Reduced nitric oxide bioavailability impairs myocardial oxygen balance during exercise in swine with multiple risk factors

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Abstract

In the present study, we tested the hypothesis that multiple risk factors, including diabetes mellitus (DM), dyslipidaemia and chronic kidney disease (CKD) result in a loss of nitric oxide (NO) signalling, thereby contributing to coronary microvascular dysfunction. Risk factors were induced in 12 female swine by intravenous streptozotocin injections (DM), a high fat diet (HFD) and renal artery embolization (CKD). Female healthy swine ( n = 13) on normal diet served as controls (Normal). After 5 months, swine were chronically instrumented and studied at rest and during exercise. DM + HFD + CKD swine demonstrated significant hyperglycaemia, dyslipidaemia and impaired kidney function compared to Normal swine. These risk factors were accompanied by coronary microvascular endothelial dysfunction both in vivo and in isolated small arteries, due to a reduced NO bioavailability, associated with perturbations in myocardial oxygen balance at rest and during exercise. NO synthase inhibition caused coronary microvascular constriction in exercising Normal swine, but had no effect in DM + HFD + CKD animals, while inhibition of phosphodiesterase 5 produced similar vasodilator responses in both groups, indicating that loss of NO bioavailability was principally responsible for the observed coronary microvascular dysfunction. This was associated with an increase in myocardial 8-isoprostane levels and a decrease in antioxidant capacity, while antioxidants restored the vasodilation to bradykinin in isolated coronary small arteries, suggesting that oxidative stress was principally responsible for the reduced NO bioavailability. In conclusion, five months of combined exposure to DM + HFD + CKD produces coronary endothelial dysfunction due to impaired NO bioavailability, resulting in impaired myocardial perfusion at rest and during exercise.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00395-021-00890-8.

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Most cited references 76

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Chronic Kidney Disease.

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The definition and classification of chronic kidney disease (CKD) have evolved over time, but current international guidelines define this condition as decreased kidney function shown by glomerular filtration rate (GFR) of less than 60 mL/min per 1·73 m(2), or markers of kidney damage, or both, of at least 3 months duration, regardless of the underlying cause. Diabetes and hypertension are the main causes of CKD in all high-income and middle-income countries, and also in many low-income countries. Incidence, prevalence, and progression of CKD also vary within countries by ethnicity and social determinants of health, possibly through epigenetic influence. Many people are asymptomatic or have non-specific symptoms such as lethargy, itch, or loss of appetite. Diagnosis is commonly made after chance findings from screening tests (urinary dipstick or blood tests), or when symptoms become severe. The best available indicator of overall kidney function is GFR, which is measured either via exogenous markers (eg, DTPA, iohexol), or estimated using equations. Presence of proteinuria is associated with increased risk of progression of CKD and death. Kidney biopsy samples can show definitive evidence of CKD, through common changes such as glomerular sclerosis, tubular atrophy, and interstitial fibrosis. Complications include anaemia due to reduced production of erythropoietin by the kidney; reduced red blood cell survival and iron deficiency; and mineral bone disease caused by disturbed vitamin D, calcium, and phosphate metabolism. People with CKD are five to ten times more likely to die prematurely than they are to progress to end stage kidney disease. This increased risk of death rises exponentially as kidney function worsens and is largely attributable to death from cardiovascular disease, although cancer incidence and mortality are also increased. Health-related quality of life is substantially lower for people with CKD than for the general population, and falls as GFR declines. Interventions targeting specific symptoms, or aimed at supporting educational or lifestyle considerations, make a positive difference to people living with CKD. Inequity in access to services for this disease disproportionally affects disadvantaged populations, and health service provision to incentivise early intervention over provision of care only for advanced CKD is still evolving in many countries.

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Filippo Crea, Paolo Camici, Cathleen Bairey Merz (2014)

Many patients undergoing coronary angiography because of chest pain syndromes, believed to be indicative of obstructive atherosclerosis of the epicardial coronary arteries, are found to have normal angiograms. In the past two decades, a number of studies have reported that abnormalities in the function and structure of the coronary microcirculation may occur in patients without obstructive atherosclerosis, but with risk factors or with myocardial diseases as well as in patients with obstructive atherosclerosis; furthermore, coronary microvascular dysfunction (CMD) can be iatrogenic. In some instances, CMD represents an epiphenomenon, whereas in others it is an important marker of risk or may even contribute to the pathogenesis of cardiovascular and myocardial diseases, thus becoming a therapeutic target. This review article provides an update on the clinical relevance of CMD in different clinical settings and also the implications for therapy.

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Author and article information

Contributors

Dirk J. Duncker:

ORCID: http://orcid.org/0000-0003-2836-2241

d.duncker@erasmusmc.nl

Journal

Journal ID (nlm-ta): Basic Res Cardiol

Journal ID (iso-abbrev): Basic Res Cardiol

Title: Basic Research in Cardiology

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0300-8428

ISSN (Electronic): 1435-1803

Publication date (Electronic): 26 August 2021

Publication date PMC-release: 26 August 2021

Publication date (Print): 2021

Volume: 116

Issue: 1

Electronic Location Identifier: 50

Affiliations

[1 ]GRID grid.5645.2, ISNI 000000040459992X, Department of Cardiology, Division of Experimental Cardiology, , Erasmus University Medical Center, ; PO Box 2040, 3000 CA Rotterdam, Netherlands

[2 ]GRID grid.7692.a, ISNI 0000000090126352, Department of Nephrology and Hypertension, , University Medical Center Utrecht, ; Utrecht, Netherlands

[3 ]GRID grid.5645.2, ISNI 000000040459992X, Department of Internal Medicine, , Erasmus MC University Medical Center, ; Rotterdam, Netherlands

[4 ]GRID grid.5252.0, ISNI 0000 0004 1936 973X, Walter Brendel Center of Experimental Medicine (WBex), , University Clinic Munich, ; 81377 LMU Munich, Germany

[5 ]GRID grid.452396.f, ISNI 0000 0004 5937 5237, German Center for Cardiovascular Research (DZHK), , Munich Heart Alliance (MHA), ; Partner Site Munich, 81377 Munich, Germany

Author information

Jens van de Wouw http://orcid.org/0000-0001-7133-3046

Oana Sorop http://orcid.org/0000-0003-3713-4136

Ruben W. A. van Drie http://orcid.org/0000-0002-5383-4960

Jaap A. Joles http://orcid.org/0000-0003-2565-242X

A. H. Jan Danser http://orcid.org/0000-0002-5052-3585

Marianne C. Verhaar http://orcid.org/0000-0002-3276-6428

Daphne Merkus http://orcid.org/0000-0002-4852-831X

Dirk J. Duncker http://orcid.org/0000-0003-2836-2241

Article

Publisher ID: 890

DOI: 10.1007/s00395-021-00890-8

PMC ID: 8387273

PubMed ID: 34435256

SO-VID: 5a0dee58-0f52-4792-b03c-38ddbecbce82

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 25 June 2020

Date accepted : 20 July 2021

Funding

Funded by: European Commission FP7-Health-2010

Award ID: MEDIA-261409

Award Recipient : Dirk J. Duncker

Funded by: FundRef http://dx.doi.org/10.13039/100010447, Deutsches Zentrum für Herz-Kreislaufforschung;

Award ID: 81Z0600207

Award Recipient : Daphne Merkus

Funded by: FundRef http://dx.doi.org/10.13039/501100002996, Hartstichting;

Award ID: CVON2014-11(RECONNECT)

Award Recipient : Dirk J. Duncker

Custom metadata

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: diabetes mellitus,chronic kidney disease,coronary blood flow,coronary microcirculation,coronary microvascular dysfunction

Data availability:

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: diabetes mellitus, chronic kidney disease, coronary blood flow, coronary microcirculation, coronary microvascular dysfunction

Reduced nitric oxide bioavailability impairs myocardial oxygen balance during exercise in swine with multiple risk factors

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Supplementary Information

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Karger: Cardiovascular System

Most cited references 76

Chronic Kidney Disease.

Ischemia and No Obstructive Coronary Artery Disease (INOCA): Developing Evidence-Based Therapies and Research Agenda for the Next Decade.

Coronary microvascular dysfunction: an update.

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