomyopathy. Int J Mol Sci 2015; 16: 76447654 doi:10.3390/ijms16047644

21. 

Sheppard R, Hsich E, Damp J, et alGNB3 C825T Polymorphism and Myocardial Recovery in Peripartum Cardiomyopathy. Results of the Multicenter Investigations of Pregnancy-Associated Cardiomyopathy Study. Circ Heart Fail 2016; 9: e002683 doi:10.1161/CIRCHEARTFAILURE.115.002683

22. 

Niklas K, Niklas A, Puszczewicz M, Radziemski A, Tykarski A Coincidence of peripartum cardiomyopathy and systemic lupus erythematosus. Kardiol Pol 2016; 742194 doi:10.5603/KP.2016.0023

23. 

Karaye KM, Lindmark K, Henein MY Left ventricular structure and function among sisters of peripartum cardiomyopathy patients. Int J Cardiol 2014; 182C: 34–35 doi:10.1016/j.ijcard.2014.12.102

24. 

Fillmore SJ, Parry EH The evolution of peripartal heart failure in Zaria. Circulation 1977; 56: 1058–1061

25. 

Sanderson JE, Adesanya CO, Anjorin FI, Parry EHO Postpartum cardiac failure-heart failure due to volume overload?. Am Heart J 1979; 97: 613–621 doi:10.1016/0002-8703(79)90189-3

26. 

Wang GY, Zhou R, Sun S, et alThe difference between whole blood and hair selenium levels of inhabitants in the endemic and nonendemic areas of Keshan disease (author’s translation). Zhonghua Yu Fang Yi Xue Za Zhi 1979; 13: 204–206

27. 

Loscalzo J Keshan Disease, Selenium Deficiency, and the Selenoproteome. N Engl J Med 2014; 370: 181756–1760 doi:10.1056/NEJMcibr1402199

28. 

Beck MA, Levander OA, Handy J Selenium deficiency and viral infection. J Nutr 2003; 133: Suppl 11463S–1467S

29. 

Fett JD, Ansari AA, Sundstrom JB, et alPeripartum cardiomyopathy: a selenium disconnection and an autoimmune connection. Int J Cardiol 2002; 86: 311–316

30. 

Asemi Z, Jamilian M, Mesdaghinia E, et alEffects of selenium supplementation on glucose homeostasis, inflammation, and oxidative stress in gestational diabetes: Randomized, double-blind, placebocontrolled trial. Nutrition 2015; 31: 101235–1242 doi:10.1016/j.nut.2015.04.014

31. 

Mesdaghinia E, Rahavi A, Bahmani F, et alClinical and Metabolic Response to Selenium Supplementation in Pregnant Women at Risk for Intrauterine Growth Restriction: Randomized, Double-Blind, Placebo-Controlled Trial. Biol Trace Elem Res 2017; 178114–21 doi:10.1007/s12011-016-0911-0

32. 

Ruys TP, Roos-Hesselink JW, Hall R, et alHeart failure in pregnant women with cardiac disease: data from the ROPAC. Heart 2014; 100: 231–238 doi:10.1136/heartjnl-2013-304888

33. 

Arany Z, Elkayam U Peripartum cardiomyopathy. Circulation 2016; 133: 1397–1409 doi:10.1161/CIRCULATIONAHA.115.020491

34. 

Melchiorre K, Sharma R, Khalil A, et alMaternal cardiovascular function in pregnancy. Evidence of maladaptation to chronic volume overload. Hypertension 2016; 67: 754–762 doi:10.1161/HYPERTENSIONAHA.115.06667

35. 

Blauwet LA, Libhaber E, Forster O, et alPredictors of outcome in 176 South African patients with peripartum cardiomyopathy. Heart 2013; 995308–313 doi:10.1136/heartjnl-2012-302760

36. 

Fett JD, Christie LG, Carraway RD, et alFive-year prospective study of the incidence and prognosis of peripartum cardiomyopathy at a single institution. Mayo Clin Proc 2005; 80121602–1606 doi:10.4065/80.12.1602

37. 

Witlin AG, Mabie WC, Sibai BM Peripartum cardiomyopathy: an omnious diagnosis. Am J Obstet Gynecol 1997; 176: 182–188

38. 

Karaye KM, Lindmark K, Henein MY One year survival in Nigerians with peripartum cardiomyopathy. Heart Views 2016; 17: 55–61 doi:10.4103/1995-705X.185114

39. 

Karaye KM, Lindmark K, Henein MY Right ventricular systolic dysfunction and remodelling in Nigerians with peripartum cardiomyopathy: a longitudinal study. BMC Cardiovasc Disord 2016; 16: 27 doi:10.1186/s12872-016-0204-8

40. 

Merlo M, Pyxaras SA, Pinamonti B, et alPrevalence and prognostic significance of left ventricular reverse remodeling in dilated cardiomyopathy receiving tailored medical treatment. J Am Coll Cardiol 2011; 5713146876 doi:10.1016/j.jacc.2010.11.030

41. 

Karaye KM, Lindmark K, Henein MY Electrocardiographic predictors of peripartum cardiomyopathy. Cardiovasc J Afr 2016; 27266–70 doi:10.5830/CVJA-2015-092

42. 

Karaye KM Right ventricular systolic function in peripartum and dilated cardiomyopathies. Eur J Echocardiogr 2011; 125372–374 doi:10.1093/ejechocard/jer024

43. 

Blauwet LA, Delgado-Montero A, Ryo K, et alIPAC Investigators. Right Ventricular Function in Peripartum Cardiomyopathy at Presentation Is Associated With Subsequent Left Ventricular Recovery and Clinical Outcomes. Circ Heart Fail 2016; 95pii: e002756 doi:10.1161/CIRCHEARTFAILURE.115.002756

44. 

Karaye KM, Lindmark K, Henein MY Prevalence and predictors of right ventricular diastolic dysfunction in peripartum cardiomyopathy. J Echocardiogr 2017; doi:10.1007/s12574-017-0333-9

45. 

Dickstein K, Cohen-Solal A, Filippatos G, et alESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008 the Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur J Heart Fail 2008 10: 933–989 doi:10.1016/j.ejheart.2008.08.005

46. 

Lang RM, Badano LP, Mor-Avi V, et alRecommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015; 2811–39 doi:10.1016/j.echo.2014.10.003

47. 

Kadish AH, Buxton AE, Kennedy HL, et alACC/AHA clinical competence statement on electrocardiography and ambulatory electrocardiography: a report of the American College of Cardiology/American Heart Association/American College of Physicians - American Society of Internal Medicine Task Force on Clinical Competence (ACC/AHA Committee to Develop a Clinical Competence Statement on Electrocardiography and Ambulatory Electrocardiography). J Am Coll Cardiol 2001; 38: 2091–2100

48. 

Lefevre G, Bonneau C, Rahma S, et alDetermination of plasma protein- bound malondialdehyde by derivative spectrophotometry. Eur J Clin Chem Clin Biochem 1996; 34: 631–636

49. 

Marklund SL, Holme E, Hellner L Superoxide dismutase in extracellular fluids. Clinica Chimica Acta 1982; 126: 41–51

50. 

Wheeler CR, Salzman JA, Elsayed NM, et alAutomated assays for superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activity. Anal Biochem 1990; 1842193–199

51. 

World Medical Association Declaration of Helsinki, Ethical Principles for Medical Research Involving Human Subjects. J Postgrad Med 2002; 48: 206–208

52. 

Shewan LG, Coats AJS, Henein M Requirements for ethical publishing in biomedical journals. International Cardiovascular Forum Journal 2015; 2: 2 doi:10.17987/icfj.v2i1.4



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