Decreased ATP production and myocardial contractile reserve in metabolic heart disease

Available online 01 February 2018Metabolic syndrome is a cluster of obesity-related metabolic abnormalities that lead to metabolic heart disease (MHD) with left ventricular pump dysfunction. Although MHD is thought to be associated with myocardial energetic deficiency, two key questions have not been answered. First, it is not known whether there is a sufficient energy deficit to contribute to pump dysfunction. Second, the basis for the energy deficit is not clear. To address these questions, mice were fed a high fat, high sucrose (HFHS) 'Western' diet to recapitulate the MHD phenotype. In isolated beating hearts, we used 31P NMR spectroscopy with magnetization transfer to determine a) the concentrations of high energy phosphates ([ATP], [ADP], [PCr]), b) the free energy of ATP hydrolysis (∆G~ATP), c) the rate of ATP production and d) flux through the creatine kinase (CK) reaction. At the lowest workload, the diastolic pressure-volume relationship was shifted upward in HFHS hearts, indicative of diastolic dysfunction, whereas systolic function was preserved. At this workload, the rate of ATP synthesis was decreased in HFHS hearts, and was associated with decreases in both [PCr] and ∆G~ATP. Higher work demands unmasked the inability of HFHS hearts to increase systolic function and led to a further decrease in ∆G~ATP to a level that is not sufficient to maintain normal function of sarcoplasmic Ca2+-ATPase (SERCA). While [ATP] was preserved at all work demands in HFHS hearts, the progressive increase in [ADP] led to a decrease in ∆G~ATP with increased work demands. Surprisingly, CK flux, CK activity and total creatine were normal in HFHS hearts. These findings differ from dilated cardiomyopathy, in which the energetic deficiency is associated with decreases in CK flux, CK activity and total creatine. Thus, in HFHS-fed mice with MHD there is a distinct metabolic phenotype of the heart characterized by a decrease in ATP production that leads to a functionally-important energetic deficiency and an elevation of [ADP], with preservation of CK flux.Ivan Luptak, Aaron L. Sverdlov, Marcello Panagia, Fuzhong Qin, David R. Pimentel, Dominique Croteau, Deborah A. Siwik, Joanne S. Ingwall, Markus M. Bachschmid, James A. Balschi, Wilson S. Colucc

Fibulin-3 is necessary to prevent cardiac rupture following myocardial infarction

Published online: 11 September 2023Despite the high prevalence of heart failure in the western world, there are few effective treatments. Fibulin-3 is a protein involved in extracellular matrix (ECM) structural integrity, however its role in the heart is unknown. We have demonstrated, using single cell RNA-seq, that fibulin-3 was highly expressed in quiescent murine cardiac fibroblasts, with expression highest prior to injury and late post-infarct (from ~ day-28 to week-8). In humans, fibulin-3 was upregulated in left ventricular tissue and plasma of heart failure patients. Fibulin-3 knockout (Efemp1-/-) and wildtype mice were subjected to experimental myocardial infarction. Fibulin-3 deletion resulted in significantly higher rate of cardiac rupture days 3-6 post-infarct, indicating a weak and poorly formed scar, with severe ventricular remodelling in surviving mice at day-28 post-infarct. Fibulin-3 knockout mice demonstrated less collagen deposition at day-3 post-infarct, with abnormal collagen fibre-alignment. RNA-seq on day-3 infarct tissue revealed upregulation of ECM degradation and inflammatory genes, but downregulation of ECM assembly/structure/organisation genes in fibulin-3 knockout mice. GSEA pathway analysis showed enrichment of inflammatory pathways and a depletion of ECM organisation pathways. Fibulin-3 originates from cardiac fibroblasts, is upregulated in human heart failure, and is necessary for correct ECM organisation/structural integrity of fibrotic tissue to prevent cardiac rupture post-infarct.Lucy A. Murtha, Sean A. Hardy, Nishani S. Mabotuwana, Mark J. Bigland, Taleah Bailey, Kalyan Raguram, Saifei Liu, Doan T. Ngo, Aaron L. Sverdlov, Tamara Tomin, Ruth Birner, Gruenberger, Robert D. Hume, Siiri E. Iismaa, David T. Humphreys, Ralph Patrick, James J. H. Chong, Randall J. Lee, Richard P. Harvey, Robert M. Graham, Peter P. Rainer and Andrew J. Boyl

Plasma concentrations of asymmetric dimethylarginine (ADMA) predict LV mass independent of afterload

Abstract 3474Aaron L Sverdlov ; Doan T Ngo ; Angus K Nightingale ; Sharmalar Rajendran ; Tamila Heresztyn ; John D Horowit

Patterns of contraceptive use among young Australian women with chronic disease: findings from a prospective cohort study

Background: Given chronic disease is increasing among young women and unintended pregnancies among these women are associated with poor maternal and fetal outcomes, these women would beneft from efective preconception care. However, there is a lack of understanding of how these women use or don’t use contraception to inform such interventions. This study examined patterns of contraceptive use among an Australian cohort of young women and investigated the infuence of chronic disease on contraceptive use over time. Methods: Using data from 15,244 young women from the Australian Longitudinal Study on Women’s Health (born 1989–1995), latent transition analysis was performed to identify distinct contraceptive patterns among women who were at risk of an unintended pregnancy. Multinomial mixed-efect models were used to evaluate the relationship between contraceptive combinations and chronic disease. Results: Contraceptive use for women with cardiac and autoinfammatory diseases difered to women without chronic disease over the observation period. Compared to women without chronic disease using the pill, women with cardiac disease had double the odds of using ‘other’ contraception and condoms (OR=2.20, 95% CI 1.34, 3.59) and a modest increase in the odds of using the combined oral contraceptive pill and condoms (OR=1.39, 95% CI 1.03, 1.89). Compared to women without chronic disease who used the pill, women with autoinfammatory disease had increased odds of using LARC and condoms (OR=1.58, 95% CI 1.04, 2.41), using ‘other’ contraception and condoms (OR=1.69, 95% CI 1.11, 2.57), and using the combined oral contraceptive pill and condoms (OR=1.38, 95% CI 1.09, 1.75). No diferences in contraceptive patterns over the observation period were found for women with asthma or diabetes when compared to women without chronic disease. Conclusion: The fndings identifed a need for efective contraceptive counselling as part of routine chronic disease care and improved communication between health care providers and women with chronic disease to improve young women’s contraceptive knowledge and agency in contraceptive choice, particularly for those with cardiac or autoinflammatory conditions. This may be the key to reducing high-risk unintended pregnancies among this vulnerable population.Melissa L. Harris, Nicholas Egan, Peta M. Forder, Deborah Bateson, Aaron L. Sverdlov, Vanessa E. Murphy, and Deborah Loxto

Outcomes following heart failure hospitalization in a regional Australian setting between 2005 and 2014

Aims: The aim of the current study is to examine 10 year trends in mortality and readmission following heart failure (HF) hospitalization in metropolitan and regional Australian settings. Methods and Results: We identified all index HF hospitalizations in the Hunter New England region from 2005 to 2014, using a 10 year 'look back' period. The primary endpoint was a composite of all-cause mortality or all-cause readmission at 1 year. Secondary endpoints included all-cause mortality, all-cause readmission, and HF readmission at 30 days and 1 year. We used logistic regression to explore the predictors of the composite outcome of either all-cause death or readmission at 1 year. There were 12 114 patients admitted with a first episode of HF between 2005 and 2014, followed up until death or the end of 2015. The mean age was 78 ± 12 years and 49% (n = 5906) were male. A total of 4831 (40%) resided in regional areas and the remainder in metropolitan areas. One hundred sixty-eight patients (1.4%) were Aboriginal. Approximately 69% of patients had either died or been readmitted for any cause within 12 months of their index event. The 30 day and 1 year all-cause mortality rates were 13% and 32%, respectively, with no change in the trend over the study period. Age, socio-economic disadvantage, ischaemic heart disease, renal failure, and chronic lower respiratory disease were predictors of the primary endpoint. Conclusions: Heart failure hospitalizations are followed by high rates of death or readmission. There was no change in this composite endpoint over the 10 year study period.Mohammed S. Al-Omary, Arshad A. Khan, Allan J. Davies, Peter J. Fletcher, Dawn Mcivor, Bruce Bastian, Christopher Oldmeadow, Aaron L. Sverdlov, John R. Attia, and Andrew J. Boyl

The endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) predicts LV mass independent of afterload

BackgroundNitric oxide (NO) is a modulator of left ventricular hypertrophy (LVH) and myocardial relaxation. The impact of NO availability on development of LVH has never been demonstrated in humans. We tested the hypotheses that elevation of asymmetric dimethylarginine (ADMA) concentrations (biochemical marker of decreased NO generation), and impairment of vascular responsiveness to NO donor GTN, would each predict the presence of LVH and associated LV diastolic dysfunction in a normal aging population.Methods and resultsIn 74 subjects aged 68±6 years, LV volumes and mass indexed to height(2.7) (LVMI) were calculated from cardiac MRI. Despite the absence of clinically-defined LVH, there was a relationship (r=0.29; p=0.01) between systolic BP and LVMI. Both elevation of ADMA levels to the highest quartile or impairment of GTN responsiveness (determined by applanation tonometry) to the lowest quartile were determinants of LVMI independent of systolic BP (p=0.01 and p=0.03, respectively). Filling pressure (E/E' ratio from echocardiography) was increased in patients with impaired vascular NO responsiveness (pConclusionsThese data imply that NO bioavailability within the myocardium modulates earliest stages of LVH development and facilitates development of diastolic dysfunction at a given LV mass.A. L. Sverdlov, D. T. M. Ngo, A. K. Nightingale, S. Rajendran, K. Mishra, T. Heresztyn, R. H. Ritchie, T. H. Marwick, M. P. Frenneaux and J. D. Horowitzhttp://www.elsevier.com/wps/find/journaldescription.cws_home/622926/description#descriptio

Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society

This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for chronic myeloid leukaemia targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies. © 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology