Browsing by Author "Sliwa, Karen"

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    Association between exercise frequency with renal and cardiovascular outcomes in diabetic and non-diabetic individuals at high cardiovascular risk
    (BioMed Central, 2022-01-20) Böhm, Michael; Schumacher, Helmut; Werner, Christian; Teo, Koon K; Lonn, Eva M; Mahfoud, Felix; Speer, Thimoteus; Mancia, Giuseppe; Redon, Josep; Schmieder, Roland E; Sliwa, Karen; Marx, Nikolaus; Weber, Michael A; Laufs, Ulrich; Williams, Bryan; Yusuf, Salim; Mann, Johannes F E
    Background: Guidelines recommend physical activity to reduce cardiovascular (CV) events. The association between physical activity and progression of chronic kidney disease (CKD) with and without diabetes is unknown. We assessed the association of self-reported physical activity with renal and CV outcomes in high-risk patients aged ≥ 55 years over a median follow-up of 56 months in post-hoc analysis of a previously randomized trial program. Methods Analyses were done with Cox regression analysis, mixed models for repeated measures, ANOVA and χ2-test. 31,312 patients, among them 19,664 with and 11,648 without diabetes were analyzed. Results Physical activity was inversely associated with renal outcomes (doubling of creatinine, end-stage kidney disease (ESRD)) and CV outcomes (CV death, myocardial infarction, stroke, heart failure hospitalization). Moderate activity (at least 2 times/week to every day) was associated with lower risk of renal outcomes and lower incidence of new albuminuria (p < 0.0001 for both) compared to lower exercise levels. Similar results were observed for those with and without diabetes without interaction for renal outcomes (p = 0.097–0.27). Physical activity was associated with reduced eGFR decline with a moderate association between activity and diabetes status (p = 0.05). Conclusions Moderate physical activity was associated with improved kidney outcomes with a threshold at two sessions per week. The association of physical activity with renal outcomes did not meaningfully differ with or without diabetes but absolute benefit of activity was even greater in people with diabetes. Thus, risks were similar between those with diabetes undertaking high physical activity and those without diabetes but low physical activity. Clinical trial registration: http://clinicaltrials.gov.uniqueidentifier :NCT00153101.
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    Biomarkers of ventricular remodelling in African hypertensives.
    (2013) Dike, Ojji; Sliwa, Karen; Lecour, Sandrine
    There is substantial evidence that the burden of hypertension, hypertension with left ventricular hypertrophy and hypertensive heart failure is very enormous in sub-Saharan Africa. There is therefore the need to look for easier and faster means, compared to electrocardiography and echocardiography of diagnosing and differentiating the different effects of long standing hypertension on cardiac remodelling which ultimately lead to systolic and diastolic dysfunctions as this affects the prognosis, management and treatment modalities of hypertension. We studied 210 subjects who were subdivided into three groups after echocardiography: those without left ventricular hypertrophy (HT) (n=83); those with left ventricular hypertrophy (HTLVH) (n=50) and those with hypertensive heart failure (HHF) (n=77).
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    Characterisation of cardiac remodeling associated with pregnancy: providing insights to peripartum cardiomyopathy
    (2021) Kodogo, Vitaris; Sliwa, Karen; Lecour, Sandrine; Azibani, Feriel
    Introduction: Maternal cardiovascular changes that occur in pregnant women are usually well tolerated by most women experiencing an uncomplicated pregnancy and are reversable postpartum. However, pregnancy can induce adverse cardiac events in previously healthy women without any known cardiovascular disease. Understanding of the maternal cardiovascular adaptation during healthy pregnancy is important to identify deviations from regular patterns caused by pathological conditions. The main objective of this study was to explore the functional, structural and molecular cardiovascular changes that are involved in healthy pregnancy with the goal to delineate possible mechanisms involved in the lack of reverse cardiovascular remodeling observed in peripartum cardiomyopathy (PPCM). Methods: Cardiovascular functional, morphological and molecular changes during pregnancy and postpartum were assessed in pregnant wild type mice (C57/BL6) and healthy women. An invitro model of cardiac hypertrophy was then used to explore the involvement of pregnancy hormones in the regulation of cardiac hypertrophy. Finally, we assessed the circulatory level of growth differentiation 15 (GDF-15) in PPCM patients and matched healthy controls. Results: Cardiac structural, functional and morphological changes were observed in mice and all the parameters were resolved postpartum. Strikingly, volume load, cardiac hypertrophy and fibrosis were sustained for a longer period postpartum than previously reported. Proteomics profiling confirmed the prolongation of cardiac hypertrophy in the postpartum and the involvement of the ubiquitin proteasome system (UPS) in the reverse remodeling of cardiac changes that occur during pregnancy. We also identified a set of transcription factors that regulates the protein expression in the postpartum. Left ventricular systolic function was significantly reduced in late pregnancy in humans. Finally, the serum level of GDF-15 was significantly lower in PPCM patients compared to healthy controls Conclusion: We conclude that pregnancy induces cardiac stress which is sustained in the postpartum period. The heart remodels and adapts to meet the demand by both the mother and the fetus. Cardiac changes that occur during pregnancy are strictly regulated and reversed postpartum. However, the postpartum period is a period of intense cardiac stress and activity which requires monitoring for any deviation that may lead to pathological conditions.
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    Characteristics and outcomes of acute heart failure in sub Saharan Africa
    (2016) Sani, Mahmoud Umar; Sliwa, Karen; Cotter, Gad
    The main objective of this thesis was to study the clinical characteristics and short-term (6 months) outcome of acute heart failure as well as determine the role of conventional biomarker BNP and the novel biomarker Gal3 in the prognostication of acute heart failure patients. To achieve this, we investigated in the first cohort; 1) the demographic and clinical characteristic of patients with AHF, 2) their echocardiographic parameters and how they predict outcome, 3) the predictors of readmission and mortality, 4) the prevalence and impact of renal dysfunction on AHF and 5) the electrocardiographic pattern in AHF. The outcome measures were worsening renal function (WRF), length of hospital stay, HF readmissions and cardiovascular death within 60 days and all cause, cardiovascular or HF death through 180 days. In the second cohort, we investigated the demographics, clinical characteristics as well as the relationship between plasma levels of BNP and galectin 3 and outcomes (cardiovascular (CV) death or HF hospitalization through week 24) as well as the relationship between the plasma levels of BNP and Gal3 and both left ventricular (LV) and right ventricular (RV) remodeling in patients with AHF.
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    Detecting subclinical anthracycline therapy related cardiac dysfunction in low income country (SATRACD study)
    (2022) Zhang, Wanzhu; Sliwa, Karen; Azibani, Feriel; Okello, Emmy
    Introduction: Anthracycline therapy-related cardiac dysfunction (ATRCD) is the most common chemotherapy-induced cardiovascular toxicity. It begins with subclinical myocardial cell injury that can be detected using speckle tracking echocardiography (STE), together with Troponin-I. Limited availability of STE in Uganda posts challenges in detecting subclinical ATRCD. Anthracycline can also affect cancer survivors' cardiovascular health through altering patients' lipid homoeostasis. This PhD project aims to describe the incidence and predictors of subclinical ATRCD, assess the accuracy of simple echocardiographic parameters on detecting subclinical ATRCD and investigate the lipoprotein subfractions change after anthracycline therapy. Methods and results: Two hundred seven cancer patients who were scheduled for anthracycline based chemotherapy were recruited and followed up to 6 months after ending chemotherapy. Patients' clinical characteristics, laboratory tests, electrocardiogram and echocardiographic data were collected at the baseline and at each follow up visits. Among the 207 patients, 178 (86.0%) were female, with a median age of 42 years. The cumulative incidence of subclinical and clinical ATRCD were 35.0% and 8.8% respectively at the 6 months after ending the therapy. No factor was found to predict subclinical ATRCD in multivariable model. The development of clinical ATRCD associated with HIV infection and development of subclinical ATRCD at the end of anthracycline therapy. The reduction of mitral annular plane systolic excursion (ΔMAPSE) ≥ 2mm or reduction of mitral annular peak systolic velocity (Δ S') ≥ 0.5cm/s from the baseline defined subclinical ATRCD with fairly good accuracy. Very low density lipoprotein subfraction increased and mean low density lipoprotein particle size decreased following anthracycline therapy. Conclusion: There is high incidence of subclinical ATRCD in Uganda cancer patients. Cardiac surveillance at baseline and ending of anthracycline therapy is essential to identify subclinical ATRCD patients who are at high risk of developing clinical ATRCD, particular in HIV positive patients. The conventional echocardiographic parameters ΔMAPSE and ΔS' may be used to screen subclinical ATRCD in resource limited settings. Anthracycline changes lipoprotein subfraction to more atherogenic pattern. Further studies are needed to explore more on its role on lipid metabolism.
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    Economic burden of heart failure: investigating outpatient and inpatient costs in abeokuta, southwest Nigeria
    (Public Library of Science, 2014) Ogah, Okechukwu S; Stewart, Simon; Onwujekwe, Obinna E; Falase, Ayodele O; Adebayo, Saheed O; Olunuga, Taiwo; Sliwa, Karen
    Background: Heart failure (HF) is a deadly, disabling and often costly syndrome world-wide. Unfortunately, there is a paucity of data describing its economic impact in sub Saharan Africa; a region in which the number of relatively younger cases will inevitably rise. Methods: Heath economic data were extracted from a prospective HF registry in a tertiary hospital situated in Abeokuta, southwest Nigeria. Outpatient and inpatient costs were computed from a representative cohort of 239 HF cases including personnel, diagnostic and treatment resources used for their management over a 12-month period. Indirect costs were also calculated. The annual cost per person was then calculated. Results: Mean age of the cohort was 58.0±15.1 years and 53.1% were men. The total computed cost of care of HF in Abeokuta was 76, 288,845 Nigerian Naira (US$508, 595) translating to 319,200 Naira (US$2,128 US Dollars) per patient per year. The total cost of in-patient care (46% of total health care expenditure) was estimated as 34,996,477 Naira (about 301,230 US dollars). This comprised of 17,899,977 Naira- 50.9% ($US114,600) and 17,806,500 naira −49.1%($US118,710) for direct and in-direct costs respectively. Out-patient cost was estimated as 41,292,368 Naira ($US 275,282). The relatively high cost of outpatient care was largely due to cost of transportation for monthly follow up visits. Payments were mostly made through out-of-pocket spending. Conclusion: The economic burden of HF in Nigeria is particularly high considering, the relatively young age of affected cases, a minimum wage of 18,000 Naira ($US120) per month and considerable component of out-of-pocket spending for those affected. Health reforms designed to mitigate the individual to societal burden imposed by the syndrome are required.
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    Genetics of Peripartum Cardiomyopathy: Current Knowledge, Future Directions and Clinical Implications
    (2021-01-15) Spracklen, Timothy F; Chakafana, Graham; Schwartz, Peter J; Kotta, Maria-Christina; Shaboodien, Gasnat; Ntusi, Ntobeko A B; Sliwa, Karen
    Peripartum cardiomyopathy (PPCM) is a condition in which heart failure and systolic dysfunction occur late in pregnancy or within months following delivery. Over the last decade, genetic advances in heritable cardiomyopathy have provided new insights into the role of genetics in PPCM. In this review, we summarise current knowledge of the genetics of PPCM and potential avenues for further research, including the role of molecular chaperone mutations in PPCM. Evidence supporting a genetic basis for PPCM has emanated from observations of familial disease, overlap with familial dilated cardiomyopathy, and sequencing studies of PPCM cohorts. Approximately 20% of PPCM patients screened for cardiomyopathy genes have an identified pathogenic mutation, with TTN truncations most commonly implicated. As a stress-associated condition, PPCM may be modulated by molecular chaperones such as heat shock proteins (Hsps). Recent studies have led to the identification of Hsp mutations in a PPCM model, suggesting that variation in these stress-response genes may contribute to PPCM pathogenesis. Although some Hsp genes have been implicated in dilated cardiomyopathy, their roles in PPCM remain to be determined. Additional areas of future investigation may include the delineation of genotype-phenotype correlations and the screening of newly-identified cardiomyopathy genes for their roles in PPCM. Nevertheless, these findings suggest that the construction of a family history may be advised in the management of PPCM and that genetic testing should be considered. A better understanding of the genetics of PPCM holds the potential to improve treatment, prognosis, and family management.
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    Haemorrhage and Other Complications in Pregnant Women on Anticoagulation for Mechanical Heart Valves; a Prospective Observational Cohort Study
    (2019) Kariv, Sarah; Sliwa, Karen
    Objective: To document maternal and foetal morbidity and mortality in anticoagulated, pregnant patients with mechanical heart valves until 42 days postpartum. Methods: In a tertiary single-centre, prospective cohort, 178 consecutive patients at the cardiac-obstetric clinic were screened for warfarin use between 1 July 2010 and 31 December 2015. Of 33 pregnancies identified, 29 were included. Patients received intravenous unfractionated heparin from six to 12 weeks’ gestation and peripartum, and warfarin from 12 to 36 weeks. Maternal outcomes including death, major haemorrhage and thrombosis, and foetal outcomes were documented. Results: There were two maternal deaths, five returns to theatre post-delivery, eight patients transfused, six major haemorrhages, one case of infective endocarditis and three ischaemic strokes. Ten pregnancies had poor foetal outcomes (six miscarriages, three terminations, one early neonatal death). Twenty patients required more than 30 days’ hospitalisation, and 15 required three or more admissions. HIV positivity was associated with surgical delivery (p = 0.0017). Conclusions: Complication rates were high despite centralized care.
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    Is there an association between sleeping patterns and other environmental factors with obesity and blood pressure in an urban African population?
    (Public Library of Science, 2015) Pretorius, Sandra; Stewart, Simon; Carrington, Melinda J; Lamont, Kim; Sliwa, Karen; Crowther, Nigel J
    Beyond changing dietary patterns, there is a paucity of data to fully explain the high prevalence of obesity and hypertension in urban African populations. The aim of this study was to determine whether other environmental factors (including sleep duration, smoking and physical activity) are related to body anthropometry and blood pressure (BP). Data were collected on 1311 subjects, attending two primary health care clinics in Soweto, South Africa. Questionnaires were used to obtain data on education, employment, exercise, smoking and sleep duration. Anthropometric and BP measurements were taken. Subjects comprised 862 women (mean age 41 ± 16 years and mean BMI 29.9 ± 9.2 kg/m 2 ) and 449 men (38 ± 14 years and 24.8 ± 8.3 kg/m 2 ). In females, ANOVA showed that former smokers had a higher BMI (p<0.001) than current smokers, while exposure to second hand smoking was associated with a lower BMI (p<0.001) in both genders. Regression analyses demonstrated that longer sleep duration was associated with a lower BMI (p<0.05) in older females only, and not in males, whilst in males napping during the day for > 30 minutes was related to a lower BMI (β = -0.04, p<0.01) and waist circumference (β = -0.03, p<0.001). Within males, napping for >30 minutes/day was related to lower systolic (β = -0.02, p<0.05) and lower diastolic BP (β = -0.02, p = 0.05). Longer night time sleep duration was associated with higher diastolic (β = 0.005, p<0.01) and systolic BP (β = 0.003, p<0.05) in females. No health benefits were noted for physical activity. These data suggest that environmental factors rarely collected in African populations are related, in gender-specific ways, to body anthropometry and blood pressure. Further research is required to fully elucidate these associations and how they might be translated into public health programs to combat high levels of obesity and hypertension.
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    Maternal and fetal outcome of subsequent pregnancy in patients with documented peripartum cardiomyopathy
    (2018) Masuku, David Sifiso; Sliwa, Karen
    AIM: Subsequent pregnancies (SSPs) in patients with peripartum cardiomyopathy (PPCM) have a high risk of heart failure relapse. We report on outcome of SSPs in PPCM patients in South Africa. METHODS AND RESULTS: Of the 18 PPCM patients with a SSP, 3 patients died within 6-months follow-up. Overall relapse rate, left ventricular ejection fraction (LVEF) <50% or death after at least 6 months follow-up, was 30%, with 16% (3/18) mortality. Persistently reduced LVEF (<50%) before entering SSP was present in 44% of patients, while full recovery (LVEF≥ 50%) was present in 85%. Persistently reduced LVEF before SSP was associated with a higher mortality (27% vs 0%) and a lower rate of full recovery at follow-up. Patients obtaining standard therapy for heart failure and bromocriptine immediately after delivery displayed significantly better LVEF at follow-up and a higher rate of full recovery, with no patient dying, compared with patients obtaining standard therapy for heart failure alone. CONCLUSION: Full recovery of LVEF before SSP was associated with lower mortality and better cardiac function at follow-up. Addition of bromocriptine to standard therapy for heart failure immediately after delivery was safe and appeared to be associated with better outcome of SSP in our patients.
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    Mortality in patients treated for tuberculous pericarditis in sub-Saharan Africa.
    (Health & Medical Publishing Group, 2008) Mayosi, Bongani M; Wiysonge, Charles Shey; Ntsekhe, Mpiko; Gumedze, Freedom; Volmink Jimmy A; Maartens, Gary; Aje, Akinyemi; Thomas, Baby M; Thomas, Kandathil M; Awotedu, Abolade A; Bongani, Thembela; Mntla, Phindile; Maritz, Frans; Blackett, Kathleen Ngu; Nkouonlack, Duquesne C; Burch, Vanessa C; Rebe, Kevin; Parrish, Andy; Sliwa, Karen; Vezi, Brian Z; Alam, Nowshad; Brown, Basil G; Gould, Trevor; Visser, Tim; Magula, Nombulelo P; Commerford, Patrick J
    Tuberculous pericarditis is one of the most severe forms of extrapulmonary tuberculosis, causing death or disability in a substantial proportion of affected people.1,2 In Africa, the incidence of tuberculous pericarditis is rising as a result of the HIV epidemic.3 The effect of HIV infection on survival in patients with tuberculous pericarditis is unknown.2,4 Whereas some investigators have suggested that HIV-infected patients with tuberculous pericarditis have a similar outcome to non-infected cases,5 others have shown that there may be an increase in mortality in HIV associated with tuberculous pericarditis.2,6,7 We established a prospective observational study, the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry, to obtain current information on the diagnosis, management and outcome of patients with presumed tuberculous pericarditis living in sub-Saharan Africa, where the burden of HIV infection is the greatest in the world.4,8-10 In this paper, we report the mortality rate and its predictors during the 6 months of antituberculosis treatment among patients enrolled in the regist
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    Occupational Post-Exposure Prophylaxis (PEP) against Human Immunodeficiency Virus (HIV) Infection in a Health District in Cameroon: Assessment of the Knowledge and Practices of Nurses
    (Public Library of Science, 2015) Aminde, Leopold Ndemnge; Takah, Noah Fongwen; Dzudie, Anastase; Bonko, Neville Mengnjo; Awungafac, George; Teno, Divine; Mbuagbaw, Lawrence; Sliwa, Karen
    BACKGROUND: Health care providers are at risk of acquiring human immunodeficiency virus (HIV) infection from occupational exposure, with nurses being the most vulnerable. There is no data on the awareness of post-exposure prophylaxis (PEP) among nurses in Cameroon. This study aimed to assess the knowledge, practices of nurses regarding PEP for HIV and their determinants in Cameroon. METHODS: A cross-sectional study was conducted between April and July 2013, and involved 80 nurses in a rural health district in the North West Region of Cameroon. Data was collected using a structured questionnaire and analysed using the SPSS software version 20. RESULTS: In all, 73.7% of the participants had poor knowledge about PEP for HIV. Though many (83.8%) had heard about PEP, just 10 (12.5%) had received formal training on PEP for HIV. Only 24 (30%) and 20 (25%) knew the correct drug regimen and duration of treatment respectively. The majority (85%) considered themselves to be at risk of acquiring HIV at work, with 54 (67.5%) having experienced an exposure in the past, mainly while setting up intravenous lines (57.4%), recapping needles (37.0%) and during delivery (24.1%). Of those exposed, ten (18.9%) received PEP, which was started after 24 hours in 50%. In multivariable regression analyses, awareness of hospital policy [OR: 0.043 (0.005-0.404), p-value = 0.006] was associated with Good knowledge on PEP for HIV. CONCLUSIONS: The knowledge and practice of nurses on PEP for HIV in Cameroon is low. There is urgent need for training programmes and workshops to increase awareness, improve practice, and reduce the risk of HIV acquisition from work related activities among health care providers.
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    Pregnancy-associated heart failure: a comparison of clinical presentation and outcome between hypertensive heart failure of pregnancy and idiopathic peripartum cardiomyopathy
    (Public Library of Science, 2015) Ntusi, Ntobeko B A; Badri, Motasim; Gumedze, Freedom; Sliwa, Karen; Mayosi, Bongani M
    AIMS: There is controversy regarding the inclusion of patients with hypertension among cases of peripartum cardiomyopathy (PPCM), as the practice has contributed significantly to the discrepancy in reported characteristics of PPCM. We sought to determine whether hypertensive heart failure of pregnancy (HHFP) (i.e., peripartum cardiac failure associated with any form of hypertension) and PPCM have similar or different clinical features and outcome. Methods and RESULTS: We compared the time of onset of symptoms, clinical profile (including electrocardiographic [ECG] and echocardiographic features) and outcome of patients with HHFP (n = 53; age 29.6 ± 6.6 years) and PPCM (n = 30; age 31.5 ± 7.5 years). The onset of symptoms was postpartum in all PPCM patients, whereas it was antepartum in 85% of HHFP cases (p<0.001). PPCM was more significantly associated with the following features than HHFP (p<0.05): twin pregnancy, smoking, cardiomegaly with lower left ventricular ejection fraction on echocardiography, and longer QRS duration, QRS abnormalities, left atrial hypertrophy, left bundle branch block, T wave inversion and atrial fibrillation on ECG. By contrast, HHFP patients were significantly more likely (p<0.05) to have a family history of hypertension, hypertension and pre-eclampsia in a previous pregnancy, tachycardia at presentation on ECG, and left ventricular hypertrophy on echocardiography. Chronic heart failure, intra-cardiac thrombus and pulmonary hypertension were found significantly more commonly in PPCM than in HHFP (p<0.05). There were 5 deaths in the PPCM group compared to none among HHFP cases (p = 0.005) during follow-up. CONCLUSION: There are significant differences in the time of onset of heart failure, clinical, ECG and echocardiographic features, and outcome of HHFP compared to PPCM, indicating that the presence of hypertension in pregnancy-associated heart failure may not fit the case definition of idiopathic PPCM.
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    The role of melatonin in peripartum cardiomyopathy
    (2013) Nicholson, Lauren; Lecour, Sandrine; Sliwa, Karen
    Peripartum cardiomyopathy (PPCM) is a heart disease of unknown aetiology emerging in previously healthy women towards the end of pregnancy or first postpartum months. Previous studies have suggested that oxidative stress contributes to the pathogenesis of PPCM. Melatonin is a powerful endogenous antioxidant that can limit the damaging effect of oxidative stress. Melatonin levels are known to be altered in sleep disruption, depression and other cardiac diseases. The aim of this study was to determine if melatonin levels are disrupted in women with PPCM compared to healthy patients. We hypothesised that sleep disruption and depression may contribute to a disruption in their melatonin levels.
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    Targeting heart rate as a novel therapeutic approach in acute heart failure
    (2018) Imamdin, Aqeela; Lecour, Sandrine; Azibani, Feriel; Sliwa, Karen; McCarthy, Joy
    Background and hypothesis: Standard pharmacological treatment for heart failure improves cardiac remodelling and survival in the setting of chronic heart failure, but is suboptimal in cases of acute heart failure (AHF). Peripartum cardiomyopathy (PPCM), de-novo hypotension (often due to haemorrhagic shock), and Takotsubo cardiomyopathy (TC) are conditions which have acute onset of heart failure, and often present with high mortality rates. In patients treated for these pathologies, a variation in the heart rate is observed and could potentially be used as a target to improve the treatment of AHF. We therefore questioned whether the use of a sinoatrial node inhibitor (ivabradine) to modulate heart rate may improve outcomes in AHF. Objectives and methods: Our objectives were 3-fold: (1) to explore the effect of a standard treatment strategy on heart rate in a South African cohort of PPCM patients after 6 and 12 months follow-up. (2) To explore the effect of ivabradine, a sinoatrial node inhibitor in an established signal transducer and activator of transcription 3 (STAT3) knockout mouse model of PPCM (with 3 consecutive pregnancies). Mice were fed ivabradine for 30 days (10mg/kg/day in drinking water), following the 3rd weaning. Trans-thoracic echocardiograms (TTE) were done at the end of the 3rd weaning, and after 30 days of treatment with ivabradine. Hearts were harvested after the second TTE for histology staining and messenger ribonucleic acid (mRNA) quantitation of transcripts involved in heart failure. (3) To explore the role of the sinoatrial node inhibitor in an ex-vivo model of de-novo AHF due to hypotension, and a newly developed ex-vivo model of TC. In the AHF model, hearts were stabilised before administering Ivabradine (3μM) in a buffer containing high free fatty-acids at a low pressure (to mimic hypotension/ haemorrhage shock conditions). A pressure- sensing balloon in the left ventricle measured heart rate, diastolic and systolic pressure, left ventricular developed pressure, rate pressure products and functional recovery. In the TC model, hearts were stabilised, then given a buffer with high free fatty-acid content and 10 times a physiological dose of adrenaline to mimic the adrenergic response seen in TC. Thereafter, hearts were restored to stabilisation pressure and substrate for recovery. Results: (1) Clinical outcomes indicated that patients on maximum standard therapy improved symptomatically and on the New York Heart Association scale. However, heart rates of PPCM patients remained elevated after 6 months of treatment. (2) In PPCM mice, a treatment with ivabradine was associated with reduced fibrotic infiltration in cardiac tissue and with a decrease in levels of atrial natriuretic peptide and Fibronectin mRNAs. (3) Both hypotensive AHF and TC models showed a tendency toward better cardiac function with ivabradine at the end of the acute phases. This advantage was lost after withdrawal of ivabradine during recovery. Conclusion: In South African women with PPCM treated with standard therapy, heart rate remains elevated, therefore suggesting that these women may benefit from the use of ivabradine as an additional therapy, particularly in patients who may be intolerant to β-blockers. The long-term use of ivabradine in the setting of cardiac dysfunction appears to have beneficial effects on remodelling, as treatment with ivabradine in our mouse PPCM model showed reduced cardiac fibrosis. The ex-vivo models of hypotensive AHF and TC both showed benefit in reducing heart rate during the acute phases, and hold the potential of being an intervention therapy to improve the outcome in patients who are brought to hospital while still in the acute phase.
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    The role and essence of pilot trials and subgroup analysis in cardiovascular research: the IMPI trial experience
    (2019) Isiguzo, Godsent Chichebem; Ntsekhe, Mpiko; Thabane, Lehana; Sliwa, Karen; Gumedze, Freedom
    Background Randomised control trials (RCTs) are capital-intensive projects and demand substantial human and capital resources. Therefore, proper planning, precise research questions and adequate thoughts are required in areas such as acceptability of the intervention, participant recruitment, and selection of measurable outcomes. Ensuring all these are possible before delving into the main work can be forecasted through pilot trials. They help in determining the feasibility of the intended critical endpoints and ensure the applicability of the result findings. However, no matter how noble and vital the results are, improper reporting can make them unusable. The thesis brings to the fore the importance of pilot trials in low- and medium-income countries and how they can help make a case for more extensive definitive trials. It then focuses on how subgroup analysis can be used as an essential statistical tool for fully understanding clinical trial results and can be used to unearth non-apparent results in RCT. In the thesis, we highlight the need for accurate, systematic and complete reporting of pilot trials, by critically appraising the literature on abstract reporting in heart failure. The thesis discusses several aspects of pilot trial processes to understand better its unique role in helping refine the components of RCT, to make the running smooth and findings affirmative. Leveraging on the experience of working as a clinical research fellow in the second Investigation for Management of Pericarditis in Africa (IMPI-2) trial, the lessons learnt in planning, designing, implementation, recruitment and reporting of the IMPI-2 pilot forms the nucleus of this thesis. The experience acquired in the process and how they can help in planning future definitive studies are discussed in different sections of the thesis. Methodology The thesis uses the experience gained in critical appraisal of the literature, participation in preliminary planning and active participation in a multicentre randomised control trial to understand the importance of some issues during an RCT. These areas include the need for specific objective setting, identification of research participants and collaborators, the acceptability of research intervention, proper identification of possible outcome measures, retention of participants and quality reporting of research findings. It begins with an overview of pilot trials, subgroup analysis and tuberculous pericarditis which is the primary disease focus of the IMPI project. Each subsequent chapter of the thesis is presented either as a published manuscript or prepared for submission as a manuscript. The quality of reporting of pilot trials is then examined by systematically surveying the reporting of abstracts of pilot trials in heart failure using the checklist of the Consolidated standard for reporting of trials (CONSORT) extension for pilot trials. A subgroup analysis of IMPI-1 trial planned a priori on the modification of the effect of prednisolone by baseline pericardiocentesis status of trial participants is used to highlight the role subgroup analysis can play in unmasking the group effect in the randomised control trial. The thesis then goes on to present the preliminary report of the IMPI-2 pilot study, highlighting the lessons learned and aspirations in need of refining. Retention of study participants is essential to achieve success in clinical trials, one way of ensuring this is by letting the study participants understand the objectives and processes of the research and gaining their confidence. Thus, in chapter six, we piloted the use of the University of California San Diego Brief Assessment of Capacity to Consent (UBACC), a screening tool for evaluation of informed consent (IC) comprehension as a training tool for iterative learning and evaluation of consent comprehension among IMPI-2 pilot trial participants. Results and Conclusion Enormous resources expended in clinical research can yield good returns before the main work commences, a well-planned micro trial run in the form of a pilot study is undertaken. Our systematic survey of abstracts of pilot trials in heart failure showed that reporting of abstracts of pilot trials is currently suboptimal. Deciding ahead of time on what to report by systematically identifying the different sections needed to inform the audience can improve the quality adequately. Planning subgroup analysis during the design of main studies can help reveal unsuspected findings. The subgroup analysis result showed that pericardiocentesis, despite its essential use among patients with pericardial effusion, did not significantly influence the effect of prednisolone on the primary critical outcomes among IMPI-1 participants. The preliminary report of IMPI-2 trial was designed as a two-phase study; phase 1 results showed that at 50mg, intrapericardial alteplase was safe in facilitating complete pericardiocentesis, while phase two showed that it was feasible to recruit, randomised and follow up patients in line with the study protocol. However, we identified participant retention as a considerable challenge. The result of the pilot revealed that more effort should be expended on participants’ education on the clinical condition, the reason for the trial and the need for follow-up adherence. There is also a need to make adequate provision for the use of field workers for contact tracing to reduce the dropout rate. In the main trial protocol, there may also be a need to reconsider the patient's selection and use of fibrinolysis in malignant effusion, judging from the high rate of 3 months mortality in this group of patients. The results of the informed consent study showed that an improved level of comprehension followed the use of iterative learning, a higher level of education and non-use of interpreters during informed consent delivery. These finding led us to conclude that every effort should be made to ensure that research participants entirely buy into the research they are asked to be part of through thorough information delivery. Doing so can help improve participants adherence to the trial follow-up.