Heart failure research paradigms using bedside observation on endothelial muscle common denominators to highlight important translational questions
Background & aim: Congestive heart failure (CHF) imposes a relevant burden on healthcare systems, as it is associated with high morbidity and mortality rates and considerable costs. Within the last three to four decades, there have been revolutionary advancements, particularly in the pharmaceutical industry. In addition, health services research at the population level has also delivered. A third avenue for advancing the clinical management of CHF is to explore established therapies with a new approach. In this perspective, we explore these established concepts and provide impetus for using bedside observations to find improvements in CHF outcomes.
Conclusion: There are potentially new concepts that can be brought to established solutions for CHF. Encouraging observations when delivering established guideline-directed medical therapies are issues that the evidence-based medicine community should factor alongside novel discoveries to improve CHF prognosis. An emphasis on innovating on the known can be considered as an important paradigm for discovery.
Relevance for patients: Patients with CHF receiving current available treatments have improved outcomes; however those not improving could be considered under evolving research paradigms.
[1] McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure: Developed by the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) with the Special Contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2021;42:3599-726.
[2] Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin M, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2022;145:e895-1032.
[3] Roger VL. Epidemiology of Heart Failure. Circ Res 2013;113:646-59.
[4] Conrad N, Judge A, Tran J, Mohseni H, Hedgecott D, Crespillo AP, et al. Temporal Trends and Patterns in Heart Failure Incidence: A Population-Based Study of 4 Million Individuals. Lancet 2018;391:572-80.
[5] Ziaeian B, Fonarow GC. Epidemiology and Aetiology of Heart Failure. Nat Rev Cardiol 2016;13:368-78.
[6] Savarese G, Lund LH. Global Public Health Burden of Heart Failure. Card Fail Rev 2017;3:7-11.
[7] Iyngkaran P, Majoni W, Cass A, Sanders P, Ronco C, Brady S, et al. Northern Territory Perspectives on Heart Failure with Comorbidities-Understanding Trial Validity and Exploring Collaborative Opportunities to Broaden the Evidence Base. Heart Lung Circ 2015;24:536-43.
[8] Fonarow GC, Stough WG, Abraham WT, Albert NM, Gheorghiade M, Greenberg BH, et al. Characteristics, Treatments, and Outcomes of Patients with Preserved Systolic Function Hospitalized for Heart Failure: A Report from the OPTIMIZE-HF Registry. J Am Coll Cardiol 2007;50:768-77.
[9] Iyngkaran P, Thomas M. Bedside-to-Bench Translational Research for Chronic Heart Failure: Creating an Agenda for Clients Who do not Meet Trial Enrollment Criteria. Clin Med Insights Cardiol 2015;9:121-32.
[10] Al-Mohammad A. Hydralazine and Nitrates in the Treatment of Heart Failure with Reduced Ejection Fraction. ESC Heart Fail 2019;6:878-83.
[11] Carson P, Ziesche S, Johnson G, Cohn JN. Racial Differences in Response to Therapy for Heart Failure: Analysis of the Vasodilator-Heart Failure Trials. Vasodilator-Heart Failure Trial Study Group. J Card Fail 1999;5:178-87.
[12] Exner DV, Dries DL, Domanski MJ, Cohn JN. Lesser Response to Angiotensin-Converting-Enzyme Inhibitor Therapy in Black as Compared with White Patients with Left Ventricular Dysfunction. N Engl J Med 2001;344:1351-7.
[13] Khazanie P, Liang L, Curtis LH, Butler J, Eapen ZJ, Heidenreich PA, et al. Clinical Effectiveness of Hydralazine-Isosorbide Dinitrate Therapy in Patients with Heart Failure and Reduced Ejection Fraction: Findings from the Get with the Guidelines-Heart Failure Registry. Circ Heart Fail 2016;9:e002444.
[14] Ziaeian B, Fonarow GC, Heidenreich PA. Clinical Effectiveness of Hydralazine-Isosorbide Dinitrate in African-American Patients with Heart Failure. JACC Heart Fail 2017;5:632-9.
[15] Brewster LM. Underuse of Hydralazine and Isosorbide Dinitrate for Heart Failure in Patients of African Ancestry: A Cross-European Survey. ESC Heart Fail 2019;6:487-98.
[16] Furchgott RF, Zawadzki JV. The Obligatory Role of Endothelial Cells in the Relaxation of Arterial Smooth Muscle by Acetylcholine. Nature 1980;288:373-6.
[17] Macdonald P, Schyvens C, Winlaw D. The Role of Nitric Oxide in Heart Failure. Potential for Pharmacological Intervention. Drugs Aging 1996;8:452-8.
[18] Kubo SH, Rector TS, Bank AJ, Williams RE, Heifetz SM. Endothelium-Dependent Vasodilation is Attenuated in Patients with Heart Failure. Circulation 1991;84:1589-96.
[19] Elkayam U, Khan S, Mehboob A, Ahsan N. Impaired Endothelium-Mediated Vasodilation in Heart Failure: Clinical Evidence and the Potential for Therapy. J Card Fail 2002;8:15-20.
[20] Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, et al. A Novel Potent Vasoconstrictor Peptide Produced by Vascular Endothelial Cells. Nature 1988;332:411-5.
[21] Rajendran P, Rengarajan T, Thangavel J, Nishigaki Y, Sakthisekaran D, Sethi G, et al. The Vascular Endothelium and Human Diseases. Int J Biol Sci 2013;9:1057-69.
[22] Dulce RA, Kulandavelu S, Schulman IH, Fritsch J, Hare JM. Nitric Oxide Regulation of Cardiovascular Physiology and Pathophysiology. Nitric Oxide Biology and Pathology. 3rd ed. United States: Academic Press; 2017. p. 313-38.
[23] Förstermann U, Sessa WC. Nitric Oxide Synthases: Regulation and Function. Eur Heart J 2012;33:829-37, 837a-d.
[24] Zuchi C, Tritto I, Carluccio E, Mattei C, Cattadori G, Ambrosio G. Role of Endothelial Dysfunction in Heart Failure. Heart Fail Rev 2020;25:21-30.
[25] Farah C, Michel LY, Balligand JL. Nitric Oxide Signalling in Cardiovascular Health and Disease. Nat Rev Cardiol 2018;15:292-316.
[26] Segers VF, Brutsaert DL, De Keulenaer GW. Cardiac Remodeling: Endothelial Cells have more to Say than Just no. Front Physiol 2018;9:382.
[27] Tsutsui H, Kinugawa S, Matsushima S. Oxidative Stress and Heart Failure. Am J Physiol Heart Circ Physiol 2011;301:H2181-90.
[28] Keller-Ross ML, Larson M, Johnson BD. Skeletal Muscle Fatigability in Heart Failure. Front Physiol 2019;10:129.
[29] Alem MM. Endothelial Dysfunction in Chronic Heart Failure: Assessment, Findings, Significance, and Potential Therapeutic Targets. Int J Mol Sci 2019;20:3198.
[30] Hafen BB, Burns B. Physiology, smooth muscle. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2022.
[31] Zhuge Y, Zhang J, Qian F, Wen Z, Niu C, Xu K, et al. Role of Smooth Muscle Cells in Cardiovascular Disease. Int J Biol Sci 2020;16:2741-51.
[32] Song T, Manoharan P, Millay DP, Koch SE, Rubinstein J, Heiny JA, et al. Dilated Cardiomyopathy-Mediated Heart Failure Induces a Unique Skeletal Muscle Myopathy with Inflammation. Skelet Muscle 2019;9:4.
[33] Zizola C, Schulze PC. Metabolic and Structural Impairment of Skeletal Muscle in Heart Failure. Heart Fail Rev 2013;18:623-30.
[34] Iyngkaran P, Liew D, Neil C, Driscoll A, Marwick TH, Hare DL. Moving from Heart Failure Guidelines to Clinical Practice: Gaps Contributing to Readmissions in Patients with Multiple Comorbidities and Older Age. Clin Med Insights Cardiol 2018;12:1179546818809358.
[35] Iyngkaran P, Liew D, McDonald P, Thomas MC, Reid C, Chew D, et al. Phase 4 Studies in Heart Failure-what is done and what is Needed? Curr Cardiol Rev 2016;12:216-30.
[36] Atkinson J. Cardiovascular and Smooth Muscle Pharmacology in the Next Decade. Front Pharmacol 2010;1:1.
[37] G-CHF Investigators, Joseph P, Roy A, Lonn E, Störk S, Floras J, et al. Global Variations in Heart Failure Etiology, Management, and Outcomes. JAMA 2023;329:1650-61.
[38] Radhoe SP, Veenis JF, Brugts JJ. Invasive Devices and Sensors for Remote Care of Heart Failure Patients. Sensors (Basel) 2021;21:2014.
[39] Iyngkaran P, Thomas MC, Johnson R, French J, Ilton M, McDonald P, et al. Contextualizing Genetics for Regional Heart Failure Care. Curr Cardiol Rev 2016;12:231-42.
[40] Nanayakkara S, Marwick TH, Kaye DM. The Ageing Heart: The Systemic and Coronary Circulation. Heart 2018;104:370-6.
[41] Lam CS, Arnott C, Beale AL, Chandramouli C, HilfikerKleiner D, Kaye DM, et al. Sex Differences in Heart Failure. Eur Heart J 2019;40:3859-68c.
[42] Umaefulam V, Kleissen T, Barnabe C. The Representation of Indigenous Peoples in Chronic Disease Clinical Trials in Australia, Canada, New Zealand, and the United States. Clin Trials 2022;19:22-32.
[43] Whyte J. Racial and Ethnic Representation of Participants in US Clinical Trials of New Drugs and Biologics. JAMA 2022;327:985.
[44] Gray LA, D’Antoine HA, Tong SY, McKinnon M, Bessarab D, Brown N, et al. Genome-Wide Analysis of Genetic Risk Factors for Rheumatic Heart Disease in Aboriginal Australians Provides Support for Pathogenic Molecular Mimicry. J Infect Dis 2017;216:1460-70.
[45] Spence JD, Rayner BL. Hypertension in Blacks: Individualized Therapy Based on Renin/Aldosterone Phenotyping. Hypertension 2018;72:263-9.
[46] Savoia C, Volpe M, Grassi G, Borghi C, Agabiti Rosei E, Touyz RM. Personalized Medicine-a Modern Approach for the Diagnosis and Management of Hypertension. Clin Sci (Lond) 2017;131:2671-85.
[47] Volpp KG, Krumholz HM, Asch DA. Mass Customization for Population Health. JAMA Cardiol 2018;3:363-4.
[48] Semsarian C, Ingles J, Ross SB, Dunwoodie SL, Bagnall RD, Kovacic JC. Precision Medicine in Cardiovascular Disease: Genetics and Impact on Phenotypes: JACC Focus Seminar 1/5. J Am Coll Cardiol 2021;77:2517-30.
[49] Leopold JA, Loscalzo J. Emerging Role of Precision Medicine in Cardiovascular Disease. Circ Res 2018;122:1302-15.