Abstract
Study objective
Cold pressor testing (CPT) is a known stimulus of the sympathetic nervous system (SNS). To better understand sympathetic contribution to coronary blood flow regulation in women with suspected ischemia and no obstructive coronary arteries (INOCA), we compared myocardial perfusion reserve during CPT stress cardiac magnetic resonance (CMR) imaging between women with suspected INOCA and reference subjects.
Design
Prospective cohort.
Setting
Academic hospital.
Participants
107 women with suspected INOCA and 21-age-matched reference women.
Interventions
CPT stress CMR was performed with measurement of myocardial perfusion reserve index (MPRI), adjusted for rate pressure product (MPRIRPP). Invasive coronary function testing in a subset of INOCA women (n = 42) evaluated for endothelial dysfunction in response to acetylcholine, including impaired coronary diameter response ≤0% and coronary blood flow response (ΔCBF) <50%.
Main outcome measure
MPRIRPP.
Results
Compared to reference women, the INOCA group demonstrated higher resting RPP (p = 0.005) and CPT MPRIRPP (1.09 ± 0.36 vs 0.83 ± 0.18, p = 0.002). Furthermore, INOCA women with impaired ΔCBF (n = 23) had higher CPT MPRIRPP (p = 0.044) compared to reference women despite lower left ventricular ejection fraction (64 ± 7% vs 69 ± 2%, p = 0.005) and higher mass-to-volume ratio (0.79 ± 0.15 vs 0.62 ± 0.09, p < 0.0001). These differences in CPT MPRIRPP did not persist after adjusting for age, body mass index, and history of hypertension. CPT MPRIRPP among INOCA women did not differ based on defined acetylcholine responses.
Conclusions
Myocardial perfusion reserve to CPT stress is greater among women with INOCA compared to reference subjects. This CPT response was also noted in women with coronary endothelial dysfunction, suggesting a greater contribution of the SNS to coronary flow than endothelial dysfunction. Therapies to modulate sympathetic activity should be studied in this population.
Keywords: Perfusion, Microcirculation, Sympathetic nervous system, Magnetic resonance imaging
Highlights
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Ischemia with no obstructive coronary arteries (INOCA) is increasingly recognized.
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Women with INOCA often have dysregulation of myocardial blood flow.
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Myocardial blood flow is influenced by sympathetic activity and the endothelium.
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Sympathetic activity may predominate over endothelial dysfunction in INOCA women.
1. Introduction
Women with symptoms and/or signs of ischemia but no obstructive coronary arteries (INOCA) have a cardiovascular prognosis that is not benign [1] but the mechanisms accounting for this impaired outcome are not well understood. Coronary endothelial dysfunction is common [2], myocardial perfusion reserve detected by cardiac magnetic resonance (CMR) imaging is lower [3], and an adverse prognosis is observed in these patients [4]. Myocardial blood flow is regulated by a combination of hormonal and neuronal influences on the coronary vascular system and myocardium. The response of the coronary vasculature to sympathetic nervous system (SNS) stimuli, such as exercise and cold pressor testing (CPT), may provide insights into its function and integrity.
CPT increases myocardial blood flow by dilation of coronary arterioles [5]. However, in the setting of coronary artery disease (CAD) or endothelial dysfunction, CPT may paradoxically induce vasoconstriction, increasing coronary resistance to blood flow [6], [7]. Abnormal vasomotor responses may also reflect heightened SNS activity. In patients with INOCA, cardiac adrenergic autonomic nervous system dysfunction with SNS predominance has been hypothesized to play a role [8], [9].
While coronary blood flow (CBF) regulation in response to sympathetic stimuli has been studied among individuals with CAD [10], it is not yet well characterized in women with INOCA. Specifically, SNS influence on CBF among women with and without endothelial dysfunction has not been previously evaluated. Improved understanding of the relative contribution of the SNS in INOCA may further guide management strategies. Accordingly, we used CPT as a sympathetic stimulus to measure stress myocardial perfusion reserve index (MPRI) in women with suspected INOCA and age-matched reference controls.
2. Materials and methods
2.1. Study participants
Women with suspected INOCA were enrolled in the National Heart, Lung, and Blood Institute (NHLBI)-sponsored Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction project (WISE-CVD) (clinicaltrials.gov NCT00832702). Inclusion and exclusion criteria have previously been described [5]. All women had undergone clinically indicated coronary angiography for signs and symptoms of myocardial ischemia and had been found to have no obstructive coronary artery disease (defined as <50% diameter stenosis in epicardial arteries). The Institutional Review Boards at Cedars-Sinai Medical Center, Los Angeles, CA and University of Florida, Gainesville, FL approved the study, and all participants gave written informed consent before study participation. Of the 374 women who completed baseline CMR, 332 completed CPT-stress and pharmacologic stress (adenosine = 225, regadenoson = 107) (Supplemental Fig. 1). Women who underwent both CPT and regadenoson-stress CMR were the focus in this analysis. Results from clinically ordered WISE protocol invasive coronary function testing were available for a subset of these women (n = 42).
An asymptomatic reference group of women (n = 21) was recruited at Cedars-Sinai Medical Center matched to the WISE-CVD women on age and hormone-use status (clinicaltrials.gov NCT00573339). The inclusion criteria were the absence of cardiovascular symptoms and absence of cardiac risk factors by Framingham/NCEP criteria. All reference women completed a standardized Bruce Protocol exercise treadmill test without any clinical or electrocardiographic evidence of ischemia and underwent CPT and regadenoson-stress CMR.
2.2. CMR protocol
A standardized protocol was conducted on 1.5 T CMR (Magnetom Avanto; Siemens Healthcare) as previously published [11], [12]. Briefly, vasoactive medications including beta-blockers and caffeine were withheld for 24 h, long-acting calcium-channel blockers for 48 h, and sublingual nitroglycerin for 4 h before testing of all participants. Rest, CPT-stress, and regadenoson-stress first-pass perfusion imaging were each performed sequentially with gadolinium contrast of 0.05 mmol/L/kg (Gadodiamide; Omniscan, Amersham), as shown in Fig. 1. CPT stress utilized an ice pack wrapped around either the forehead (n = 15) or forearm (n = 92) contralateral to the contrast injection, for 2 min prior to first-pass perfusion imaging, and removed after completion of imaging data acquisition. WISE investigators previously demonstrated no difference in coronary vasodilator response to forehead vs forearm CPT [5]. Pharmacologic stress was performed 10 min later using regadenoson (Lexiscan, Astellas Pharma) 0.4 mg/5 mL intravenous bolus, and perfusion images were acquired approximately 60 s after the administration of regadenoson. Heart rate and blood pressure at rest and peak stress were recorded to calculate rate-pressure product (RPP) at rest, CPT stress, and regadenoson stress. CPT-stress and pharmacologic stress MPRI were each measured as a ratio of the stress and rest upslopes of the left ventricular myocardium normalized to left ventricular cavity blood pool input function, using CAAS MRV 3.4 software (Pie Medical Imaging, Netherlands), as previously described [3], [11]. MPRI was adjusted for rest RPP (MPRIRPP) by multiplying MPRI with rest RPP and divided by 10,000 [13], [14]. An American Heart Association 16-segment model was used (true apex not imaged); mean MPRI was the average of 16 segments. Left ventricular structure and function were assessed using CAAS MRV 3.4 software, as previously described [11]. Late gadolinium enhancement (LGE) images were acquired to assess presence of scar, using a 2D inversion-recovery turbo FLASH, as previously described [15].
Fig. 1.
CPT and regadenoson stress CMR protocol. Women with INOCA and reference subjects underwent standardized CMR with rest, CPT stress, and regadenoson stress first-pass perfusion imaging.
bSSFP, balanced steady-state free precession; CMR, cardiac magnetic resonance; CPT, cold pressor testing; GRE-EPI, gradient echo – echo planar imaging; HLA, horizontal long axis; INOCA, ischemia and no obstructive coronary arteries; IR-SSP, inversion recovery-steady state free precession; LGE, late gadolinium enhancement; LVOT, left ventricular outflow tract; SAX, short axis; VLA, ventricular long-axis.
2.3. Coronary function testing protocol
Coronary function testing was performed per WISE protocol, and data were interpreted in a core laboratory masked to other information [11], [16]. Four measures were assessed: (1) abnormal coronary flow reserve (CFR), defined as CFR <2.5 in response to intracoronary adenosine; (2) abnormal endothelial dysfunction, defined as an increase in CBF ≤50% or change in epicardial coronary artery diameter ≤0% in response to acetylcholine (∆ACH); (3) abnormal nonendothelial function defined as a change in epicardial coronary artery diameter ≤20% in response to intracoronary nitroglycerin (∆NTG). CBF was determined as π(coronary artery diameter / 2)2 x (average peak velocity / 2).
2.4. Statistical analysis
Values are expressed as mean ± standard deviation or percentages as indicated. Fisher's Exact, Wilcoxon Rank sum, t-test and ANOVA tests were used to compare baseline and CMR characteristics among groups. Multivariable linear regression models with different variables as the outcome were run to adjust for potential confounding factors of the difference in averages between groups. Type III F test from multiple linear regression adjusting for age, body mass index, and history of hypertension was performed to compare the CPT CMR characteristics between groups. A p value <0.05 was considered statistically significant. SAS version 9.3 was used for all analyses.
3. Results
Baseline characteristics of the INOCA (n = 107) and reference women (n = 21) who underwent CPT and regadenoson stress are presented in Table 1 and demonstrate higher body mass index in the INOCA group (p < 0.001). The INOCA group had lower regadenoson-stress MPRI compared to the reference group (2.11 ± 0.54 vs 2.38 ± 0.44, p = 0.04), with lower MPRI indicating worse perfusion reserve. Of the 42 INOCA women who had coronary function testing results, 32 women (76%) had at least one abnormal invasive coronary function measure (Table 3). Baseline characteristics of all INOCA women who underwent CPT and pharmacologic stress (n = 332) are presented in Supplemental Table 1, to include those who underwent adenosine or regadenoson stress.
Table 1.
Baseline characteristics of suspected INOCA vs reference women.
| Characteristics (mean ± SD or %) | INOCA women (n = 107) | Reference women (n = 21) | p value |
|---|---|---|---|
| Age (years) | 55 ± 11 | 51 ± 10 | 0.09 |
| Body mass index | 31 ± 8 | 25 ± 4 | <0.001 |
| Ethnicity (% Caucasian) | 82% | 73% | 0.15 |
| Diabetes | 18% | 0% | 0.21 |
| Hypertension | 44% | 0% | <0.001 |
| Dyslipidemia | 17% | 0% | 0.20 |
| Smoking (former or current) | 36% | 14% | 0.05 |
| Menopausal | 76% | 48% | 0.07 |
| Regadenoson CMR MPRI | 2.11 ± 0.54 | 2.38 ± 0.44 | 0.04 |
| LGE scar present (n, %) | 8.4% | 0% |
CMR, cardiac magnetic resonance; INOCA, ischemia and no obstructive coronary arteries;
MPRI, myocardial perfusion reserve index.
Bold values denote statistical significance at the p < 0.05 level.
Table 3.
Cold-pressor testing stress myocardial perfusion reserve of INOCA women stratified by coronary function testing results (n = 42).
| CPT MPRI | CPT MPRIRPP | p value | ||
|---|---|---|---|---|
| Coronary flow reserve (CFR) to adenosine | ||||
| CFR <2.5, n = 9 | 1.20 ± 0.29 | 1.16 ± 0.40 | 0.690⁎ | 0.257⁎⁎ |
| CFR ≥2.5, n = 33 | 1.16 ± 0.22 | 1.02 ± 0.30 | ||
| Coronary blood flow change (∆CBF) to acetylcholine | ||||
| ∆CBF <50%, n = 23 | 1.14 ± 0.21 | 1.03 ± 0.36 | 0.300⁎ | 0.781⁎⁎ |
| ∆CBF ≥50%, n = 19 | 1.21 ± 0.23 | 1.04 ± 0.30 | ||
| Coronary artery diameter change to acetylcholine | ||||
| ∆ACH ≤0%, n = 21 | 1.16 ± 0.22 | 1.01 ± 0.33 | 0.556⁎ | 0.571⁎⁎ |
| ∆ACH >0%, n = 26 | 1.19 ± 0.22 | 1.06 ± 0.31 | ||
| Coronary artery diameter change to nitroglycerin | ||||
| ∆NTG <20%, n = 33 | 1.18 ± 0.23 | 1.02 ± 0.34 | 0.449⁎ | 0.493⁎⁎ |
| ∆NTG ≥20%, n = 14 | 1.18 ± 0.21 | 1.07 ± 0.28 | ||
Results reported as mean ± standard deviation.
ACH, acetylcholine, ΔCBF, coronary blood flow change in response to acetylcholine; CFR, coronary flow reserve; CPT, cold pressor testing; INOCA, ischemia and no obstructive coronary arteries; MPRI, myocardial perfusion reserve index; NTG, nitroglycerin; RPP, rate-pressure product.
p value comparing cold pressor testing MPRI.
p value comparing cold pressor testing MPRIRPP.
3.1. Hemodynamic responses to CPT
Rest and CPT-stress RPP during CMR were lower in the reference women compared to INOCA women (p = 0.005 and p = 0.007, respectively). These differences were no longer significant when adjusted for age, body mass index, and history of hypertension (Table 2). The CPT stress-induced change in RPP (ΔRPP) was not significantly different between study groups.
Table 2.
Cold pressor testing CMR characteristics stratified by endothelial dysfunction as measured by coronary blood flow change to acetylcholine.
| Parameters (mean ± SD) | INOCA women (n = 107) | INOCA women with invasive CBF testing (n = 42) |
Reference women (n = 21) | p value | Adjusted p valuec | |
|---|---|---|---|---|---|---|
| ΔCBF ≥ 50% (n = 19) | ΔCBF < 50% (n = 23) | |||||
| Rest HR | 70 ± 11 | 69 ± 8 | 68 ± 13 | 62 ± 10 |
0.001a 0.10b |
0.13a 0.53b |
| Rest SBP | 130 ± 20 | 124 ± 15 | 131 ± 15 | 124 ± 15 | 0.21a 0.18b |
0.99a 0.53b |
| Rest RPP | 9192 ± 2360 | 8505 ± 1383 | 8964 ± 2261 | 7666 ± 1626 |
0.005a 0.07b |
0.28a 0.86b |
| CPT stress HR | 72 ± 13 | 70 ± 9 | 68 ± 13 | 63 ± 10 |
0.002a 0.13b |
0.66a 0.90b |
| CPT stress SBP | 134 ± 22 | 127 ± 19 | 132 ± 18 | 129 ± 13 | 0.31a 0.61b |
0.92a 0.81b |
| Δ HR (stress − rest) | 2 ± 8.9 | 1.5 ± 4.9 | 0.1 ± 8.5 | 1.2 ± 6.6 | 0.70a 0.80b |
0.23a 0.33a |
| Δ SBP (stress − rest) | 4.6 ± 13.1 | 2.7 ± 7.3 | 1.1 ± 16.6 | 5.1 ± 13.5 | 0.85a 0.61b |
0.87a 0.97b |
| Stress RPP | 9774 ± 2584 | 8868 ± 1698 | 9040 ± 2370 | 8159 ± 1714 |
0.007a 0.31b |
0.71a 0.99b |
| Δ RPP (stress − rest) | 581 ± 1686 | 363 ± 780 | 82 ± 1793 | 493 ± 1218 | 0.82a 0.60b |
0.41a 0.67b |
| CPT MPRI | 1.18 ± 0.22 | 1.21 ± 0.23 | 1.14 ± 0.21 | 1.09 ± 0.15 | 0.09a 0.20b |
0.51a 0.64b |
| CPT MPRIRPP | 1.09 ± 0.36 | 1.04 ± 0.30 | 1.03 ± 0.36 | 0.83 ± 0.18 |
0.002a 0.04b |
0.22a 0.79b |
| CPT MPRI subendocardial | 1.17 ± 0.22 | 1.19 ± 0.20 | 1.11 ± 0.19 | 1.11 ± 0.15 | 0.23a 0.28b |
0.88a 0.56b |
| CPT MPRI subepicardial | 1.19 ± 0.25 | 1.28 ± 0.28 | 1.19 ± 0.28 | 1.09 ± 0.13 | 0.08a 0.05b |
0.35a 0.42b |
| Ejection fraction (%) | 67 ± 7 | 70 ± 6 | 64 ± 7 | 69 ± 2 | 0.36a 0.005b |
0.85a 0.001a |
| End systolic volume (mL) | 40 ± 14 | 39 ± 11 | 48 ± 14 | 39 ± 8 | 0.68a 0.03b |
0.91a 0.002b |
| End systolic volume index (ESV/BSA) | 22.78 ± 8.12 | 21.11 ± 5.84 | 26.39 ± 6.41 | 22.46 ± 4.15 | 0.32a 0.008b |
0.62a <0.001b |
| End diastolic volume (mL) | 124 ± 27 | 129 ± 21 | 134 ± 28 | 125 ± 19 | 0.78a 0.49b |
0.91a 0.26b |
| End diastolic volume index (EDV/BSA) | 69.07 ± 14.03 | 69.73 ± 8.13 | 73.43 ± 11.44 | 71.97 ± 9.52 | 0.37a 0.49b |
0.52a 0.15b |
| Mass to volume ratio (g/mL) | 0.80 ± 0.20 | 0.76 ± 0.11 | 0.79 ± 0.15 | 0.62 ± 0.09 |
0.0001a <0.0001b |
0.008a 0.012b |
MPRIRPP = MPRI × (rest RPP / 10,000).
ΔCBF, coronary blood flow change in response to acetylcholine; CPT, cold pressor testing; INOCA, ischemia and no obstructive coronary arteries; MPRI, myocardial perfusion reserve index; RPP, rate-pressure product; SD, standard deviation.
Bold values denote statistical significance at the p < 0.05 level.
INOCA group vs Reference.
INOCA ΔCBF ≥ 50% vs ΔCBF < 50% vs Reference.
Type III F test comparing groups from multiple linear regression adjusting for age, body mass index, and history of hypertension.
CPT CMR characteristics of all INOCA women who underwent CPT and pharmacologic stress (n = 332) are presented in Supplemental Table 2, with similar findings of higher rest and stress heart rates and blood pressures in this overall INOCA group compared to reference women.
3.2. Myocardial perfusion response to CPT
CPT MPRIRPP was not different among INOCA women stratified by invasive coronary function testing pathways including acetylcholine responses (Table 3). Compared to reference women, both the INOCA group and the impaired ΔCBF<50% subgroup demonstrated higher CPT MPRIRPP (p = 0.002 and p = 0.044, respectively) However, these differences were no longer significant when adjusted for age, body mass index, and history of hypertension (Table 2). The INOCA group with impaired ΔCBF<50% had lower left ventricular ejection fraction (p = 0.001) and higher mass-volume ratio (p < 0.012) compared to the reference group (Table 2).
In the overall INOCA group who underwent CPT and pharmacologic stress (n = 332), similar trends were found regarding CPT MPRIRPP comparisons of the overall INOCA group and the impaired ΔCBF<50% subgroup to the reference women but these were not significant when adjusting for age, body mass index and history of hypertension (Supplemental Table 2). Similarly, MPRIRPP did not differ when stratified by invasive coronary function testing results in this larger cohort (Supplemental Table 3).
Compared to those without LGE, INOCA women with LGE trended to higher CPT MPRI (regadenoson group [n = 107]: 1.29 ± 0.22 vs 1.19 ± 0.23, p = 0.20; overall INOCA group [n = 332]: 1.21 ± 0.21 vs 1.12 ± 0.21, p = 0.03). None of the reference control women had LGE.
4. Discussion
Women with suspected INOCA had higher CPT MPRIRPP when compared with the reference group. Our study demonstrates that 1) the response to CPT stimulus leads to higher myocardial blood flow response in INOCA women compared to reference controls and 2) this higher myocardial blood flow response occurs despite the presence of coronary endothelial dysfunction as demonstrated by impaired ΔCBF to acetylcholine. Interestingly, we found that resting and CPT RPP were higher among women with INOCA compared to the reference group; however, the change in RPP from the resting to the stressed state (ΔRPP) was not significantly different between the two groups. Our findings suggest a greater contribution of the SNS to myocardial blood flow than endothelial dysfunction in this cohort.
As expected, women with INOCA had lower MPRI to pharmacologic stress compared to the reference group, consistent with the prior analysis of INOCA women by our group [3]. While CPT MPRIRPP was higher in the INOCA group compared to reference group, we found no difference in CPT MPRIRPP when stratified by individual coronary function testing measures. The INOCA women with endothelial dysfunction had lower EF and higher mass-volume ratio, indices of left ventricular (LV) dysfunction and remodeling. We previously demonstrated that myocardial tissue deformation is impaired in women with INOCA, as measured by LV diastolic strain rate [17], [18].
The presence of higher CPT MPRIRPP among women with INOCA, even in the presence of endothelial dysfunction, was contrary to our initial hypothesis, suggesting that sympathetic input may contribute more to myocardial blood flow regulation and potentially outweigh the presence of endothelial dysfunction in women with INOCA. In healthy vessels, sympathetic stimulation results in vasodilatation by direct stimulation of beta-adrenergic receptors on smooth muscle cells and by heightened myocardial oxygen demand, driving shear stress-mediated nitric oxide release by the vascular endothelium [19]. The capacity for CPT to induce higher response among INOCA women compared to reference controls suggests underlying differences in sympathetic autonomic response. Prior ischemic heart disease studies suggest that there may be upregulation of beta-adrenergic receptors or alternative compensatory pathways that render coronary vessels more amenable to SNS-driven increases in CBF than normal vasculature [20]. A similar hypothesis of heightened sympathetic innervation and/or SNS hyperresponsiveness as a mechanism for INOCA has been previously described [9], [21]. In patients with obstructive CAD, Nabel et al. found that while CPT led to significantly increased CBF in normal arteries, CBF decreased in those with >50% stenosis [22]. Similarly, in other CPT studies, myocardial blood flow increased significantly in response to CPT among controls, but not diabetics or smokers [23], [24]. The paradoxical high CPT MPRI observed among our INOCA subjects, even in the presence of coronary endothelial dysfunction, may reflect one or more non-endothelial dependent mechanisms that increase myocardial blood flow in response to sympathetic stress in women with angina and non-obstructive CAD. In addition, there was a trend toward higher CPT subepicardial MPRI in the INOCA and ΔCBF<50% subgroup compared to reference women. Since the subendocardium is more vulnerable to ischemia than the subepicardium, this suggests that CPT stimulates a higher subepicardial flow response in INOCA patients, possibly to compensate for the relatively impaired flow response in the subendocardium, particularly in those with coronary microvascular endothelial dysfunction. Such mechanisms require further study.
Prior studies have shown that systemic adenosine increase during CPT is driven by sympathetic activation [25], which may be enhanced in women with INOCA and contribute to increased CBF. Interestingly, although our study revealed a higher baseline heart rate and RPP among our women with INOCA compared with normal controls, suggesting differences in resting sympathetic activation, there was no difference in ΔRPP in response to CPT stress between the two groups. Given that MPRIRPP did increase among INOCA women, this lack of difference in ΔRPP suggests a dissociation between the coronary vascular and systemic hemodynamic reactivity among INOCA women. This could further support the hypothesis that different adrenergic pathways (alpha vs beta receptors) may be responsible for the coronary vascular and systemic hemodynamic responses in this population. While the two groups were hormone matched, hormonal influence may have affected hemodynamic reactivity in our study population. Menopause appears to be associated with increased cardiac sympathetic tone and diminished vagal activity, driven by reduced estrogen levels [26]. However, previous studies of CPT hand immersion indicated that there were no differences in cardiovascular reactivity based on hormone levels [27], [28]. Lastly, presence of scar in the INOCA cohort may have influenced the findings, as women with LGE had higher CPT MPRI compared to women without LGE. Possible mechanisms leading to higher CPT response in LGE patients may be reflex sympathetic activation of non-infarcted myocardium [29] or presence of more severe underlying coronary vascular dysfunction [15].
Our prior work in invasive coronary function testing with CPT stress demonstrated that CPT coronary diameter response correlates with acetylcholine coronary diameter response, indicating that CPT response is a marker of endothelial dysfunction [5]. In this study, we did not demonstrate a significant difference in CPT MPRI in women stratified by invasive coronary function testing results, including acetylcholine response, consistent with our prior publication of a larger cohort of INOCA women [12]. Thus, CPT MPRI may not be a robust method to non-invasively identify coronary endothelial dysfunction in patients with no obstructive CAD.
Our study had some limitations. As we are focusing on INOCA in women, our results may not be generalizable to other populations. Another limitation may be the timing of the perfusion imaging acquisition to the CPT, as a biphasic response of the heart rate has been reported following CPT [30]. The CPT methods used in our study may also not elicit the same degree of sympathetic activation as the traditional CPT method of a hand in the ice bucket, as reported by others [22], [31]. Future studies in large cohorts are needed to further understand the contribution of the SNS to endothelial dysfunction and angina in INOCA, as well as to adequately control for confounding factors such as underlying atherosclerosis burden. The differences in CPT MPRIRPP between the INOCA and reference groups did not persist in the multivariable linear regression model adjusting for age, body mass index, and history of hypertension, which may be driving the differences in CPT response. Interestingly, sympathetic nerve overactivity has been increasingly recognized as a common mechanism in aging and obesity and contributing to chronic hypertension [32]. Thus, this additional analysis highlights the importance in studying the sympathetic nervous system in the pathophysiology of INOCA.
5. Conclusions
Among women with INOCA, coronary reactivity to CPT stress is greater compared to reference women despite no significant hemodynamic difference to CPT stress. CPT also induced a higher MPRIRPP in women with coronary endothelial dysfunction. These findings suggest a greater contribution of the SNS to coronary flow than endothelial dysfunction, as well as a difference in the SNS mechanisms underlying coronary vascular reactivity among women with INOCA. Further work in a larger cohort is needed to understand SNS effects on the coronary microcirculation in INOCA.
Funding
This work was supported by contracts from the National Heart, Lung, and Blood Institute nos. N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, grants U0164829, U01 HL649141, U01 HL649241, K23HL105787, K23HL125941, K23HL127262, T32HL69751, R01 HL090957, R01 HL146158, U54 AG065141, 1R03AG032631 from the National Institute on Aging, GCRC grant MO1-RR00425 from the National Center for Research Resources, the National Center for Advancing Translational Sciences Grant UL1TR000124 and UL1TR000064, and grants from the Gustavus and Louise Pfeiffer Research Foundation, Danville, NJ, The Women's Guild of Cedars-Sinai Medical Center, Los Angeles, CA, The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA, and QMED, Inc., Laurence Harbor, NJ, the Edythe L. Broad and the Constance Austin Women's Heart Research Fellowships, Cedars-Sinai Medical Center, Los Angeles, California, the Barbra Streisand Women's Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, The Society for Women's Health Research (SWHR), Washington, D.C., The Linda Joy Pollin Women's Heart Health Program, the Erika Glazer Women's Heart Research Initiative, and the Adelson Family Foundation, Cedars-Sinai Medical Center, Los Angeles, California. Dr. Pepine was also supported by National Institutes of Health grants HL33610, HL56921; UM1 HL087366; the Gatorade Trust through funds distributed by the University of Florida, Department of Medicine; NIH NCATS—University of Florida Clinical and Translational Science UL1TR001427; and PCORnet-OneFlorida Clinical Research Consortium CDRN-1501-26692.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Footnotes
Study Locations: Los Angeles, California and Gainesville, Florida.
Supplementary data to this article can be found online at https://doi.org/10.1016/j.ahjo.2021.100080.
Appendix A. Supplementary data
Supplementary data of all INOCA women who underwent cold pressor and pharm stress CMR.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary data of all INOCA women who underwent cold pressor and pharm stress CMR.