Coronary microvascular dysfunction and right ventricular structure and function

Introduction

Previous studies have suggested associations between coronary microvascular dysfunction (CMD) and alterations in left ventricular (LV) structure and function (1,2). As well, CMD shares pathophysiological mechanisms with heart failure with preserved ejection fraction (HFpEF) and has been proposed to contribute to its development (3). In the context of CMD, the right ventricle (RV) could also be affected, related to mechanisms potentially involving ischemia from CMD, shared pathophysiological milieu leading to adverse ventricular remodeling, and/or increased afterload secondary to increased LV end-diastolic pressure (LVEDP) or even HFpEF with pulmonary hypertension.

We therefore sought to evaluate the relationship between measures of RV structure and function with cardiac magnetic resonance imaging (CMRI) and invasively measured CMD in individuals with suspected ischemia and no obstructive coronary artery (INOCA) disease.

Methods

We included participants with suspected INOCA from the multicentric observational WISE-HFpEF (NCT02582021), WISE-preHFpEF (NCT00832702) and WISE-CVD (NCT00832702) cohorts. Included participants had signs and/or symptoms suggestive of myocardial ischemia, were undergoing a clinically-ordered coronary angiography at Cedars-Sinai Medical Center or University of Florida, Gainesville, and were found not to have obstructive coronary artery disease defined as a stenosis ≥50% or previous revascularization. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional ethics review board of Cedars-Sinai Medical Center (No.: Pro00054999/MOD00007799, Pro00037321/MOD00002588, Pro00014906/MOD00002456), and University of Florida (WISE-CVD: #IRB201602478; WISE-preHFpEF: #CED000000640). Informed consent was obtained from all individual participants. Invasive coronary function testing was performed in the left anterior descending artery as previously described, to quantify coronary flow reserve (CFR) in response to intracoronary adenosine, the coronary blood flow response (∆CBF) to acetylcholine, and LVEDP (2). As part of the research protocol, participants agreed to data collection and underwent additional CMRI (1.5 or 3 Tesla Siemens), using a standardized imaging protocol and imaging analyses as previously described (2). RV cavity volume was assessed with short-axis cine images, considering RV trabeculations as part of the volume and indexing cavity volume for body surface area. RV longitudinal strain was measured on the 4-chamber long axis cine image, by feature tracking of the free wall using commercially available software (CVI⁴², V 5.13.5, Circle Cardiovascular Imaging Inc., Calgary, AB, Canada). Clinical characteristics and MRI data were compared between abnormal vs. normal CFR (≤2.5 vs. >2.5) with the Student t-test or Fisher’s exact test as applicable. Correlations between CMRI RV parameters (end-diastolic volume, ejection fraction and longitudinal strain) and coronary microvascular function were evaluated using the Pearson correlation coefficient for normally distributed variables and the Spearman correlation coefficient for non-normally distributed variables.

Results

Our analysis included 297 participants (99% female), with a mean age of 54±11 years, and body mass index 27.6±6.5 kg/m². Among them, 104 (39%) had hypertension, 31 (11%) had diabetes, 114 (40%) had a smoking history and 18 (7%) had chronic obstructive pulmonary disease. CMRI measurements are presented in Table 1. During coronary function testing, mean CFR was 2.9±0.7, with 103 (36%) presenting a CFR ≤2.5. The median ∆CBF was 44.2% (interquartile range, 5.3–98.2%), with 139 (53%) presenting a ∆CBF ≤50%. Mean LV end-diastolic pressure was 12.4±6.0 mmHg. We found no significant correlation between RV parameters and coronary microvascular function, with Pearson correlation coefficient ranging from −0.05 to 0.07 (P=0.26–0.53) and Spearman correlation coefficient ranging from −0.02 to 0.03 (P=0.69–0.87) (Figure 1). RV parameters were similar between the normal and abnormal CFR groups (Table 1).

Figure 1 Assessment of linear correlation between right ventricular parameters and microvascular coronary function. Scatterplot graphs showing the distribution of coronary function test results, coronary flow reserve and coronary blood flow response to acetylcholine, according to parameters of right ventricular structure (end-diastolic volume indexed to body surface area) and function (ejection fraction and longitudinal strain). Linear and non-linear correlation estimated with the Pearson (r) and Spearman (ρ) correlation coefficient respectively. RV, right ventricular; EDV, end-diastolic volume; CFR, coronary flow reserve; ∆CBF, coronary blood flow response to acetylcholine;

Discussion

To the best of our knowledge, this is the first study to specifically report associations between invasively measured CMD and CMRI parameters of RV structure and function among patients with suspected INOCA. Despite a large sample size and using advanced imaging and function testing, we found no significant relationship between RV structure or function and coronary microvascular function. These results suggest that RV health is not significantly impacted by CMD among individuals with suspected INOCA.

Prior literature evaluating relations between CMD and the RV is generally sparse. Mahfouz et al. assessed the relationship between parameters of RV size and function and CFR measured by echocardiography among 71 CMD and 30 apparently healthy reference subjects (4). Notably, these authors observed a significant correlation between CFR and RV longitudinal strain (r=0.63, P<0.001). However, CMD participants included in their study had more advanced disease compared to ours, with a lower mean CFR (2.4±0.35) and worse mean RV longitudinal strain (−22.6%±2.2%). By contrast, most participants in our cohort had LV and RV CMRI parameters within the normal range, as well as a higher mean CFR. Therefore, it is possible that abnormal RV findings could be encountered at a later disease stage of CMD. Furthermore, the relationship between the RV and HFpEF, and whether CMD would play a role within this connection remains to be elucidated.

These results should however be considered in light of their limitations. Their observational nature does not allow for causal inference. Furthermore, coronary function testing was not typically performed in the right coronary artery (RCA). Recent evidence suggests variability in the distribution of coronary function test results, particularly regarding the index of microcirculatory reserve (5). Future studies are needed to evaluate if RCA-specific testing could be associated with adverse changes in RV structure and function. As well, while CFR is the gold-standard measurement to assess CMD, it can be influenced by epicardial vascular resistance, which was not accounted for in the present analysis (6,7). New variables that allow quantification of CMD are currently under investigation and their possible relationship with the RV should be addressed in the future.

The absence of detectable associations between coronary microvascular function and the RV in our cohort potentially provides valuable information toward improving our understanding of factors leading to adverse prognosis in INOCA. Accordingly, we hypothesize that RV dysfunction may not contribute to the incidence of major adverse cardiac events observed in this population (8,9). Longitudinal prospective studies are needed to evaluate if RV deterioration may occur later during the course of CMD and among patients with HFpEF.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-303/prf

Funding: This work was supported by the National Institutes of Health (R01 HL146158-04S1, R01 HL153500, R01 HD106096, U54 AG065141, W81XWH-17-2-0030, HT9425-23-1-0659), Barbra Streisand Women’s Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, (CA, USA), the Linda Joy Pollin Women’s Heart Health Program, and the Erika Glazer Women’s Heart Health Project.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-303/coif). M.D.N. receives funding from extramural grant organization for his research (NIH R01HL136601, NIH P01HL137630, NIH R01 HL146158, NIH U54 AG065141, NIH R01HL153963, NIH R01HL153500, NIH R01HL160892, NIH R21HL167171A); these grants cover part of his time and effort and payments are made to his institution. J.W. participates on Advisory Board for Abbott Vascular Coronary Microvascular Dysfunction (paid to institution). M.G. receives payment for serving on advisory boards of Esperion and Medtronic; serves on Data Safety Monitoring Board for Merck, and served as the President of the American Society for Preventive Cardiology (no payment). E.M.H. receives research grants from Aastrom Biosciences, Amorcyte, BioCardia, Brigham and Women’s Hospital, Capricor, Cytori Therapeutics, Department of Defense, Direct Flow Medical, Duke Clinical Research Institute, East Carolina University, Every fit Inc., Medtronic, Merck & Co., Mesoblast, National Institutes of Health (NIH), NIH through University of Rochester, NIH through Brigham and Women’s Health, NIH through University of Texas, PCORI, and Sanofi Aventis; research grant and educational grant from Gilead Sciences; unrestricted educational grants for the Vascular Biology Working Group from Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Ionis, and Relypsa; and consultant fees from Bristol-Myers Squibb Company. C.J.P. receives research grants from GE Healthcare, Merck, Sanofi, CLS Behring, BioCardia, McJunkin Family Foundation, Brigham & Women’s Hospital, Gatorade Trust through the University of Florida Department of Medicine, and Mesoblast, Inc.; has received consultant fees/honoraria from Verily Life Sciences, LLC Project Baseline OSMB (Google), Ironwood, XyloCor, Slack Inc., Imbria Pharmaceuticals, Milestone Pharmaceuticals Inc., Ventrix, Inc., AstraZeneca Pharmaceuticals, and Sanofi-Aventis. C.N.B.M. reports WISE Grant (NCT02582021, NCT00832702, NCT00832702); serves as a director and holds stock in iRhythm and receives consulting fees from SHL Telemedicine. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional ethics review board of Cedars-Sinai Medical Center (No.: Pro00054999/MOD00007799, Pro00037321/MOD00002588, Pro00014906/MOD00002456), and University of Florida (WISE-CVD: #IRB201602478; WISE-preHFpEF: #CED000000640). Informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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