Melatonin as a novel cardioprotective therapy in pulmonary hypertension

Includes bibliographical references.Pulmonary hypertension (PH) is characterized by elevated pulmonary arterial pressure which leads to right ventricular hypertrophy and failure. The mechanism involved in the pathophysiology of the disease remains unclear but it is suggested that oxidative stress may trigger cardiovascular dysfunction associated with the disease. To date, there is no efficient therapy against PH and novel therapies are urgently needed. Melatonin is a powerful antioxidant that can confer benefit against ischemia-reperfusion injury and hypertension. We therefore hypothesised that melatonin may confer cardiovascular benefits against PH. Methods: Oxidative stress (plasma lipid peroxidation, antioxidant capacity and antioxidant enzyme activity) was assessed in healthy (n=10), in patients with PH (n=10), in Long Evans rats (n≥6) or in a rat model of PH induced 28 days after the injection of monocrotaline (MCT, 80mg/kg, subcutaneous) (n≥6). Melatonin (75ng/L, nutritional concentration), 4mg/kg or 6mg/kg (therapeutic dose) was given daily in the drinking water of rats, with the treatment started 5 days before the injection of MCT, on the day of the injection or 14 days after the injection of MCT. The development of PH was measured by assessing right ventricular hypertrophy, cardiac fibrosis, oxidative stress and cardiac function (via echocardiography and the isolated heart Langendorff perfusion model). Results: Plasma oxidative stress was increased in both patients and rats with PH compared with their respective controls. A chronic treatment with melatonin (75ng/L, 4mg/kg or 6mg/kg) starting on the day of the injection with MCT in rats with PH reduced right ventricular hypertrophy, cardiac dysfunction and plasma oxidative stress compared with control rats. Furthermore, the beneficial effect of melatonin (6mg/kg) could be observed when given as a preventive (5 days prior to the injection of MCT) or as a curative therapy (14 days after the injection of MCT). Conclusions: Our data demonstrate that chronic treatment of melatonin confers cardioprotection in a rat model of PH. As melatonin is inexpensive, safe (no reported side effects) and already available over the counter in many countries, we propose that melatonin should be considered as a novel preventive/curative therapy to limit cardiac dysfunction in patients with PH

A comprehensive review: The evolution of animal models in pulmonary hypertension research; are we there yet?

Pulmonary hypertension (PH) is a disorder that develops as a result of remodeling of the pulmonary vasculature and is characterized by narrowing/obliteration of small pulmonary arteries, leading to increased mean pulmonary artery pressure and pulmonary vascular resistance. Subsequently, PH increases the right ventricular afterload, which leads to right ventricular hypertrophy and eventually right ventricular failure. The pathophysiology of PH is not fully elucidated, and current treatments have only a modest impact on patient survival and quality of life. Thus, there is an urgent need for improved treatments or a cure. The use of animal models has contributed extensively to the current understanding of PH pathophysiology and the investigation of experimental treatments. However, PH in current animal models may not fully represent current clinical observations. For example, PH in animal models appears to be curable with many therapeutic interventions, and the severity of PH in animal models is also believed to correlate poorly with that observed in humans. In this review, we discuss a variety of animal models in PH research, some of their contributions to the field, their shortcomings, and how these have been addressed. We highlight the fact that the constant development and evolution of animal models will help us to more closely model the severity and heterogeneity of PH observed in humans

Gut microbiota crosstalk mechanisms are key in pulmonary hypertension: The involvement of melatonin is instrumental too

The microbiota refers to a plethora of microorganisms with a gene pool of approximately three million, which inhabits the human gastrointestinal tract or gut. The latter, not only promotes the transport of nutrients, ions, and fluids from the lumen to the internal environment but is linked with the development of diseases including coronary artery disease, heart failure, and lung diseases. The exact mechanism of how the microbiota achieves crosstalk between itself and distant organs/tissues is not clear, but factors released to other organs may play a role, like inflammatory and genetic factors, and now we highlight melatonin as a novel mediator of the gut-lung crosstalk. Melatonin is present in high concentrations in the gut and the lung and has recently been linked to the pathogenesis of pulmonary hypertension (PH). In this comprehensive review of the literature, we suggest that melatonin is an important link between the gut microbiota and the development of PH (where suppressed melatonin-crosstalk between the gut and lungs could promote the development of PH). More studies are needed to investigate the link between the gut microbiota, melatonin and PH. Studies could also investigate whether microbiota genes play a role in the epigenetic aspects of PH. This is relevant because, for example, dysbiosis (caused by epigenetic factors) could reduce melatonin signaling between the gut and lungs, reduce subcellular melatonin concentrations in the gut/lungs, or reduce melatonin serum levels secondary to epigenetic factors. This area of research is largely unexplored and further studies are warranted

Determination of HIV status and identification of incident HIV infections in a large, community-randomized trial: HPTN 071 (PopART).

INTRODUCTION: The HPTN 071 (PopART) trial evaluated the impact of an HIV combination prevention package that included "universal testing and treatment" on HIV incidence in 21 communities in Zambia and South Africa during 2013-2018. The primary study endpoint was based on the results of laboratory-based HIV testing for> 48,000 participants who were followed for up to three years. This report evaluated the performance of HIV assays and algorithms used to determine HIV status and identify incident HIV infections in HPTN 071, and assessed the impact of errors on HIV incidence estimates. METHODS: HIV status was determined using a streamlined, algorithmic approach. A single HIV screening test was performed at centralized laboratories in Zambia and South Africa (all participants, all visits). Additional testing was performed at the HPTN Laboratory Center using antigen/antibody screening tests, a discriminatory test and an HIV RNA test. This testing was performed to investigate cases with discordant test results and confirm incident HIV infections. RESULTS: HIV testing identified 978 seroconverter cases. This included 28 cases where the participant had acute HIV infection at the first HIV-positive visit. Investigations of cases with discordant test results identified cases where there was a participant or sample error (mixups). Seroreverter cases (errors where status changed from HIV infected to HIV uninfected, 0.4% of all cases) were excluded from the primary endpoint analysis. Statistical analysis demonstrated that exclusion of those cases improved the accuracy of HIV incidence estimates. CONCLUSIONS: This report demonstrates that the streamlined, algorithmic approach effectively identified HIV infections in this large cluster-randomized trial. Longitudinal HIV testing (all participants, all visits) and quality control testing provided useful data on the frequency of errors and provided more accurate data for HIV incidence estimates

Cardioprotection conferred by rooibos (Aspalathus linearis): A mini review to highlight a potential mechanism of action

A number of cardioprotective interventions have been identified throughout the years, and these include the use of natural antioxidants in sources like rooibos (Aspalathus linearis) tea. Recent studies have demonstrated that rooibos (either its isolated components or the crude rooibos extract/tea) confers cardioprotection in diabetic cardiomyopathy and myocardial ischaemic injury. In addition, a clinical study has shown that regular rooibos consumption reduces the risk for cardiovascular disease in adults. However, rooibos is currently not considered an official treatment against cardiac disease, mainly because the underlying mechanisms for rooibos-induced cardioprotection are not fully elucidated. Physiological actions of rooibos must be well investigated before rooibos can be used in a clinical setting as adjunct treatment for patients with heart disease. Thus, research to delineate the underlying mechanisms of rooibos-induced cardioprotection is key. In the light of the aforementioned, the available literature on rooibos-induced cardioprotection is reviewed here, highlighting the fact that rooibos preserves and maintains cardiac energy homeostasis. It is postulated that rooibos activates an AMPK-GLUT-4 glucose oxidation (cardiac energy-shortage sensing) pathway to shift cardiac energy usage, thereby conferring cardioprotection. Significance: It is hypothesised that rooibos may alter the way in which the human heart uses energy and oxygen, in order to protect the heart against disease. The heart’s mitochondria are responsible for the heart’s energy processes, and therefore are most likely involved in rooibos-induced cardioprotection. Cardioprotection conferred by rooibos is likely via an AMPK-GLUT-4 glucose oxidation pathway. The mechanism of cardioprotection is important for future studies investigating how rooibos alters cardiac mitochondria. The more information gathered about the underlying mechanisms of rooibos, the easier it will be to recommend rooibos as an official cardioprotective intervention in patients with heart disease

Cardioprotection conferred by rooibos (Aspalathus linearis) : a mini review to highlight a potential mechanism of action

CITATION: Maarman, G. J. 2019. Cardioprotection conferred by rooibos (Aspalathus linearis) : a mini review to highlight a potential mechanism of action. South African Journal of Science, 115(7/8), Art. #4653, doi:10.17159/sajs.2019/4653.The original publication is available at http://sajs.co.zaENGLISH ABSTRACT: A number of cardioprotective interventions have been identified throughout the years, and these include the use of natural antioxidants in sources like rooibos (Aspalathus linearis) tea. Recent studies have demonstrated that rooibos (either its isolated components or the crude rooibos extract/tea) confers cardioprotection in diabetic cardiomyopathy and myocardial ischaemic injury. In addition, a clinical study has shown that regular rooibos consumption reduces the risk for cardiovascular disease in adults. However, rooibos is currently not considered an official treatment against cardiac disease, mainly because the underlying mechanisms for rooibos-induced cardioprotection are not fully elucidated. Physiological actions of rooibos must be well investigated before rooibos can be used in a clinical setting as adjunct treatment for patients with heart disease. Thus, research to delineate the underlying mechanisms of rooibos-induced cardioprotection is key. In the light of the aforementioned, the available literature on rooibos-induced cardioprotection is reviewed here, highlighting the fact that rooibos preserves and maintains cardiac energy homeostasis. It is postulated that rooibos activates an AMPK-GLUT-4 glucose oxidation (cardiac energy-shortage sensing) pathway to shift cardiac energy usage, thereby conferring cardioprotection.https://www.sajs.co.za/article/view/4653Publishers versio

The effect of CPT-1 inhibition on myocardial function and resistance to ischemia/reperfusion injury in a rodent model of the metabolic syndrome

Thesis (MScMedSc (Dept. of Biomedical Sciences. Medical Physiology))University of Stellenbosch, 2010.ENGLISH ABSTRACT: Background: Obesity is associated with dyslipidemia, insulin resistance and glucose intolerance and together these components characterise the metabolic syndrome (Dandona et al. 2005). In the state of obesity, there are high levels of circulating free fatty acids and increased rates of fatty oxidation which inhibit glucose oxidation. This: (i) reduce the heart‘s contractile ability, (ii) exacerbates ischemic/reperfusion injury and (iii) decreases cardiac mechanical function during reperfusion (Kantor et al. 2000; Liu et al. 2002; Taegtmeyer, 2000). Aim: The aim of our study was to investigate the effect of inhibiting fatty acid oxidation, with oxfenicine (4-Hydroxy-L-phenylglycine), on (i) cardiac mechanical function, (ii) mitochondrial respiration, (iii) myocardial tolerance to ischemia/reperfusion injury, (iv) CPT-I expression, MCAD expression, IRS-1 activation, total GLUT- 4 expression and (v) the RISK pathway (ERK42/44 and PKB/Akt). Methods: Male Wistar rats were fed a control rat chow diet or a high calorie diet (HCD) for 16 weeks. The HCD caused diet induced obesity (DIO). The animals were randomly divided into 4 groups [Control, DIO, Control + oxfen and DIO + oxfen]. The drug was administered for the last 8 weeks of feeding (200mg/kg/day). Animals were sacrificed and the hearts were perfused on the Langendorff perfusion system. After being subjected to regional ischemia and two hours of reperfusion, infarct size was determined. A separate series of animals were fed and/or treated and hearts were collected after 25 minutes global ischemia followed by 30 min reperfusion for determination of GLUT- 4, CPT-1, IRS -1, MCAD, ERK (42/44) and PKB/Akt expression/phosphorylation using Western blot analysis. A third series of hearts were excised and used for the isolation of mitochondria. Results: In the DIO rats, chronic oxfenicine treatment improved cardiac mechanical function by improving mitochondrial respiration. Oxfenicine inhibited CPT-1 expression but had no effect on MCAD or GLUT- 4 expression. Oxfenicine decreased IRS-1 iv expression, but not IRS-1 activation. Oxfenicine also improved myocardial tolerance to ischemia/reperfusion without activation of the RISK pathway (ERK & PKB). In the control rats, chronic oxfenicine treatment worsened cardiac mechanical function by adversely affecting mitochondrial respiration. Oxfenicine also worsened myocardial tolerance to ischemia/reperfusion in the control rats without changes in the RISK pathway (ERK & PKB). Oxfenicine had no effect on CPT-1, MCAD or GLUT- 4 expression. Oxfenicine increased IRS-1 expression, but not IRS-1 activity. Conclusion: Chronic oxfenicine treatment improved cardiac mechanical function and myocardial resistance to ischemia/reperfusion injury in obese animals, but worsened it in control animals. The improved cardiac mechanical function and tolerance to ischemia/reperfusion injury may be due to improvement in mitochondrial respiration.AFRIKAANSE OPSOMMING: Agtergrond: Vetsug word geassosieer met dislipidemie, insulien weerstandigheid en glukose intoleransie, wat saam die metaboliese sindroom karakteriseer (Dandona et al. 2005). Met vetsug is daar ‗n hoë sirkulasie van vetsure, sowel as verhoogde vertsuur oksidasie wat gevolglik glukose oksidasie onderdruk. Dit: (i) verlaag die hart se vermoë om saam te trek, (ii) vererger isgemiese/herperfusie skade en (iv) verlaag kardiale effektiwiteit gedurende herperfusie (Kantor et al. 2000; Liu et al. 2002; Taegtmeyer, 2000). Doel: Die doel van die studie was om die effekte van vetsuur onderdrukking m.b.v. oksfenisien (4-Hidroksie-L-fenielglisien) op (i) meganiese hart funksie, (ii) mitokondriale respirasie, (iii) miokardiale toleransie teen isgemiese/herperfusie skade, (iv) CPT-I uitdrukking, MCAD uitdrukking, IRS-1 aktiwiteit, totale GLUT-4 uitdrukking en (v) die RISK pad (ERK42/44 en PKB/Akt) te ondersoek. Metodes: Manlike Wistar rotte was gevoer met ‗n kontrole rot dieet of ‗n hoë kalorie dieet (HKD) vir 16 weke. Die HKD lei tot dieet-geïnduseerde vetsug (DGV). Die diere was lukraak verdeel in 4 groepe [kontrole, DGV, kontrole + oksfen en DGV + oksfen]. Die behandeling met die middel was toegedien vir die laaste 8 weke van die voeding protokol (200mg/kg/dag). Die diere was geslag en die harte was geperfuseer op die Langendorff perfusie sisteem. Na blootstelling aan streeks- of globale isgemie en 2 ure herperfusie was infark groottes bepaal. ‗n Aparte reeks diere was gevoer en/of behandel en die harte was versamel na 25 minute globale isgemie gevolg deur 30 minute herperfusie vir die bepaling van GLUT-4, CPT 1, IRS -1, MCAD, ERK (42/44) en PKB/Akt uitdrukking/aktivering d.m.v. Western blot analise. ‗n Derde reeks diere was gebruik vir die isolasie van mitokondria. Resultate: In die DGV diere, het kroniese oksfenisien behandeling meganiese hart funksie verbeter d.m.v. die verbetering van mitokondriale respirasie. Oksfenisien het CPT-1 uitdrukking verlaag terwyl GLUT- 4 en MCAD uitdrukking nie geaffekteer was vi nie. Oksfenisien het IRS-1 uitdrukking verlaag, maar nie IRS-1 aktiwiteit nie. Oksfenisien het ook miokardiale weerstand teen isgemiese/herperfusie verbeter met sonder aktivering van die RISK pad (ERK & PKB). In die kontrole diere, het kroniese oksfenisien behandeling die meganiese hart funksie versleg d.m.v. negatiewe effekte op mitokondriale respirasie. Oksfenisien het die miokardiale weerstand teen isgemiese/herperfusie van die kontrole rotte versleg sonder veranderinge in die RISK pad (ERK & PKB). Oksfenisien het geen effek gehad op CPT-1, MCAD en GLUT-4 uitdrukking nie. Oksfenisien het IRS-1 uitdrukking verhoog, maar nie IRS-1 aktiwiteit nie. Samevatting: Kroniese oksfenisien behandeling het die meganiese hart funksie en miokardiale weerstand teen isgemiese/herperfusie skade in die vet diere verbeter, maar versleg in die kontrole diere. Hierdie verbetering van meganiese hart funksie en weerstand teen isgemiese/herperfusie skade kon dalk wees a.g.v. ‗n verbetering in mitokondriale respirasie

A philosophical perspective on pulmonary hypertension : what is 'rare'?

CITATION: Maarman, G. J. 2020. A philosophical perspective on pulmonary hypertension : what is 'rare'? South African Journal of Science, 116(5/6):#7939, doi:10.17159/sajs.2020/7939.The original publication is available at https://www.sajs.co.zaENGLISH ABSTRACT: Pulmonary hypertension (PH) is a fatal disease and public health concern.1 The global prevalence of PH is not known1 and a major focus is to establish registries in order to determine the actual prevalence of PH per country2. PH prevalence is largely subject to aetiology, geographical region and the tools used to make a diagnosis (e.g. echocardiography or right heart catheterisation).1 In Africa, the prevalence of PH that is secondary to HIV differs from its prevalence that is secondary to rheumatic heart disease or schistosomiasis. For example, PH prevalence in HIV is approximately 14%3, while the prevalence can be 1% or 10% in schistosomiasis4. In comparison with a world population of some eight billion people, the relatively ‘low’ number of people who have been diagnosed with or who have succumbed to PH has triggered the assumption that it is a rare disease, which is how it is also reported throughout the literature.Publisher's versio

A philosophical perspective on pulmonary hypertension: What is ‘rare’?

CITATION: Maarman, G. J. 2020. A philosophical perspective on pulmonary hypertension : what is 'rare'? South African Journal of Science, 116(5/6):#7939, doi:10.17159/sajs.2020/7939.The original publication is available at https://www.sajs.co.zaENGLISH ABSTRACT: Pulmonary hypertension (PH) is a fatal disease and public health concern.1 The global prevalence of PH is not known1 and a major focus is to establish registries in order to determine the actual prevalence of PH per country2. PH prevalence is largely subject to aetiology, geographical region and the tools used to make a diagnosis (e.g. echocardiography or right heart catheterisation).1 In Africa, the prevalence of PH that is secondary to HIV differs from its prevalence that is secondary to rheumatic heart disease or schistosomiasis. For example, PH prevalence in HIV is approximately 14%3, while the prevalence can be 1% or 10% in schistosomiasis4. In comparison with a world population of some eight billion people, the relatively ‘low’ number of people who have been diagnosed with or who have succumbed to PH has triggered the assumption that it is a rare disease, which is how it is also reported throughout the literature.Publisher's versio

Melatonin in Heart Failure: A Promising Therapeutic Strategy?

Heart failure is a multifactorial clinical syndrome characterized by the inability of the heart to pump sufficient blood to the body. Despite recent advances in medical management, poor outcomes in patients with heart failure remain very high. This highlights a need for novel paradigms for effective, preventive and curative strategies. Substantial evidence supports the importance of endogenous melatonin in cardiovascular health and the benefits of melatonin supplementation in various cardiac pathologies and cardiometabolic disorders. Melatonin plays a crucial role in major pathological processes associated with heart failure including ischemic injury, oxidative stress, apoptosis, and cardiac remodeling. In this review, available evidence for the role of melatonin in heart failure is discussed. Current challenges and possible limitations of using melatonin in heart failure are also addressed. While few clinical studies have investigated the role of melatonin in the context of heart failure, current findings from experimental studies support the potential use of melatonin as preventive and adjunctive curative therapy in heart failure