Coronary microvascular dysfunction results in impaired coronary flow reserve and altered oxygen balance in a swine model of INOCA with multiple risk factors

Abstract Introduction Comorbidities of ischemic heart disease, including diabetes mellitus (DM), hypercholesterolemia and chronic kidney disease (CKD), are associated with coronary microvascular dysfunction (CMD) and may contribute to myocardial “Ischemia and No Obstructive Coronary Artery disease” (INOCA). Purpose We studied myocardial perfusion and oxygen delivery using a novel swine model with multiple comorbidities. Methods DM (streptozotocin), HFD (high fat diet) and CKD (renal embolization), were induced in 12 female swine (DM+HFD+CKD), while 12 healthy female swine on a normal diet served as controls (CON). After 6 months, in the absence of coronary atherosclerosis, myocardial perfusion and function were studied at rest and during treadmill exercise. Results DM+HFD+CKD animals showed hyperglycemia, hypercholesterolemia and impaired kidney function. During exercise, DM+HFD+CKD demonstrated impaired myocardial blood flow and oxygen delivery, necessitating higher myocardial oxygen extraction (despite reduced capillary density), resulting in lower coronary venous oxygen levels, (Fig. 1). These perturbations were associated with lower myocardial efficiency, requiring higher oxygen consumption for a given level of myocardial work (Fig. 1), lower myocardial lactate consumption, stroke volume and LVdP/dtmax, suggestive of myocardial ischemia and dysfunction. Furthermore DM+HFD+CKD showed a reduction in adenosine-recruitable coronary flow reserve (2.69±0.26 vs 3.64±0.2 in CON, p<0.05), which was exclusively the result of an increase in basal coronary blood flow, while maximal coronary flow per gram of myocardium was maintained. The latter was consistent with the unchanged arteriolar wall/lumen ratio, arteriolar density and peri-arteriolar collagen content. eNOS blockade indicated loss of NO bioavailability in DM+HFD+CKD swine in vivo (Fig. 1), which was supported by blunted endothelium-dependent vasodilation to bradykinin in isolated small arteries. These findings suggest that changes in coronary microvascular function rather than structure contributed to the perturbations in myocardial oxygen delivery. Conclusion Common comorbidities result in CMD and impaired NO bioavailability rather than structural alterations in the microvasculature in swine, in the absence of appreciable atherosclerosis. These alterations are severe enough to produce perturbations in myocardial oxygen balance and coronary metabolism and function, particularly during exercise, resembling key features of INOCA. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): This study was supported by grants from the European Commission FP7-Health-2010 grant MEDIA-261409, the Netherlands CardioVascular Research Initiative: an initiative with support of the Dutch Heart Foundation [CVON2014-11 (RECONNECT)].

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PSORIASIS EARLY IMPAIRS CORONARY FLOW RESERVE: NEW INSIGHTS INTO INFLAMMATION AND CORONARY MICROVASCULAR DYSFUNCTION

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(10)61565-3 ◽

2010 ◽

Vol 55 (10) ◽

pp. A167.E1564

Author(s):

Elena Osto ◽

Stefano Piaserico ◽

Anna Maddalozzo ◽

Giulia Forchetti ◽

Roberta Montisci ◽

...

Keyword(s):

Coronary Flow Reserve ◽

Coronary Flow ◽

Microvascular Dysfunction ◽

Coronary Microvascular Dysfunction ◽

Flow Reserve

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Coronary microvascular function in athletes with abnormal exercise test results

Netherlands Heart Journal ◽

10.1007/s12471-019-01336-6 ◽

2019 ◽

Vol 27 (12) ◽

pp. 621-628

Author(s):

D. A. J. P. van de Sande ◽

P. C. Barneveld ◽

J. Hoogsteen ◽

P. A. Doevendans ◽

H. M. C. Kemps

Keyword(s):

Coronary Flow Reserve ◽

Myocardial Ischaemia ◽

Coronary Flow ◽

A Priori ◽

Microvascular Dysfunction ◽

Microvascular Function ◽

Coronary Microvascular Dysfunction ◽

Endothelin 1 ◽

Flow Reserve ◽

Coronary Microvascular Function

Abstract Aims In asymptomatic athletes, abnormal exercise test (ET) results have a poor positive predictive value. It is unknown whether abnormal ET results in the absence of obstructive coronary artery disease (CAD) are related to coronary microvascular dysfunction. It is also unknown whether they should be considered false-positive ET results or a consequence of physiological adaptation to sport. In our study, we evaluated whether athletes with abnormal ET results and documented myocardial ischaemia in the absence of obstructive CAD have an attenuated microvascular function and whether coronary microvascular dysfunction is related to endothelial dysfunction. Methods and results Nine athletes with concordant abnormal ET and myocardial perfusion scintigraphy (MPS) results without obstructive CAD were compared with age- and gender-matched individuals with a low-to-intermediate a priori risk of CAD. Coronary flow reserve was assessed by Rubidium-82 positron emission tomography (PET) imaging. Endothelin‑1 concentrations were measured to evaluate endothelial function. Coronary flow reserve was significantly lower in athletes (3.3 ± 0.8 versus 4.2 ± 0.6, p = 0.014 respectively). Endothelin‑1 levels were significantly higher in athletes (1.3 ± 0.2 pg/ml versus 1.0 ± 0.2 pg/ml, p = 0.012 respectively). There was no correlation between endothelin‑1 concentrations and mean global coronary flow reserve (r = 0.12). Conclusion Athletes with abnormal ET and MPS outcomes indicative for myocardial ischaemia and no obstructive CAD have a lower coronary flow reserve compared with non-athletes with low-to-intermediate a priori risk of CAD, suggesting an attenuated coronary microvascular function. Higher endothelin‑1 concentrations in athletes suggest that endothelial-dependent dysfunction is an important determinant of the attenuated microvascular function.

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Angiogenic CD34 Stem Cell Therapy in Coronary Microvascular Repair—A Systematic Review

Cells ◽

10.3390/cells10051137 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1137

Author(s):

Balaj Rai ◽

Janki Shukla ◽

Timothy D. Henry ◽

Odayme Quesada

Keyword(s):

Quality Of Life ◽

Cell Therapy ◽

Coronary Flow Reserve ◽

Coronary Flow ◽

Controlled Trial ◽

Microvascular Dysfunction ◽

Treatment Modalities ◽

Coronary Microvascular Dysfunction ◽

Flow Reserve

Ischemia with non-obstructive coronary arteries (INOCA) is an increasingly recognized disease, with a prevalence of 3 to 4 million individuals, and is associated with a higher risk of morbidity, mortality, and a worse quality of life. Persistent angina in many patients with INOCA is due to coronary microvascular dysfunction (CMD), which can be difficult to diagnose and treat. A coronary flow reserve <2.5 is used to diagnose endothelial-independent CMD. Antianginal treatments are often ineffective in endothelial-independent CMD and thus novel treatment modalities are currently being studied for safety and efficacy. CD34+ cell therapy is a promising treatment option for these patients, as it has been shown to promote vascular repair and enhance angiogenesis in the microvasculature. The resulting restoration of the microcirculation improves myocardial tissue perfusion, resulting in the recovery of coronary microvascular function, as evidenced by an improvement in coronary flow reserve. A pilot study in INOCA patients with endothelial-independent CMD and persistent angina, treated with autologous intracoronary CD34+ stem cells, demonstrated a significant improvement in coronary flow reserve, angina frequency, Canadian Cardiovascular Society class, and quality of life (ESCaPE-CMD, NCT03508609). This work is being further evaluated in the ongoing FREEDOM (NCT04614467) placebo-controlled trial.

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Coronary Flow Reserve in Patients With Prior Spontaneous Coronary Artery Dissection and Recurrent Angina

Journal of the American Heart Association ◽

10.1161/jaha.120.015834 ◽

2020 ◽

Vol 9 (16) ◽

Author(s):

Tara Sedlak ◽

Andrew Starovoytov ◽

Karin Humphries ◽

Jacqueline Saw

Keyword(s):

Chest Pain ◽

Coronary Artery ◽

Coronary Flow ◽

Fibromuscular Dysplasia ◽

Microvascular Dysfunction ◽

Artery Dissection ◽

Coronary Microvascular Dysfunction ◽

Coronary Artery Dissection ◽

Flow Reserve ◽

Index Of Microcirculatory Resistance

Background A significant proportion of patients with spontaneous coronary artery dissection (SCAD) have ongoing chronic chest pain despite healing of their dissection. We sought to determine whether coronary microvascular dysfunction contributes to post‐SCAD chronic chest pain by performing coronary reactivity testing in the cardiac catheterization laboratory. Methods and Results Eighteen patients consented to coronary reactivity testing at least 3 months post‐SCAD. Coronary flow reserve (CFR) and index of microcirculatory resistance were measured in the previously affected SCAD artery and 1 non‐SCAD artery. CFR <2.5 was defined as diagnostic of coronary microvascular dysfunction. An abnormal index of microcirculatory resistance was defined as >25 units. Seventeen women underwent coronary reactivity testing (1 had chronic dissection and was excluded). All presented with myocardial infarction and 2 underwent coronary stenting during the initial SCAD event. Fibromuscular dysplasia was present in 70.6% upon screening renal, iliac, and cerebrovascular arteries. Twelve patients (70.6%) had CFR <2.5 and 13 (76.5%) had an index of microcirculatory resistance >25 in at least 1 artery. There was no difference in the frequency of a low CFR measurement between SCAD and non‐SCAD arteries. Conclusions Among patients with chronic chest pain after an SCAD event, >70% had coronary microvascular dysfunction as indicated by abnormal CFR or index of microcirculatory resistance in at least 1 coronary artery on invasive coronary reactivity testing. Presence of coronary microvascular dysfunction in both SCAD and non‐SCAD arteries suggests that underlying microvascular abnormalities from vasculopathies such as coronary fibromuscular dysplasia may be the underlying etiology.

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Abstract 5636: Major Depression is Associated with Decreased Coronary Flow Reserve Detected by Positron Emission Tomography

Circulation ◽

10.1161/circ.118.suppl_18.s_976-c ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Viola Vaccarino ◽

J D Bremner ◽

John Votaw ◽

Tracy Faber ◽

Emir Veledar ◽

...

Keyword(s):

Risk Factors ◽

Positron Emission Tomography ◽

Myocardial Perfusion ◽

Coronary Flow Reserve ◽

Coronary Flow ◽

Microvascular Dysfunction ◽

Emission Tomography ◽

Coronary Microvascular Dysfunction ◽

Flow Reserve ◽

Positron Emission

Introduction. Major depressive disorder (MDD) is associated with coronary heart disease, but the underlying mechanisms are unclear. Coronary flow reserve (CFR) in response to adenosine is an index of coronary microvascular dysfunction which predisposes to myocardial ischemia. We examined the relationship between MDD and CFR in a genetically informative sample. Methods. We studied 141 twin pairs drawn from the Vietnam Era Twin Registry who were born between 1946 and 1956 (mean age 54). For all twins, a lifetime history of MDD was determined with the Structured Clinical Interview for Psychiatry Disorders; 53 pairs were discordant for MDD and 88 pairs were free of MDD. Standard cardiovascular risk factors were obtained by interview and examination. We performed myocardial perfusion imaging and blood flow quantitation with [13N] ammonia positron emission tomography at rest and after adenosine stress. A perfusion defect score summed the number and severity of defects across 20 myocardial regions. CFR was measured as the ratio of maximum flow to baseline flow at rest. Mixed-effect and GEE models were used to conduct matched-pair analyses. Results. There was no difference in the distribution of abnormal scans, in summed rest or stress defect scores, and in heart rate/blood pressure responses to adenosine between twins with and without MDD. Among the DZ twin pairs discordant for MDD, the mean CFR was lower in twins with MDD than their brothers without MDD (2.36 ± 0.66 vs 2.75 ± 0.90; p=0.03); no significant difference in mean CFR was found in MZ discordant pairs (2.90±0.78 vs 2.64±0.64, p=0.13). The zygosity by MDD interaction was significant (p=0.01). Results did not change substantially after adjusting for cardiovascular disease risk factors and antidepressant use (adjusted interaction p=0.007). There were no differences in myocardial perfusion comparing twins in discordant pairs with twins in healthy pairs. Conclusions. MDD is associated with lower CFR in spite of no differences in visible perfusion defects, suggesting microvascular dysfunction. This association is largely due to shared genetic liability between depression and CFR, suggesting a common underlying pathophysiological process linking depression and coronary microvascular dysfunction. This research has received full or partial funding support from the American Heart Association, AHA National Center.

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Optimale Diagnostik und Therapie der mikrovaskulären Angina pectoris

DMW - Deutsche Medizinische Wochenschrift ◽

10.1055/s-0043-104469 ◽

2017 ◽

Vol 142 (21) ◽

pp. 1586-1593 ◽

Cited By ~ 2

Author(s):

Peter Ong ◽

Udo Sechtem

Keyword(s):

Angina Pectoris ◽

Coronary Flow Reserve ◽

Coronary Flow ◽

Beta Blockers ◽

Microvascular Dysfunction ◽

Coronary Microvascular Dysfunction ◽

Channel Blockers ◽

Microvascular Angina ◽

Flow Reserve ◽

Diagnostik Und Therapie

AbstractPatients with microvascular angina are characterized by angina pectoris with proof of myocardial ischemia in the absence of any relevant epicardial stenosis and without myocardial disease (type 1 coronary microvascular dysfunction according to Crea and Camici). Structural and functional alterations of the coronary microvessels (diameter < 500 µm) are the reason for this phenomenon. Frequently such alterations are associated with cardiovascular risk factors. Patients with angina pectoris without epicardial stenoses represent for 10 – 50 % of all patients undergoing coronary angiography depending on the clinical presentation. Diagnostic approaches include non-invasive (e. g. combination of coronary CT-angiography and positron emission tomography/echo Doppler-based coronary flow reserve measurements) as well as invasive procedures (coronary flow reserve measurements in response to adenosine, intracoronary acetylcholine testing). Pharmacological treatment of these patients is often challenging and should be based on the characterization of the underlying mechanisms. Moreover, strict risk factor control and individually titrated combinations of antianginal substances (e. g. beta blockers, calcium channel blockers, nitrates, ranolazine, ivabradine etc.) are recommended.

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Histone Acetyltransferase p300 Inhibitor Improves Coronary Flow Reserve in SIRT3 (Sirtuin 3) Knockout Mice

Journal of the American Heart Association ◽

10.1161/jaha.120.017176 ◽

2020 ◽

Vol 9 (18) ◽

Cited By ~ 1

Author(s):

Han Su ◽

Heng Zeng ◽

Xiaochen He ◽

Shai-Hong Zhu ◽

Jian-Xiong Chen

Keyword(s):

Heart Failure ◽

Pulse Wave Velocity ◽

Coronary Flow ◽

Histone Acetyltransferase ◽

Pulse Wave ◽

Microvascular Dysfunction ◽

Coronary Microvascular Dysfunction ◽

Sirtuin 3 ◽

Flow Reserve ◽

H3k56 Acetylation

Background Coronary microvascular dysfunction is common in patients of myocardial infarction with non‐obstructive coronary artery disease. Coronary flow reserve (CFR) reflects coronary microvascular function and is a powerful independent index of coronary microvascular dysfunction and heart failure. Our previous studies showed that knockout of SIRT3 (Sirtuin 3) decreased CFR and caused a diastolic dysfunction. Few studies focus on the treatment of impaired CFR and heart failure. In the present study, we explored the role of C646, a histone acetyltransferase p300 inhibitor, in regulating CFR and cardiac remodeling in SIRT3 knockout (SIRT3KO) mice. Methods and Results After treating with C646 for 14 days, CFR, pulse‐wave velocity, and cardiac function were measured in SIRT3KO mice. SIRT3KO mice treated with C646 showed a significant improvement of CFR, pulse‐wave velocity, ejection fraction, and fractional shortening. Treatment with C646 reversed pre‐existing cardiac fibrosis, hypertrophy, and capillary rarefaction in SIRT3KO mice. Mechanistically, knockout of Sirtuin 3 resulted in significant increases in p300 expression and H3K56 acetylation. Treatment with C646 significantly reduced levels of p300 and H3K56 acetylation in SIRT3KO mice. Furthermore, treatment with C646 increased endothelial nitric oxide synthase expression and reduced arginase II expression and activity. The expression of NF‐κB (nuclear factor kappa‐light‐chain‐enhancer of activated B cells) and VCAM‐1 (vascular cell adhesion molecule 1) was also significantly suppressed by C646 treatment in SIRT3KO mice. Conclusions C646 treatment attenuated p300 and H3K56 acetylation and improved arterial stiffness and CFR via improvement of endothelial cell (EC) dysfunction and suppression of NF‐κB.

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Clinical characteristics and biomarkers of coronary microvascular dysfunction and obstructive coronary artery disease

Journal of International Medical Research ◽

10.1177/0300060519859134 ◽

2019 ◽

Vol 47 (12) ◽

pp. 6149-6159

Author(s):

Henry Anselmo Mayala ◽

Wang Yan ◽

Hu Jing ◽

Liu Shuang-ye ◽

Yi Gui-wen ◽

...

Keyword(s):

Coronary Flow ◽

Clinical Characteristics ◽

Obstructive Coronary Artery Disease ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Microvascular Dysfunction ◽

Coronary Microvascular Dysfunction ◽

Low Density ◽

Flow Reserve ◽

Artery Disease

Objective The purpose of this study was to determine the clinical characteristics and biomarkers in patients with coronary microvascular dysfunction (CMVD) and to compare them with patients with obstructive coronary artery disease (OCAD). Methods We conducted a single-center, hospital-based, observational, descriptive, comparative, clinical study of 40 patients, including 20 patients with CMVD and 20 with OCAD. We assessed laboratory biomarkers (low-density lipoprotein [LDL], high-density lipoprotein [HDL], red blood cell distribution width [RDW], brain natriuretic protein [BNP], troponin I), and PET/CT coronary flow reserve was performed. Results The mean coronary flow reserve (CFR) in patients with CMVD was 1.96±0.55. Mean low-density lipoprotein cholesterol (LDL-C) levels were significantly higher in the CMVD subgroup (2.53±0.63 mmol/L) compared with the OCAD subgroup (1.76±0.97 mmol/L). Logistic regression analysis identified LDL-C as a predictor for the development of CMVD (odds ratio, 5.24). Conclusion It is difficult to differentiate between OCAD and CMVD based on the patient’s medical history, clinical characteristics, and coronary angiography results. Further investigations may be needed to allow an accurate diagnosis. CFR measurements based on non-invasive positron emission tomography/computed tomography may aid the diagnosis of CMVD. We also identified LDL-C as a predictor for the development of CMVD.

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Abstract 9946: Impact of Sex Differences on Invasive Measures of Coronary Microvascular Dysfunction in Patients With Angina in the Absence of Obstructive Coronary Artery Disease

Circulation ◽

10.1161/circ.130.suppl_2.9946 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Yuhei Kobayashi ◽

Yasuhiro Honda ◽

William F Fearon ◽

Shigemitsu Tanaka ◽

Peter J Fitzgerald ◽

...

Keyword(s):

Coronary Artery Disease ◽

Sex Differences ◽

Coronary Artery ◽

Coronary Flow ◽

Obstructive Coronary Artery Disease ◽

Microvascular Dysfunction ◽

Microvascular Function ◽

Coronary Microvascular Dysfunction ◽

Flow Reserve ◽

Artery Disease

Background: Coronary microvascular dysfunction is associated with worse long-term outcomes, especially in women. Coronary flow reserve (CFR) is typically used to interrogate microvascular function; however its variability limits reliability. Alternatively, the index of microcirculatory resistance (IMR) is a direct measure of the microvasculature, but has been less thoroughly studied. We investigated sex differences in CFR and IMR in patients with angina in the absence of obstructive coronary artery disease (CAD). Methods: We prospectively enrolled 117 women and 40 men with angina in the absence of obstructive CAD. We performed CFR, IMR, fractional flow reserve (FFR), and quantitative coronary angiography (QCA) in the left anterior descending artery. Coronary flow was assessed with a thermodilution method by obtaining mean transit time (Tmn: an inverse correlate to absolute flow) at rest and hyperemia. IMR was measured as distal coronary pressure at hyperemia x hyperemic Tmn. Results: All patients had minimal or no atherosclerosis by QCA (%diameter stenosis: 23.2±12.3%), and epicardial disease was milder in women (FFR: 0.88±0.04 vs. 0.87±0.04, p=0.04). IMR was similar between the sexes (20.7±9.8 vs. 19.1±8.0, p=0.45), but CFR was lower in women (3.8±1.6 vs. 4.8±1.9, p=0.004). This was primarily due to a shorter resting Tmn in women (p=0.005), while hyperemic Tmn was identical (p=0.79) (Figure). The shorter resting Tmn in women, reflecting increased resting coronary flow, accounted for the lower CFR. In multivariate analysis, female sex was an independent predictor of lower CFR and shorter resting Tmn, but not a predictor of IMR or hyperemic Tmn. Conclusions: Despite women and men having similar microvascular function by IMR, CFR is lower in women. This discrepancy appears to be due to differences in resting coronary flow between the sexes. The impact of sex differences should be considered in interpretation of physiologic indices using resting coronary flow.

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Abstract 13792: Association of Immunocompromised State With Coronary Microvascular Dysfunction in Patients With Well-controlled HIV

Circulation ◽

10.1161/circ.142.suppl_3.13792 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Leah Rethy ◽

Joseph Kern ◽

Chad Achenbach ◽

Michael Angarone ◽

Stephen Dvorak ◽

...

Keyword(s):

Coronary Flow ◽

Microvascular Dysfunction ◽

Immune Dysfunction ◽

Cd4 Count ◽

Coronary Microvascular Dysfunction ◽

Linear Regression Models ◽

Cvd Risk ◽

Hiv Patients ◽

Flow Reserve ◽

Immunocompromised State

Introduction: Patients with HIV have an elevated risk of cardiovascular disease (CVD) that may be partially driven by inflammation and residual immune dysfunction despite treatment with antiretroviral therapy (ART). Coronary microvascular dysfunction (CMD) is an important pathophysiological link between inflammation, immune dysfunction, and CVD and may provide mechanistic insight into CVD risk among HIV+ patients. Methods: We recruited 3 groups of adults aged 40-80 years free of CVD: HIV with evidence of prior/current immunocompromise (n=17), HIV without immunocompromise (n=19), and HIV- controls. All HIV+ participants were on ART and had suppressed viral loads. All controls were on HIV pre-exposure prophylaxis (PrEP). Immunocompromise was defined as nadir CD4 count <200 cells/μL or current CD4 count <500 cells/μL. Participants underwent Doppler echocardiography with coronary flow velocity measurement in the distal left anterior descending coronary artery at rest and during adenosine infusion. CMD was defined as coronary flow reserve (CFR) < 2.50. Multivariable linear regression models assessed the association of HIV group with CFR. Results: Of 51 individuals who underwent CFR testing, median (IQR) age was 54 (46-58) and 92% were male. CFR was 3.71 (2.90-4.72) in controls, 3.49 (2.52-4.20) in HIV+/ immunocompromise-, and 2.35 (2.12-2.92) in HIV+/ immunocompromise+ (p=0.002). CMD was present in 7% of controls, 21% of HIV+/immunocompromise-, and 53% of HIV+/immunocompromise+ (p= 0.01). Compared with controls, HIV+/immunocompromise+ was significantly associated with lower CFR after multivariable adjustment ( Table ). Conclusions: HIV+ patients with current/prior immunocompromise free of CVD had high prevalence of CMD and had significantly lower CFR compared with controls on PrEP. Future studies should investigate CMD as a possible target for CVD prevention in HIV+ patients, particularly those with a prior or current immunocompromised state.

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