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Heart of Africa and Cardiac Disease & Maternity Research Group

The Heart of Africa and the Cardiac Disease in Maternity Research Groups were established in 2010 by the Director, Prof Karen Sliwa.

HEART OF AFRICA GROUP

The ‘Heart of Soweto Study’ (8000 patients) reporting on the prevalence, presentation and management of cardiac disease in an urban African population was published in the Lancet in 2008 (IF 59, CI 367). This seminal paper led to more than 25 publications describing the impact of HIV/AIDS on CVD (Sliwa. European Heart Journal, 2012), the prevalence of rheumatic heart disease diagnosed in adulthood (Sliwa. European Heart Journal, 2010) and the spectrum of conditions leading to heart failure (Stewart/Sliwa; Circulation 2008). The Heart of Soweto studies included cohort studies in tertiary, secondary and primary care facilities.

Those population studies were expanded (under the umbrella of the ‘Heart of Africa Studies’) to other African countries, through the design of several innovative research programs and leveraging of funding. One such study was the THESUS study, which documented the factors contributing to acute heart failure management and outcome in a multi-centre cohort study (Damasceno et al. Archives of Internal Medicine 2012). A large team of researchers from Africa, linked to the Hatter Institute for Cardiovascular Research in Africa, continue to perform several other African clinical studies. A few examples are listed below:

RESEARCH COLLABORATORS:  Prof Karen Sliwa (HICRA), Prof Mpiko Ntsekhe  Cardiology, UCT), Prof Albertino Damasceno  and Prof Ana Mocumbi  Eduardo Modlane University, Mozambique); Prof Elija Ogola (Nairobi, Kenya), Prof Mahmoud Sani (Kano, Nigeria), Prof Dike Ojji (Abuja, Nigeria), Dr Anastase Dzudie (Douala, Cameroon), Prof S. Ba (Dakar, Senegal), Prof Gad Cotter (Momentum Research, USA & Visiting Professor UCT); Prof Simon Stewart (Melbourne, Australia & Visiting Professor UCT), Prof Friedrich Thienemann (UCT & ETH Zurich, Switzerland), Prof Ntobeko Ntusi (Head of Medicine, UCT), Prof Gary Maartens (Head of Clinical Pharmacology, UCT), Dr Hadiza Saidu Bala (Murtala Muhammad Specialist Hospital, Kano, Nigeria), Prof Pindile Mntla (Sefako Makgatho Health Sciences University), Prof Rampule Ratsela (University of Limpopo), Dr K Thomas & Dr MB Thomas (Nelson Mandela Academic Hospital, Mthatha), Prof Makoali Makotoko (University of the Free State - Universitas Hospital)

SELECTED PROJECTS:

‘STRONG-HF’ Study in AFRICA (Registry and Number:ClinicalTrials.gov NCT03412201 )

STRONG-HF is a global, multicentre, randomized, parallel group study designed to evaluate the efficacy and safety of up-titration of standard of care medical therapy including beta-blockers; ACEi, ARB or ARNi; and MRAs, on morbidity and mortality when initiated and up-titrated early during hospitalization for acute heart failure (AHF).

Primary objective: To assess the effects of optimization of medical therapy with beta-blocker; ACEi, ARB or ARNi; and MRAs on 90-day all-cause mortality, or heart failure readmission in patients admitted with acute heart failure and clinical and biological signs of congestion.

Secondary objectives:  To assess the effect of such intervention on 90-day all-cause mortality, 180-day all-cause mortality, change in quality of life (QoL), as measured by the EQ-5D questionnaire, and 90-day change in NT-proBNP. The STRONG-HF study started enrolment in Africa in November 2018.

To date we have enrolled more than 400 of the 900 patients.

The ADHERENCE Study (Sub-study of the above STRONG-HF study)

Drug concentrations of heart failure medication in plasma, dried blood spots, and/or hair as predictors of clinical outcomes. (ADHERENCE) UCT HREC Ref: 480/2018

In the adherence sub-study, patients who were enrolled in and screened for STRONG-HF, but who do not meet the biomarker criteria for persistent congestion, will be included (NT-proBNP > 2,500 pg/mL at screening, and NT-proBNP > 1,500 pg/mL at randomization).    

Primary objective:  To determine if low or undetectable concentrations of carvedilol and enalaprilat/perindoprilat in plasma and DBS predict poor outcomes (combined endpoint of re-admission to hospital and death) in study participants.

Secondary objectives: (1) To determine the proportion of study participants with undetectable or low concentrations of carvedilol and enalaprilat/perindoprilat in plasma and DBS.  (2) To determine if lower hair concentrations of carvedilol and enalapril/perindopril predict poor outcomes (combined endpoint of re-admission to hospital and death) in study participants.

The ADHERENCE Sub-study is only conducted in Africa and to date has enrolled 50 participants

Both the STRONG-HF Study and the ADHERENCE Sub-study are currently being conducted in South Africa, Nigeria and Mozambique, with Prof Karen Sliwa as the national Leader for South Africa (STRONG-HF) and the Principal Investigator and Study leader for the ADHERENCE Study. Olivia Briton is the Lead Study Coordinator for both studies in Africa. The STRONG-HF study is sponsored by ‘The Heart Initiative’ based in Durham, NC, USA

Global Congestive Heart Failure (G-CHF): A global registry to study the demographics, socioeconomic and clinical factors, aetiologies, pathophysiology, management, barriers to care and outcomes of heart failure patients.

The G-CHF Study is a prospective, global, registry study of 20 000 – 25 000 Heart Failure (HF) patients enrolled over 5 years. The baseline data was obtained on demographic and socioeconomic data, clinical and laboratory variables, echocardiography, HF aetiology, medication use, management patterns, quality of life, barriers to care and health systems. Six-month, 12-month, 18-month and 24-month follow-up data will be obtained to determine changes in management and patient outcomes.

The study in South Africa is presently busy with follow-up and they have managed to enrol 111 patients into the main study, which is led by Prof Karen Sliwa as the National Leader, together with her Study Coordinator, Olivia Briton. Prof Sliwa is also part of the G-CHF Steering Committee.

The Contributing Investigators in South Africa are Prof Mpiko Ntsekhe (Groote Schuur Hospital, Cape Town), Dr MB Thomas (Nelson Mandela Academic Hospital, Mthatha), Prof EM Makotoko (Universitas Hospital, Bloemfontein) Prof Pindile Mntla (Dr George Mukhari Hospital, Ga-Rankuwa, Gauteng) and Prof Rampule Ratsela (Polokwane Pietersburg Hospital, Pietersburg)

To date there have been 22,135 patients enrolled globally, since 20 December 2016. The initial target for recruitment completion was 2021. However, PHRI stopped the main study (only) recruitment prematurely at the end of 2018 because they were hugely successful in recruiting so many patients in such a small amount time. A wonderful accomplishment.

The Pan African Pulmonary Hypertension Cohort (PAPUCO) Study

The main objective of this research is to describe the epidemiology of pulmonary hypertension (PH) in patients from several African countries.

The main outcome of the study has been published: Prevalence and predictive value of electrocardiographic abnormalities in pulmonary hypertension: evidence from the Pan-African Pulmonary Hypertension Cohort (PAPUCO) study (Cardiovasc J Afr. 2017 Nov/Dec 23;28(6):370-376) and The causes, treatment, and outcome of pulmonary hypertension in Africa: Insights from the Pan African Pulmonary Hypertension Cohort (PAPUCO) Registry (Int J Cardiol. 2016 Oct 15;221:205-11). Further analysis and manuscripts are currently submitted.

PH is a condition of varying aetiologies that is primarily characterised by narrowing of the pulmonary vasculature and consequential right heart failure (RHF). It is a devastating, progressive disease associated with increasingly debilitating symptoms and a poor prognosis. However, the majority of reports emanate from high-income countries. Based on the hypothesis that the underlying pathways to this deadly condition would in Africa be many and varied and produce a high burden of disease (relative to high-income countries), we initiated the Pan African Pulmonary Hypertension Cohort (PAPUCO) Registry Study; a unique study in the African context. The study provides prospective, standardised Profiling and outcome data (including 6-month survival Profiles) in a series of consecutive African patients, newly diagnosed with PH, from participating centres across the African continent. Our data provide new insights into PH from a developing world perspective; with clear opportunities to improve its prevention, treatment and outcomes and taking into account the relative lack of health resources and the need to provide practical guidelines for its rapid detection and optimal management in the African context.

B-A-HEF STUDY

Recent research in cardiovascular disease in African populations (Heart of Soweto Study), specifically of heart failure (THESUS Study – Damasceno et al. The causes, treatment and outcome of acute heart failure  in 1006 Africans from 9 countries. Arch Intern Med, 2012), has shown that heart failure is not treated optimally in Africa.  Prof Sliwa has been the principal investigator of a prospective, placebo-controlled, double-blind, randomized study to compare treatment with Hydralazine-Isosorbide–Dinitrate (HYIS) versus placebo on top of standard care in African patients admitted with Acute Heart Failure (AHF) and left ventricular dysfunction - the BA-HEF study. This study commenced in January 2013 and the results were reported at the European Cardiac Society meeting in Florence, Italy in May 2016 and, simultaneously, published in the European Journal of Heart Failure. The use of different medications such as ACEi and hydralazine/nitrates, has never been examined in patients admitted with acute heart failure. The BA-HEF trial demonstrated challenges in recruiting the expected number of patients with acute heart failure in several African countries, thus highlighting the need for strategic logistic support.

 

CARDIAC DISEASE IN MATERNITY RESEARCH GROUP

Over the last decade a steady increase in the rate of institutional maternal mortality for cardiac disease in South Africa has been reported. We have found that after non-pregnancy related infections, cardiac disease is the second most common cause of indirect maternal death, with Peripartum Cardiomyopathy (PPCM) and complications due to rheumatic heart disease contributing to more than 50% of cases.  The objective of this research group is to investigate cardiac disease that is interlinked with pregnancy or the postpartum period.

RESEARCH COLLABORATORS:  Prof Karen Sliwa (HICRA); Prof John Anthony (Dept Obstetrics & Gynaecology, UCT); Prof Liesl Zϋhlke (UCT); Prof Ana Mocumbi (Mavelane Hospital, Mozambique); Prof Albertino Damasceno (Eduardo Mondlane University, Maputo, Mozambique);  Prof Kamilu Karaye and Prof Mahmoud Sani (Kano University, Nigeria);  Prof Abel Makubi (Muhimbili National Hospital, Dar Es Salaam, Tanzania);  Mrs Olivia Briton (HICRA);  Prof Sandrine Lecour (HICRA);  Prof Denise Hilfiker-Kleiner (Hannover University, Germany);  Prof Michael Böhm ( University of Saarland, Homburg, Germany), Dr Kemi Tibazarwa (Muhimbili Hospital, Tanzania); Prof Jolien Roos-Hesselink (Erasmus Medical Centre, Rotterdam, Netherlands);  Prof Mark Johnson (Imperial College, London, UK); Prof  Alexandre Mebazaa and Dr Feriel Azibani (Hôpitaux Universitaires Saint-Louis-Lariboisière University Paris Diderot); Dr Naisa Manafe (Maputo Mozambique); Prof Mark Petrie and Dr Alice Jackson (University of Glasgow, Scotland); Prof Johann Bauersachs (Medizinische Hochschule Hannover, Germany); Dr Ranio Zhang Zu (HICRA), Mr Vitaris Kodogo (HICRA) and Dr Graham Chakafana (HICRA).

SELECTED PROJECTS:

Peripartum Cardiomyopathy – Current Research

The team has for many years investigated the pathogenesis, etiology, epidemiology and management of a condition, peripartum cardiomyopathy (PPCM), which is common in African women. PPCM is a disease which develops in previously healthy women before delivery, or in the postpartum period, with a reported mortality of about 25%.

This research has resulted in numerous publications in prestigious journals such as the European Heart Journal (2006, 2014, 2016), Journal of the American College of Cardiology, The Lancet (2006), Cell (2007) and Circulation (2011, 2012, 2013).  Research into subsequent pregnancies in women who had PCM resulted in a practical guidance paper:  Sliwa K, Petrie MC, Hilfiker-Kleiner D, et al. Long-term prognosis, subsequent pregnancy, contraception and overall management of peripartum cardiomyopathy: practical guidance paper from the Heart Failure Association of the European Society of Cardiology Study Group on Peripartum Cardiomyopathy. Eur J Heart Fail. 2018 20(6):951-962

The positive results of the proof-of-concept pilot was published in Circulation in March 2010 and confirmed in a multi-centre study performed in Germany (Hilfiker-Kleiner, Haghikia A, Berliner D, … Sliwa K, Bauersachs J.  Bromocriptine for the treatment of peripartum cardiomyopathy: a multicentre randomized study.  European Heart Journal. 2017; 0: 1-9).

The use of bromocriptine, 2.5 mg daily for 7 days post diagnosis of PPCM, was also included in the 2018 ESC Guidelines on Cardiac Disease in Pregnancy.

We recently highlighted the importance of the contribution of PPCM to later maternal death in The Lancet (2016). Some aspects of our research forms part of collaborative projects with the University of Hannover, Germany (Prof Hilfiker-Kleiner), and the University of Saarland, Homburg, Germany (Prof Böhm).

PPCM Working Group of Heart Failure Association of European Society of Cardiology

Prof Sliwa’s research translated into the establishment (in 2009) of the Peripartum Cardiomyopathy Working Group of the Heart Failure Association (PPCM HFA) of the European Cardiac Society (ESC).  The aims of this study group, chaired by Prof Karen Sliwa and Prof Johann Bauersachs (Hannover University, Germany), are to:

•             Establish a platform where current knowledge on PPCM, based on experimental and clinical studies, is summarized and
               regularly updated.

•             Raise awareness of this uncommon but devastating problem by promoting sessions at congresses and publishing articles.

•             Coordinate the collection and analyses of data internationally to foster better understanding of the condition.

•             Meet regularly to discuss and update management strategies, with a focus on novel diagnostic and therapeutic approaches.

•             Provide information and contact addresses on our webpage for physicians and patients concerned about PPCM.

•             Initiate and be advocates for the PPCM Registry.

A number of position papers have been published, such as Sliwa et al. Eur J Heart Failure 2010 and 2014, Bauersachs et al. Eur J Heart Failure 2016 and 2019 and Bauersachs J, König T, van der Meer P, Petrie MC, … . Pathophysiology, diagnosis and management of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Study Group on peripartum cardiomyopathy.  Eur J Heart Fail. 2019

PPCM EuroObservational Research Program

The PPCM HFA Study Group has subsequently leveraged funding for a global registry on PPCM. Prof K Sliwa and Prof J Bauersachs are the chairs of the EORP Program on PPCM.  The study design has been published: Sliwa K, Mebazaa A, Hilfiker-Kleiner D, et al. Clinical characteristics of patients from the worldwide registry on peripartum cardiomyopathy (PPCM): EURObservational Research Programme in conjunction with the Heart Failure Association of the European Society of Cardiology Study Group on PPCM. Eur J Heart Fail.  Eur J Heart Fail. 2017 Sep;19(9):1131-1141

The results of the 6-months outcome of more than 700 patients were presented as a Late Breaking Trial session at the ESC Heart Failure Congress, Athens, May 2019. Figure 1 Shows Global recruitment. The data is now in press (Sliwa et al. Eur Heart J, 2020).

Groote Schuur Hospital Cardiac Disease in Maternity Cohort Study

The rationale for this cohort study is that the incidence of cardiovascular disease during pregnancy is increasing across the world, resulting in significant morbidity and mortality. Etiology and outcome varies between developing and developed countries. In developing countries, women may have a pre-existing disease unmasked by pregnancy (e.g. mitral stenosis due to rheumatic heart disease), a superimposed condition unique to pregnancy (e.g. PPCM), or a complication of pregnancy itself (e.g. pregnancy-induced hypertension). There is, however, a lack of data from Africa on this important topic.

This cohort study was initiated by Prof Karen Sliwa at the Cardiac Clinic, Department of Medicine, Groote Schuur Hospital, in conjunction with Prof John Anthony, Department of Obstetrics and Gynaecology, Groote Schuur Hospital, in July 2011.

The objective was to study the natural history of these pregnant women with cardiovascular disease, pre- and postpartum, as well as to identify risk factors and clinical predictors of outcome.

Clinicians are invited to refer patients with a known cardiac condition (e.g. operated congenital heart disease, operated valvular disease), or patients with a suspected cardiac condition, during or post pregnancy, to the Cardiac Disease and Maternity Clinic. More than 500 patients from Cape Town have been entered into the cohort so far.

Serum and plasma are stored at the Hatter Institute. Detailed information on clinical presentation, socio-economic factors, laboratory markers, ECG and echocardiography are collected via a web-based data entry platform. A number of papers have been reported from this cohort.

Other sub-studies such as e.g. studying the use of loop recorders in pregnant women with arrhythmias (CDM-REVEAL) have recently be published.

 

 

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