Browsing by Author "Azibani, Feriel"

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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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    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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    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.