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  1. Article ; Online: Role of Cardiac Energetics in Aortic Stenosis Disease Progression: Identifying the High-risk Metabolic Phenotype.

    Monga, Shveta / Valkovič, Ladislav / Myerson, Saul G / Neubauer, Stefan / Mahmod, Masliza / Rider, Oliver J

    Circulation. Cardiovascular imaging

    2023  Volume 16, Issue 10, Page(s) e014863

    Abstract: Background: Severe aortic stenosis (AS) is associated with left ventricular (LV) hypertrophy and cardiac metabolic alterations with evidence of steatosis and impaired myocardial energetics. Despite this common phenotype, there is an unexplained and wide ...

    Abstract Background: Severe aortic stenosis (AS) is associated with left ventricular (LV) hypertrophy and cardiac metabolic alterations with evidence of steatosis and impaired myocardial energetics. Despite this common phenotype, there is an unexplained and wide individual heterogeneity in the degree of hypertrophy and progression to myocardial fibrosis and heart failure. We sought to determine whether the cardiac metabolic state may underpin this variability.
    Methods: We recruited 74 asymptomatic participants with AS and 13 healthy volunteers. Cardiac energetics were measured using phosphorus spectroscopy to define the myocardial phosphocreatine to adenosine triphosphate ratio. Myocardial lipid content was determined using proton spectroscopy. Cardiac function was assessed by cardiovascular magnetic resonance cine imaging.
    Results: Phosphocreatine/adenosine triphosphate was reduced early and significantly across the LV wall thickness quartiles (Q2, 1.50 [1.21-1.71] versus Q1, 1.64 [1.53-1.94]) with a progressive decline with increasing disease severity (Q4, 1.48 [1.18-1.70];
    Conclusions: A gradient of myocardial energetic deficit and steatosis exists across the spectrum of hypertrophied AS hearts, and these metabolic changes precede irreversible LV remodeling and subclinical dysfunction. As such, cardiac metabolism may play an important and potentially causal role in disease progression.
    MeSH term(s) Humans ; Phosphocreatine/metabolism ; Hypertrophy, Left Ventricular/diagnostic imaging ; Hypertrophy, Left Ventricular/etiology ; Hypertrophy, Left Ventricular/metabolism ; Aortic Valve Stenosis/diagnostic imaging ; Aortic Valve Stenosis/complications ; Adenosine Triphosphate/metabolism ; Cardiomyopathies/complications ; Fibrosis ; Phenotype ; Disease Progression ; Ventricular Function, Left
    Chemical Substances Phosphocreatine (020IUV4N33) ; Adenosine Triphosphate (8L70Q75FXE)
    Language English
    Publishing date 2023-10-17
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2435045-X
    ISSN 1942-0080 ; 1941-9651
    ISSN (online) 1942-0080
    ISSN 1941-9651
    DOI 10.1161/CIRCIMAGING.122.014863
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  2. Article: Role of Trientine in Hypertrophic Cardiomyopathy: A Review of Mechanistic Aspects.

    Ramli, Fitri Fareez / Hashim, Syed Alhafiz Syed / Raman, Betty / Mahmod, Masliza / Kamisah, Yusof

    Pharmaceuticals (Basel, Switzerland)

    2022  Volume 15, Issue 9

    Abstract: Abnormality in myocardial copper homeostasis is believed to contribute to the development of cardiomyopathy. Trientine, a copper-chelating drug used in the management of patients with Wilson's disease, demonstrates beneficial effects in patients with ... ...

    Abstract Abnormality in myocardial copper homeostasis is believed to contribute to the development of cardiomyopathy. Trientine, a copper-chelating drug used in the management of patients with Wilson's disease, demonstrates beneficial effects in patients with hypertrophic cardiomyopathy. This review aims to present the updated development of the roles of trientine in hypertrophic cardiomyopathy. The drug has been demonstrated in animal studies to restore myocardial intracellular copper content. However, its mechanisms for improving the medical condition remain unclear. Thus, comprehending its mechanistic aspects in cardiomyopathy is crucial and could help to expedite future research.
    Language English
    Publishing date 2022-09-14
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2193542-7
    ISSN 1424-8247
    ISSN 1424-8247
    DOI 10.3390/ph15091145
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  3. Article ; Online: COVID-19 and Major Organ Thromboembolism: Manifestations in Neurovascular and Cardiovascular Systems.

    Pillai, Presaad / Joseph, Joyce Pauline / Fadzillah, Nurul Huda Mohamad / Mahmod, Masliza

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association

    2020  Volume 30, Issue 1, Page(s) 105427

    Abstract: COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been shown to cause multisystemic damage. We undertook a systematic literature review and comprehensive analysis of a total of 55 articles on arterial and venous ... ...

    Abstract COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been shown to cause multisystemic damage. We undertook a systematic literature review and comprehensive analysis of a total of 55 articles on arterial and venous thromboembolism in COVID-19 and articles on previous pandemics with respect to thromboembolism and compared the similarities and differences between them. The presence of thrombosis in multiple organ systems points to thromboembolism being an integral component in the pathogenesis of this disease. Thromboembolism is likely to be the main player in the morbidity and mortality of COVID -19 in which the pulmonary system is most severely affected. We also hypothesize that D-dimer values could be used as an early marker for prognostication of disease as it has been seen to be raised even in the pre-symptomatic stage. This further strengthens the notion that thromboembolism prevention is necessary. We also examined literature on the neurovascular and cardiovascular systems, as the manifestation of thromboembolic phenomenon in these two systems varied, suggesting different pathophysiology of damage. Further research into the role of thromboembolism in COVID-19 is important to advance the understanding of the virus, its effects and to tailor treatment accordingly to prevent further casualties from this pandemic.
    MeSH term(s) Arterial Occlusive Diseases/diagnosis ; Arterial Occlusive Diseases/etiology ; Arterial Occlusive Diseases/mortality ; Arterial Occlusive Diseases/prevention & control ; COVID-19/complications ; COVID-19/diagnosis ; COVID-19/drug therapy ; COVID-19/mortality ; Cerebrovascular Disorders/diagnosis ; Cerebrovascular Disorders/etiology ; Cerebrovascular Disorders/mortality ; Cerebrovascular Disorders/prevention & control ; Fibrinolytic Agents/therapeutic use ; Humans ; Prognosis ; Pulmonary Embolism/diagnosis ; Pulmonary Embolism/etiology ; Pulmonary Embolism/mortality ; Pulmonary Embolism/prevention & control ; Risk Assessment ; Risk Factors ; Venous Thromboembolism/diagnosis ; Venous Thromboembolism/etiology ; Venous Thromboembolism/mortality ; Venous Thromboembolism/prevention & control ; Venous Thrombosis/diagnosis ; Venous Thrombosis/etiology ; Venous Thrombosis/mortality ; Venous Thrombosis/prevention & control
    Chemical Substances Fibrinolytic Agents
    Keywords covid19
    Language English
    Publishing date 2020-10-24
    Publishing country United States
    Document type Journal Article ; Systematic Review
    ZDB-ID 1131675-5
    ISSN 1532-8511 ; 1052-3057
    ISSN (online) 1532-8511
    ISSN 1052-3057
    DOI 10.1016/j.jstrokecerebrovasdis.2020.105427
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  4. Article ; Online: Insights Into the Metabolic Aspects of Aortic Stenosis With the Use of Magnetic Resonance Imaging.

    Monga, Shveta / Valkovič, Ladislav / Tyler, Damian / Lygate, Craig A / Rider, Oliver / Myerson, Saul G / Neubauer, Stefan / Mahmod, Masliza

    JACC. Cardiovascular imaging

    2022  Volume 15, Issue 12, Page(s) 2112–2126

    Abstract: Pressure overload in aortic stenosis (AS) encompasses both structural and metabolic remodeling and increases the risk of decompensation into heart failure. A major component of metabolic derangement in AS is abnormal cardiac substrate use, with down- ... ...

    Abstract Pressure overload in aortic stenosis (AS) encompasses both structural and metabolic remodeling and increases the risk of decompensation into heart failure. A major component of metabolic derangement in AS is abnormal cardiac substrate use, with down-regulation of fatty acid oxidation, increased reliance on glucose metabolism, and subsequent myocardial lipid accumulation. These changes are associated with energetic and functional cardiac impairment in AS and can be assessed with the use of cardiac magnetic resonance spectroscopy (MRS). Proton MRS allows the assessment of myocardial triglyceride content and creatine concentration. Phosphorous MRS allows noninvasive in vivo quantification of the phosphocreatine-to-adenosine triphosphate ratio, a measure of cardiac energy status that is reduced in patients with severe AS. This review summarizes the changes to cardiac substrate and high-energy phosphorous metabolism and how they affect cardiac function in AS. The authors focus on the role of MRS to assess these metabolic changes, and potentially guide future (cellular) metabolic therapy in AS.
    MeSH term(s) Humans ; Predictive Value of Tests ; Aortic Valve Stenosis/diagnostic imaging ; Magnetic Resonance Imaging
    Language English
    Publishing date 2022-06-15
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2491503-8
    ISSN 1876-7591 ; 1936-878X
    ISSN (online) 1876-7591
    ISSN 1936-878X
    DOI 10.1016/j.jcmg.2022.04.025
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  5. Article ; Online: Editorial Expression of Concern: Splenic T1-mapping: a novel quantitative method for assessing adenosine stress adequacy for cardiovascular magnetic resonance.

    Liu, Alexander / Wijesurendra, Rohan S / Ariga, Rina / Mahmod, Masliza / Levelt, Eylem / Greiser, Andreas / Petrou, Mario / Krasopoulos, George / Forfar, John C / Kharbanda, Rajesh K / Channon, Keith M / Neubauer, Stefan / Piechnik, Stefan K / Ferreira, Vanessa M

    Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance

    2023  Volume 25, Issue 1, Page(s) 27

    Language English
    Publishing date 2023-05-25
    Publishing country England
    Document type Journal Article ; Expression of Concern
    ZDB-ID 1458034-2
    ISSN 1532-429X ; 1097-6647
    ISSN (online) 1532-429X
    ISSN 1097-6647
    DOI 10.1186/s12968-023-00935-y
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  6. Article: COVID-19 and Major Organ Thromboembolism: Manifestations in Neurovascular and Cardiovascular Systems

    Pillai, Presaad / Joseph, Joyce Pauline / Fadzillah, Nurul Huda Mohamad / Mahmod, Masliza

    J Stroke Cerebrovasc Dis

    Abstract: COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been shown to cause multisystemic damage. We undertook a systematic literature review and comprehensive analysis of a total of 55 articles on arterial and venous ... ...

    Abstract COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been shown to cause multisystemic damage. We undertook a systematic literature review and comprehensive analysis of a total of 55 articles on arterial and venous thromboembolism in COVID-19 and articles on previous pandemics with respect to thromboembolism and compared the similarities and differences between them. The presence of thrombosis in multiple organ systems points to thromboembolism being an integral component in the pathogenesis of this disease. Thromboembolism is likely to be the main player in the morbidity and mortality of COVID -19 in which the pulmonary system is most severely affected. We also hypothesize that D-dimer values could be used as an early marker for prognostication of disease as it has been seen to be raised even in the pre-symptomatic stage. This further strengthens the notion that thromboembolism prevention is necessary. We also examined literature on the neurovascular and cardiovascular systems, as the manifestation of thromboembolic phenomenon in these two systems varied, suggesting different pathophysiology of damage. Further research into the role of thromboembolism in COVID-19 is important to advance the understanding of the virus, its effects and to tailor treatment accordingly to prevent further casualties from this pandemic.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #899242
    Database COVID19

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  7. Article ; Online: Metabolic profiling of aortic stenosis and hypertrophic cardiomyopathy identifies mechanistic contrasts in substrate utilization.

    Pal, Nikhil / Acharjee, Animesh / Ament, Zsuzsanna / Dent, Tim / Yavari, Arash / Mahmod, Masliza / Ariga, Rina / West, James / Steeples, Violetta / Cassar, Mark / Howell, Neil J / Lockstone, Helen / Elliott, Kate / Yavari, Parisa / Briggs, William / Frenneaux, Michael / Prendergast, Bernard / Dwight, Jeremy S / Kharbanda, Rajesh /
    Watkins, Hugh / Ashrafian, Houman / Griffin, Julian L

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology

    2024  Volume 38, Issue 6, Page(s) e23505

    Abstract: Aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) are distinct disorders leading to left ventricular hypertrophy (LVH), but whether cardiac metabolism substantially differs between these in humans remains to be elucidated. We undertook an ... ...

    Abstract Aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) are distinct disorders leading to left ventricular hypertrophy (LVH), but whether cardiac metabolism substantially differs between these in humans remains to be elucidated. We undertook an invasive (aortic root, coronary sinus) metabolic profiling in patients with severe AS and HCM in comparison with non-LVH controls to investigate cardiac fuel selection and metabolic remodeling. These patients were assessed under different physiological states (at rest, during stress induced by pacing). The identified changes in the metabolome were further validated by metabolomic and orthogonal transcriptomic analysis, in separately recruited patient cohorts. We identified a highly discriminant metabolomic signature in severe AS in all samples, regardless of sampling site, characterized by striking accumulation of long-chain acylcarnitines, intermediates of fatty acid transport across the inner mitochondrial membrane, and validated this in a separate cohort. Mechanistically, we identify a downregulation in the PPAR-α transcriptional network, including expression of genes regulating fatty acid oxidation (FAO). In silico modeling of β-oxidation demonstrated that flux could be inhibited by both the accumulation of fatty acids as a substrate for mitochondria and the accumulation of medium-chain carnitines which induce competitive inhibition of the acyl-CoA dehydrogenases. We present a comprehensive analysis of changes in the metabolic pathways (transcriptome to metabolome) in severe AS, and its comparison to HCM. Our results demonstrate a progressive impairment of β-oxidation from HCM to AS, particularly for FAO of long-chain fatty acids, and that the PPAR-α signaling network may be a specific metabolic therapeutic target in AS.
    MeSH term(s) Humans ; Peroxisome Proliferator-Activated Receptors ; Cardiomyopathy, Hypertrophic/genetics ; Hypertrophy, Left Ventricular/genetics ; Aortic Valve Stenosis/genetics ; Fatty Acids/metabolism
    Chemical Substances Peroxisome Proliferator-Activated Receptors ; Fatty Acids
    Language English
    Publishing date 2024-03-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 639186-2
    ISSN 1530-6860 ; 0892-6638
    ISSN (online) 1530-6860
    ISSN 0892-6638
    DOI 10.1096/fj.202301710RR
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  8. Article ; Online: Safety and Efficacy of Metabolic Modulation With Ninerafaxstat in Patients With Nonobstructive Hypertrophic Cardiomyopathy.

    Maron, Martin S / Mahmod, Masliza / Abd Samat, Azlan Helmy / Choudhury, Lubna / Massera, Daniele / Phelan, Dermot M J / Cresci, Sharon / Martinez, Matthew W / Masri, Ahmad / Abraham, Theodore P / Adler, Eric / Wever-Pinzon, Omar / Nagueh, Sherif F / Lewis, Gregory D / Chamberlin, Paul / Patel, Jai / Yavari, Arash / Dehbi, Hakim-Moulay / Sarwar, Rizwan /
    Raman, Betty / Valkovič, Ladislav / Neubauer, Stefan / Udelson, James E / Watkins, Hugh

    Journal of the American College of Cardiology

    2024  

    Abstract: Background: In nonobstructive hypertrophic cardiomyopathy (nHCM), there are no approved medical therapies. Impaired myocardial energetics is a potential cause of symptoms and exercise limitation. Ninerafaxstat, a novel cardiac mitotrope, enhances ... ...

    Abstract Background: In nonobstructive hypertrophic cardiomyopathy (nHCM), there are no approved medical therapies. Impaired myocardial energetics is a potential cause of symptoms and exercise limitation. Ninerafaxstat, a novel cardiac mitotrope, enhances cardiac energetics.
    Objectives: To evaluate the safety and efficacy of ninerafaxstat in nHCM.
    Methods: Patients with HCM and left ventricular (LV) outflow gradient <30 mmHg, ejection fraction ≥50% and peak VO
    Results: A total of 67 patients with nHCM were enrolled at 12 centers (57 yrs ± 11.8; 55% women). Serious adverse events occurred in 11.8% (4/34) in the ninerafaxstat group and 6.1% of patients (2/33) in placebo. From baseline to 12 weeks, ninerafaxstat was associated with significantly better ventilatory efficiency (V
    Conclusions: In symptomatic nHCM, novel drug therapy targeting myocardial energetics was safe and well tolerated and associated with better exercise performance and health status among those most symptomatically limited. The findings support assessing ninerafaxstat in a Phase 3 study.
    Language English
    Publishing date 2024-04-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 605507-2
    ISSN 1558-3597 ; 0735-1097
    ISSN (online) 1558-3597
    ISSN 0735-1097
    DOI 10.1016/j.jacc.2024.03.387
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  9. Article ; Online: Right ventricular function declines prior to left ventricular ejection fraction in hypertrophic cardiomyopathy.

    Mahmod, Masliza / Raman, Betty / Chan, Kenneth / Sivalokanathan, Sanjay / Smillie, Robert W / Samat, Azlan H Abd / Ariga, Rina / Dass, Sairia / Ormondroyd, Elizabeth / Watkins, Hugh / Neubauer, Stefan

    Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance

    2022  Volume 24, Issue 1, Page(s) 36

    Abstract: Background: The right ventricle (RV) in hypertrophic cardiomyopathy (HCM) tends to be neglected, as previous efforts have predominantly focused on examining the prognostic value of left ventricular (LV) abnormalities. The objectives of this study were ... ...

    Abstract Background: The right ventricle (RV) in hypertrophic cardiomyopathy (HCM) tends to be neglected, as previous efforts have predominantly focused on examining the prognostic value of left ventricular (LV) abnormalities. The objectives of this study were to assess RV function in HCM, changes over time, and association with clinical outcomes.
    Methods: Two hundred and ninety HCM patients with preserved LV ejection fraction (LVEF ≥ 55%) and 30 age- and sex-matched controls underwent cardiovascular magnetic resonance (CMR). All patients were followed up for clinical events for a median duration of 4.4 years. Sixty-three patients had a follow-up CMR undertaken at a median interval of 5.4 years. Main study measures and outcomes were RV function (RV ejection fraction (RVEF) and RV strain) at baseline, temporal changes in RV function over time and prognostic value of RV dysfunction for predicting cardiovascular outcomes in HCM.
    Results: When compared to controls, HCM patients exhibited lower RV and LV peak global longitudinal systolic strains on feature-tracking analysis of cine images, while RVEF and LVEF were within the normal range. On follow-up CMR, both RV and LV strain parameters decreased over time. RVEF decreased at follow-up (65 ± 7% to 62 ± 7%, P < 0.001) but the change in LVEF was not significant (68 ± 10% to 66 ± 8%, P = 0.30). On clinical follow up, reduced RVEF was an independent predictor of non-sustained ventricular tachycardia (NSVT) [HR 1.10 (95% CI 1.06-1.15), P < 0.001] and composite cardiovascular events (NSVT, stroke, heart failure hospitalisation and cardiovascular death) [HR 1.07 (95% CI 1.03-1.10), P < 0.001]. RV longitudinal strain was an independent predictor of NSVT [HR 1.05 (95% CI 1.01-1.09), P = 0.029]. Patients with RVEF < 55% showed an increased risk of NSVT and composite cardiovascular events. In contrast, LVEF and LV global longitudinal strain were not predictive of such events on multivariable analysis.
    Conclusions: In HCM, RV function, including RV strain, and LV strain decrease over time despite preserved LVEF. Reduction in RV but not LV function is associated with adverse cardiovascular outcomes. Assessing RV function in early HCM disease might have a role in risk stratification to prevent future cardiovascular events.
    MeSH term(s) Cardiomyopathy, Hypertrophic/complications ; Cardiomyopathy, Hypertrophic/diagnostic imaging ; Humans ; Magnetic Resonance Imaging, Cine/methods ; Predictive Value of Tests ; Stroke Volume ; Ventricular Function, Left ; Ventricular Function, Right
    Language English
    Publishing date 2022-06-13
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1458034-2
    ISSN 1532-429X ; 1097-6647
    ISSN (online) 1532-429X
    ISSN 1097-6647
    DOI 10.1186/s12968-022-00868-y
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  10. Article ; Online: Discrepancy Between Pathological Progression and Clinical Stability in a Young Patient With Hypertrophic Cardiomyopathy.

    Raman, Betty / Wen, David / Chan, Kenneth / Watkins, Hugh / Neubauer, Stefan / Mahmod, Masliza

    Circulation. Cardiovascular imaging

    2018  Volume 11, Issue 11, Page(s) e008154

    MeSH term(s) Cardiomyopathy, Hypertrophic/diagnosis ; Cardiomyopathy, Hypertrophic/physiopathology ; Disease Progression ; Echocardiography ; Follow-Up Studies ; Heart Ventricles/diagnostic imaging ; Heart Ventricles/physiopathology ; Humans ; Magnetic Resonance Imaging, Cine/methods ; Male ; Myocardial Contraction/physiology ; Myocardium/pathology ; Time Factors ; Ventricular Function, Left/physiology ; Young Adult
    Language English
    Publishing date 2018-12-20
    Publishing country United States
    Document type Case Reports ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2435045-X
    ISSN 1942-0080 ; 1941-9651
    ISSN (online) 1942-0080
    ISSN 1941-9651
    DOI 10.1161/CIRCIMAGING.118.008154
    Database MEDical Literature Analysis and Retrieval System OnLINE

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