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Past Project

The effect of acute stressors on the diabetic heart, and the cardioprotective effect of exercise training (2008-2020)

This project was a continuation of research activity focusing on understanding the underlying mechanism of heart failure associated with obesity and diabetes. We have previously focused on the role of systemic factors - lipid oversupply, insulin resistance and inflammation - and how they can be attenuated by pharmacologic and lifestyle interventions (exercise, dietary supplementation).  The objectives of this project were to study the metabolic and mechanoenergetic changes in the diabetic heart during acute stresses (such as a high lipid load and/or ischemia-reperfusion), as well as the cardiopotective effect of exercise training.

Members: Ellen Aasum, Terje Larsen, Neoma Boardman, Anne Hafstad

Financial/grant information:

The Research Council of Norway (Post Doc/Hafstad), UiT- The Arctic University of Norway (PhD/Lund), NASAT-Unikard (Researcher/Boardman), Norwegian Health Association (PhD/Pedersen and Post Doc/Boardman). Running cost: UiT- The Arctic University of Norway, Helse Nord, Norwegian Health Association, NovoNordic Foundation, Norwegian Diabetes Association.

The project has led to 10 research publications, one review and 2 PhD thesis: doi:10.1152/ajpheart.00284.2020;  doi:10.3389/fphys.2019.01274; doi:10.1371/journal.pone.0204843; dio:10.1152/ajpheart.00382.2017; doi:10.1089/ars.2015.6304; doi:10.1152/ajpheart.00734.2014; doi:10.2337/db12-1580; doi:10.1152/ajpheart.01190.2010; doi:10.1152/japplphysiol.00594.2011; doi:10.1152/ajpheart.01264.2008; doi:10.1161/CIRCRESAHA.109.199810

PhD thesis: Tina Pedersen (2017); Jim Lund (2015)

Oxygen wastage of inotropy

Our studies challenge the conventional understanding of oxygen wastage in inotropy, especially with beta-adrenergic stimuli. The use of a β3 adrenergic receptor antagonist attenuates dobutamine-induced cardiac inefficiency while preserving inotropy, suggesting a complex relationship. Adrenomedullin-epinephrine cotreatment enhances cardiac function through energetically neutral mechanisms, hinting at the possibility of improving performance without increasing oxygen consumption. Another study questions the oxygen-wasting effect of inotropy, emphasizing the need for a reevaluation and suggesting a more nuanced understanding. Together, these findings underscore the controversy around inotropy and oxygen consumption, urging a reconsideration of established notions in cardiac function. The β3 Adrenergic Receptor Antagonist L-748,337 Attenuates Dobutamine-Induced Cardiac Inefficiency While Preserving Inotropy in Anesthetized Pigs.

Members: Ole-Jakob How

Publications:

The β3 Adrenergic Receptor Antagonist L-748,337 Attenuates Dobutamine-Induced Cardiac Inefficiency While Preserving Inotropy in Anesthetized Pigs. Rødland L, Rønning L, Kildal AB, How OJ. J Cardiovasc Pharmacol Ther. 2021 Nov;26(6):714-723. doi: 10.1177/10742484211048762. Epub 2021 Sep 23. PMID: 34551626 Free PMC article.

Adrenomedullin-epinephrine cotreatment enhances cardiac output and left ventricular function by energetically neutral mechanisms. Stenberg TA, Kildal AB, How OJ, Myrmel T. Am J Physiol Heart Circ Physiol. 2012 Apr 15;302(8):H1584-90. doi: 10.1152/ajpheart.00887.2011. Epub 2012 Feb 3. PMID: 22307666

Oxygen-wasting effect of inotropy: is there a need for a new evaluation? An experimental large-animal study using dobutamine and levosimendan. Müller S, How OJ, Jakobsen Ø, Hermansen SE, Røsner A, Stenberg TA, Myrmel T. Circ Heart Fail. 2010 Mar;3(2):277-85. doi: 10.1161/CIRCHEARTFAILURE.109.865519. Epub 2009 Dec 16. PMID: 20018954

Optimizing cardiac efficiency and diastolic function in acute heart failure treatment

The investigation into novel inotropic treatments for acute heart failure reveals critical insights into the cardiovascular effects of Omecamtiv Mecarbil and Ivabradine. The primary conclusion drawn from the findings is that Omecamtiv Mecarbil poses potential dangers due to excessive cardiac energy consumption and impaired diastole. The studies conducted, particularly the work by Rødland et al. (2019) in pigs with ischemic acute heart failure, highlight that the combined therapy of Dobutamine and Omecamtiv Mecarbil can be attributed to the effects of Dobutamine rather than a positive impact of Omecamtiv Mecarbil.

Additionally, Rønning et al. (2018) demonstrate opposite diastolic effects of Omecamtiv Mecarbil compared to Dobutamine and Ivabradine co-treatment in pigs with acute ischemic heart failure. This emphasizes the unfavorable diastolic consequences associated with Omecamtiv Mecarbil. The study by Bakkehaug et al. (2015) further supports this by revealing that the myosin activator Omecamtiv Mecarbil increases myocardial oxygen consumption and impairs contractile efficiency, mediated by resting myosin ATPase activity.

In contrast, the research on Ivabradine suggests potential benefits. Bakkehaug et al. (2015) demonstrate that Ivabradine, when co-treated with Dobutamine in acute heart failure, prolongs the diastolic time interval, thereby increasing stroke volume without compromising cardiac efficiency. This implies that Ivabradine may stimulate contractility through adrenergic stimuli while avoiding undesirable tachycardia, presenting a potentially advantageous alternative in the management of acute heart failure.

Furthermore, Bakkehaug et al. (2016) showcase the potential of Ivabradine in reversing Dobutamine-induced tachycardia, leading to increased stroke volume with a neutral effect on cardiac energetics in left ventricular post-ischemia dysfunction. This highlights the versatility of Ivabradine in mitigating adverse effects induced by other treatments.

In summary, the key findings underscore the potential dangers of Omecamtiv Mecarbil, indicating excessive cardiac energy consumption and impaired diastole. On the other hand, Ivabradine emerges as a promising option, offering the potential to stimulate contractility while avoiding detrimental effects on heart function. These insights contribute valuable information to the ongoing exploration of novel inotropic treatments for acute heart failure.

Members: Ole-Jakob How

Publications:

Rødland, L., Rønning, L., Kildal, A. B., Myrmel, T., & How, O.-J. (2019). Combined Therapy With Dobutamine and Omecamtiv Mecarbil in Pigs With Ischemic Acute Heart Failure Is Attributed to the Effect of Dobutamine. Journal of Cardiovascular Pharmacology and Therapeutics, 1074248419881996. https://doi.org/10.1177/1074248419881996

Rønning, L., Bakkehaug, J. P., Rødland, L., Kildal, A. B., Myrmel, T., & How, O.-J. (2018). Opposite diastolic effects of omecamtiv mecarbil versus dobutamine and ivabradine co-treatment in pigs with acute ischemic heart failure. Physiological Reports, 6(19), e13879. https://doi.org/10.14814/phy2.13879

Bakkehaug, J. P., Naesheim, T., Torgersen Engstad, E., Kildal, A. B., Myrmel, T., & How, O.-J. (2016). Reversing dobutamine induced tachycardia using ivabradine increases stroke volume with neutral effect on cardiac energetics in left ventricular postischaemia dysfunction. Acta Physiologica (Oxford, England). https://doi.org/10.1111/apha.12704

Bakkehaug, J. petter, Kildal, A. B., Engstad, E. T., Næsheim, T., Rønning, L., Aasum, E., … How, O.-J. (2015). The myosin-activator Omecamtiv mecarbil increases myocardial oxygen consumption and impairs contractile efficiency mediated by resting myosin ATP ase activity. Circulation: Heart Failure. 2015;8:766–775 https://doi.org/10.1161/CIRCHEARTFAILURE.114.002152

Bakkehaug, J. P., Kildal, A. B., Engstad, E. T., Boardman, N., Næsheim, T., Rønning, L., … How, O.-J. (2015). Response to Letter Regarding Article, “Myosin Activator Omecamtiv Mecarbil Increases Myocardial Oxygen Consumption and Impairs Cardiac Efficiency Mediated by Resting Myosin ATPase Activity”. Circulation. Heart Failure, 8(6), 1142. https://doi.org/10.1161/CIRCHEARTFAILURE.115.002548

Microcirculation during acute heart failure

The study by Stenberg et al. delves into the acute phase of experimental cardiogenic shock, elucidating how microcirculatory and mitochondrial adaptations play a crucial role in mitigating its impact. Our findings highlight the intricate mechanisms that come into play during cardiogenic shock and emphasize the need for a comprehensive understanding of these adaptive processes. This knowledge could potentially pave the way for targeted interventions and therapies aimed at improving outcomes in acute heart failure.

Kildal et al. adds another layer to this narrative by focusing on the effects of arginine vasopressin on sublingual microcirculation in pigs. Through prolonged observation, the study reveals temporal fluctuations in microcirculatory responses, shedding light on the dynamic nature of these processes. This temporal perspective is crucial for capturing nuances in the microcirculatory system influenced by arginine vasopressin.

Collectively, these studies underscore the importance of microcirculatory assessment during acute heart failure. By unraveling the intricate interplay of microcirculation and mitochondrial adaptations, researchers gain a deeper understanding of the physiological responses during cardiogenic shock. This knowledge is not only crucial for advancing our theoretical understanding of acute heart failure but also holds practical implications for developing targeted therapeutic strategies. Accurate and timely assessment of microcirculatory dynamics can provide clinicians with valuable information for optimizing interventions and improving outcomes in patients experiencing acute heart failure.

Members: Ole-Jakob How

Publications:

The acute phase of experimental cardiogenic shock is counteracted by microcirculatory and mitochondrial adaptations.

Stenberg TA, Kildal AB, Sanden E, How OJ, Hagve M, Ytrehus K, Larsen TS, Myrmel T. PLoS One. 2014 Sep 4;9(9):e105213. doi: 10.1371/journal.pone.0105213. eCollection 2014. PMID: 25188581 Free PMC article.

Prolonged observation time reveals temporal fluctuations in the sublingual microcirculation in pigs given arginine vasopressin. Kildal AB, Stenberg TA, Sanden E, Myrmel T, How OJ. J Appl Physiol (1985). 2015 Apr 15;118(8):965-70. doi: 10.1152/japplphysiol.00900.2014. Epub 2015 Feb 12. PMID: 25678699