Impact of sex on the assessment of the microvascular resistance reserve.

BACKGROUND: The microvascular resistance reserve (MRR) is an innovative index to assess the vasodilatory capacity of the coronary circulation while accounting for the presence of concomitant epicardial disease. The MRR has shown to be a valuable diagnostic and prognostic tool in the general coronary artery disease (CAD) population. However, considering the fundamental aspects of its assessment and the unique hemodynamic characteristics of women, it is crucial to provide additional considerations for evaluating the MRR specifically in women. AIM: The aim of this study was to assess the diagnostic and prognostic applicability of the MRR in women and assess the potential differences across different sexes. METHODS: From the ILIAS Registry, we enrolled all patients with a stable indication for invasive coronary angiography, ensuring complete physiological and follow-up data. We analyzed the diagnostic value by comparing differences between sexes and evaluated the prognostic value of the MRR specifically in women, comparing it to that in men. RESULTS: A total of 1494 patients were included of which 26% were women. The correlation between MRR and CFR was good and similar between women (r = 0.80, p < 0.005) and men (r = 0.81, p < 0.005). The MRR was an independent and important predictor of MACE in both women (HR 0.67, 0.47-0.96, p = 0.027) and men (HR 0.84, 0.74-0.95, p = 0.007). The optimal cut-off value for MRR in women was 2.8 and 3.2 in men. An abnormal MRR similarly predicted MACE at 5-year follow-up in both women and men. CONCLUSION: The MRR seems to be equally applicable in both women and men with stable coronary artery disease.

Combined Assessment of FFR and CFR for Decision Making in Coronary Revascularization: From the Multicenter International ILIAS Registry.

OBJECTIVES: The aim of this study was to demonstrate the clinical implications of combined assessment of fractional flow reserve (FFR) and coronary flow reserve (CFR). BACKGROUND: Combined assessment of FFR and CFR allows detailed characterization of pathophysiology in chronic coronary syndromes. Data on the clinical implications of distinct FFR and CFR patterns are limited, leading to uncertainty regarding their relevance. METHODS: Patients with chronic coronary syndromes and obstructive coronary artery disease were selected from the multicenter ILIAS (Inclusive Invasive Physiological Assessment in Angina Syndromes) registry. Patients were classified into 4 groups on the basis of FFR ≤0.80 and CFR <2.0. The endpoint was the 5-year target vessel failure (TVF) rate. RESULTS: A total of 2,143 patients with 2,725 lesions were included. Compared with normal FFR/normal CFR, low FFR/low CFR carried the highest risk for TVF (HR: 5.4; 95% CI: 3.2-9.3; P < 0.001), significantly higher than in revascularized vessels (P = 0.007). Discordance, with either low FFR/normal CFR or normal FFR/low CFR, was associated with increased TVF rates compared with normal FFR/normal CFR (low FFR/normal CFR: HR: 3.5 [95% CI: 2.2-5.4; P < 0.001]; normal FFR/low CFR: HR: 3.0 [95% CI: 1.9-4.7; P < 0.001]). No difference in 5-year TVF was observed between the 2 discordant groups (P = 0.57) or between the discordant groups and the revascularized group (P = 0.26 vs low FFR/normal CFR; P = 0.60 vs normal FFR/low CFR). CONCLUSIONS: Impaired coronary hemodynamics are uniformly associated with increased 5-year TVF rates. Nonrevascularized vessels with discordant FFR and CFR are associated with 5-year event rates that are equivalent to those of vessels that undergo revascularization, whereas vessels with combined low FFR and CFR exhibit event rates that are significantly higher than after revascularization. (Inclusive Invasive Physiological Assessment in Angina Syndromes Registry [ILIAS Registry]; NCT04485234).

Assessment of Enhanced Thermal Effect Due to Gold Nanoparticles during MR-Guided High-Intensity Focused Ultrasound (HIFU) Procedures Using a Mouse-Tumor Model.

An in vivo study was conducted using a mouse tumor model, to assess the utility of using gold nanoparticles (gNPs) during HIFU procedures to locally enhance heating at low powers. Tumors were grown using melanoma tumor cells (B16/F10) subcutaneously on the right flanks of mice (C57Bl/6J). Physiologically relevant concentrations (0 and 0.125%) of gNPs were directly injected into the tumors. Sonications at acoustic powers of 10 and 30 W were performed for a duration of 16 s inside a magnetic-resonance system. Temperature increases and lesion volumes were calculated and compared for procedures with and without gNPs. Histopathology study was conducted using a cleaved caspase 3 antibody and hematoxylin and eosin staining after removing the tumors from the mice. For an acoustic power of 30 W, end-of-sonication temperature increases of 25.4 ± 3.8 °C (0% gNP) and 42.2 ± 4.6 °C (0.125% gNP) were measured. Using cleaved caspase 3 antibody, it was observed that more than 1% of nuclei are affected in the case of 0.125% and 30 W but only 0.01% of nuclei are affected in the 0% case. For 30 W and a gNP concentration of 0.125%, a lesion volume of 0.33 ± 0.22 mm3 was obtained, while no lesion was observed without gNP's.

Assessment of Gold Nanoparticle-Mediated-Enhanced Hyperthermia Using MR-Guided High-Intensity Focused Ultrasound Ablation Procedure.

High-intensity focused ultrasound (HIFU) has gained increasing popularity as a noninvasive therapeutic procedure to treat solid tumors. However, collateral damage due to the use of high acoustic powers during HIFU procedures remains a challenge. The objective of this study is to assess the utility of using gold nanoparticles (gNPs) during HIFU procedures to locally enhance heating at low powers, thereby reducing the likelihood of collateral damage. Phantoms containing tissue-mimicking material (TMM) and physiologically relevant concentrations (0%, 0.0625%, and 0.125%) of gNPs were fabricated. Sonications at acoustic powers of 10, 15, and 20 W were performed for a duration of 16 s using an MR-HIFU system. Temperature rises and lesion volumes were calculated and compared for phantoms with and without gNPs. For an acoustic power of 10 W, the maximum temperature rise increased by 32% and 43% for gNPs concentrations of 0.0625% and 0.125%, respectively, when compared to the 0% gNPs concentration. For the power of 15 W, a lesion volume of 0, 44.5 ± 7, and 63.4 ± 32 mm3 was calculated for the gNPs concentration of 0%, 0.0625%, and 0.125%, respectively. For a power of 20 W, it was found that the lesion volume doubled and tripled for concentrations of 0.0625% and 0.125% gNPs, respectively, when compared to the concentration of 0% gNPs. We conclude that gNPs have the potential to locally enhance the heating and reduce damage to healthy tissue during tumor ablation using HIFU.

Noninvasive Electroretinography Assessment of Intravitreal Sustained-Release Methotrexate Microimplants in Rabbit Eyes.

PURPOSE: The purpose of this study is to noninvasively evaluate the safety and toxicity of a chitosan (CS) and polylactic acid (PLA)-based sustained-release methotrexate (MTX) intravitreal microimplant in normal rabbit eyes using electroretinography (ERG). METHODS: PLA-coated CS-based microimplants containing 400 µg of MTX and placebo microimplants (without drug) were surgically implanted in the vitreous of the right and the left eyes, respectively, in each of the 8 New Zealand rabbits using minimally invasive technique. At each predetermined time points (days 5, 12, 19, and 33), ERG was conducted on 2 rabbits to evaluate the safety of the microimplants administered in each eye. ERG was carried out using 2 protocols, scotopic and photopic, on each eye prior to surgery (PS) and prior to euthanasia (PE) conditions. The safety of the microimplants was assessed using statistical analysis of the ERG data (B/A ratio analysis, oscillatory potential analysis, and Naka-Rushton analysis) and subsequently quantifying and comparing functional integrity of the retina between the PS and PE conditions of each eye. RESULTS: Statistical analysis of the ERG data showed no change in retinal functional integrity because of the PLA-coated CS-based MTX microimplant and the placebo microimplant. ERG analysis also revealed absence of any evident bioelectrical dysfunction caused by the microimplants. CONCLUSION: ERGs were performed to determine whether the microimplants containing MTX and the placebo microimplants were associated with any profound retinal bioelectrical dysfunction that might be attributable to toxicity not apparent on histological studies of such eyes. The results shown in this report indicate that there were no such evident adverse effects of the microimplants or contained drug.

Ultrasonographical assessment of implanted biodegradable device for long-term slow release of methotrexate into the vitreous.

Our group has developed a biodegradable drug delivery device (micro-implant) for long-term slow intraocular release of methotrexate (MTX) that can be implanted in the peripheral vitreous. The purpose of this study was to assess the position of the implanted devices and the status of the adjacent vitreous and peripheral retina over time using B-scan ocular ultrasonography (US). In each of the eight New Zealand rabbits used in this study, a chitosan (CS) and poly-lactic acid (PLA)-based micro-implant containing approximately 400 µg of MTX and a placebo micro-implant without MTX were inserted into the peripheral vitreous of the right and left eyes, respective, employing minimally invasive surgery. B-scan US imaging was performed on all of the rabbits immediately after implant insertion and on two rabbits at each of several pre-determined time points post-insertion (post-insertion days 5, 12, 19, and 33) to evaluate the position of the micro-implants and identify any evident morphological changes in the micro-implants and in the peripheral retina and vitreous during treatment. US imaging revealed stable positioning of the PLA-coated CS-based MTX micro-implant and the placebo micro-implant in the respective eyes throughout the study and lack of any changes in size, shape or sonoreflectivity of the micro-implants or abnormalities of the peripheral vitreous or retina in any of the study eyes. In summary, US did not show any evident morphological changes in the micro-implants, shifts in post-insertion position of the micro-implants, or identifiable changes in the micro-implants or peripheral vitreous and retina of the study eyes.

Methodology for implementing patient-specific spatial boundary condition during a cardiac cycle from phase-contrast MRI for hemodynamic assessment.

Pulmonary insufficiency (PI) can render the right ventricle dysfunctional due to volume overloading and hypertrophy. The treatment requires a pulmonary valve replacement surgery. However, determining the right time for the valve replacement surgery has been difficult with currently employed clinical techniques such as, echocardiography and cardiac MRI. Therefore, there is a clinical need to improve the diagnosis of PI by using patient-specific (PS) hemodynamic endpoints. While there are many reported studies on the use of PS geometry with time varying boundary conditions (BC) for hemodynamic computation, few use spatially varying PS velocity measurement at each time point of the cardiac cycle. In other words, the gap is that, there are limited number of studies which implement both spatially- and time-varying physiologic BC directly with patient specific geometry. The uniqueness of this research is in the incorporation of spatially varying PS velocity data obtained from phase-contrast MRI (PC-MRI) at each time point of the cardiac cycle with PS geometry obtained from angiographic MRI. This methodology was applied to model the complex developing flow in human pulmonary artery (PA) distal to pulmonary valve, in a normal and a subject with PI. To validate the methodology, the flow rates from the proposed method were compared with those obtained using QFlow software, which is a standard of care clinical technique. For the normal subject, the computed time average flow rates from this study differed from those obtained using the standard of care technique (QFlow) by 0.8 ml/s (0.9%) at the main PA, by 2 ml/s (3.4%) at the left PA and by 1.4 ml/s (3.8%) at the right PA. For the subject with PI, the difference was 7 ml/s (12.4%) at the main PA, 5.5 ml/s (22.6%) at the left PA and 4.9 ml/s (18.0%) at the right PA. The higher percentage differences for the subject with PI, was the result of overall lower values of the forward mean flow rate caused by excessive flow regurgitation. This methodology is expected to provide improved computational results when PS geometry from angiographic MRI is used in conjunction with PS PC-MRI data for solving the flow field.

Diagnostic uncertainties during assessment of serial coronary stenoses: an in vitro study.

Currently, the diagnosis of coronary stenosis is primarily based on the well-established functional diagnostic parameter, fractional flow reserve (FFR: ratio of pressures distal and proximal to a stenosis). The threshold of FFR has a "gray" zone of 0.75-0.80, below which further clinical intervention is recommended. An alternate diagnostic parameter, pressure drop coefficient (CDP: ratio of trans-stenotic pressure drop to the proximal dynamic pressure), developed based on fundamental fluid dynamics principles, has been suggested by our group. Additional serial stenosis, present downstream in a single vessel, reduces the hyperemic flow, Q˜h, and pressure drop, Δp˜, across an upstream stenosis. Such hemodynamic variations may alter the values of FFR and CDP of the upstream stenosis. Thus, in the presence of serial stenoses, there is a need to evaluate the possibility of misinterpretation of FFR and test the efficacy of CDP of individual stenoses. In-vitro experiments simulating physiologic conditions, along with human data, were used to evaluate nine combinations of serial stenoses. Different cases of upstream stenosis (mild: 64% area stenosis (AS) or 40% diameter stenosis (DS); intermediate: 80% AS or 55% DS; and severe: 90% AS or 68% DS) were tested under varying degrees of downstream stenosis (mild, intermediate, and severe). The pressure drop-flow rate characteristics of the serial stenoses combinations were evaluated for determining the effect of the downstream stenosis on the upstream stenosis. In general, Q˜h and Δp˜ across the upstream stenosis decreased when the downstream stenosis severity was increased. The FFR of the upstream mild, intermediate, and severe stenosis increased by a maximum of 3%, 13%, and 19%, respectively, when the downstream stenosis severity increased from mild to severe. The FFR of a stand-alone intermediate stenosis under a clinical setting is reported to be ∼0.72. In the presence of a downstream stenosis, the FFR values of the upstream intermediate stenosis were either within (0.77 for 80%-64% AS and 0.79 for 80%-80% AS) or above (0.88 for 80%-90% AS) the "gray" zone (0.75-0.80). This artificial increase in the FFR value within or above the "gray" zone for an upstream intermediate stenosis when in series with a clinically relevant downstream stenosis could lead to misinterpretation of functional stenosis severity. In contrast, a distinct range of CDP values was observed for each case of upstream stenosis (mild: 8-10; intermediate: 47-54; and severe: 130-155). The nonoverlapping range of CDP could better delineate the effect of the downstream stenosis from the upstream stenosis and allow for the accurate diagnosis of the functional severity of the upstream stenosis.

Longitudinal assessment of hemodynamic endpoints in predicting arteriovenous fistula maturation.

Arteriovenous fistula (AVF) nonmaturation is currently a significant clinical problem; however, the mechanisms responsible for this have remained unanswered. Previous work by our group and others has suggested that anatomical configuration and the corresponding hemodynamic endpoints could have an important role in AVF remodeling. Thus, our goal was to assess the longitudinal (temporal) effect of wall shear stress (WSS) on remodeling process of AVFs with two different configurations. The hypothesis is that early assessment of hemodynamic endpoints such as temporal gradient of WSS will predict the maturation status of AVF at later time points. Two AVFs with curved (C-AVF) and straight (S-AVF) configurations were created between the femoral artery and vein of each pig. Three pigs were considered in this study and in total six AVFs (three C-AVF and three S-AVF) were created. The CT scan and ultrasound were utilized to numerically evaluate local WSS at 20 cross-sections along the venous segment of AVFs at 2D (D: days), 7D, and 28D postsurgery. These cross-sections were located at 1.5 mm increments from the anastomosis junction. Local WSS values at these cross-sections were correlated with their corresponding luminal area over time. The WSS in C-AVF decreased from 22.3 ± 4.8 dyn/cm(2) at 2D to 4.1 ± 5.1 dyn/cm(2) at 28D, while WSS increased in S-AVF from 13.0 ± 5.0 dyn/cm(2) at 2D to 36.7 ± 5.3 dyn/cm(2) at 28D. Corresponding to these changes in WSS levels, luminal area of C-AVF dilated (0.23 ± 0.14 cm(2) at 2D to 0.87 ± 0.14 cm(2) at 28D) with attendant increase in flow rate. However, S-AVF had minimal changes in area (0.26 ± 0.02 cm(2) at 2D to 0.27 ± 0.03 cm(2) at 28D) despite some increase in flow rate. Our results suggest that the temporal changes of WSS could have significant effects on AVF maturation. Reduction in WSS over time (regardless of initial values) may result in dilation (p < 0.05), while increase in WSS may be detrimental to maturation. Thus, creation of AVFs in a specific configuration which results in a decline in WSS over time may reduce AVF maturation failure.

Concurrent assessment of epicardial coronary artery stenosis and microvascular dysfunction using diagnostic endpoints derived from fundamental fluid dynamics principles.

BACKGROUND: Simultaneously measured pressure and flow distal to coronary stenoses can be combined, in conjunction with anatomical measurements, to assess the status of both the epicardial and microvascular circulations. METHODS AND RESULTS: Assessments of coronary hemodynamics were performed using fundamental fluid dynamics principles. We hypothesized that the pressure-drop coefficient (CDPe; trans-stenotic pressure drop divided by the dynamic pressure in the distal vessel) correlates linearly with epicardial and microcirculatory resistances concurrently. In 14 pigs, simultaneous measurements of distal coronary arterial pressure and flow were performed using a dual sensor-tipped guidewire in the setting of both normal and disrupted microcirculation, with the presence of epicardial coronary lesions of lt; 50% area stenosis (AS) and > 50% AS. The CDPe progressively increased from lesions of < 50% AS to > 50% AS and had a higher resolving power (45 +/- 22 to 193 +/- 140 in normal microcirculation; 248 +/- 137 to 351 +/- 140 in disrupted microcirculation) as compared to fractional flow reserve (FFR) and coronary flow reserve (CFR). Strong multiple linear correlation was observed for CDPe with combined FFR and CFR (r = 0.72; p < 0.0001). Further, the ratio of maximum pressure drop coefficient evaluated at the site of stenosis and its theoretical limiting value of minimum cross-sectional area was also able to distinguish different combinations of coronary artery diseases. CONCLUSIONS: The CDPe can be readily obtained during routine pressure and flow measurements during cardiac catheterization. It is a promising clinical diagnostic parameter that can independently assess the severity of epicardial stenosis and microvascular impairment.

Characterizing momentum change and viscous loss of a hemodynamic endpoint in assessment of coronary lesions.

Myocardial fractional flow reserve (FFR(myo)) and coronary flow reserve (CFR), measured with guidewire, and quantitative angiography (QA) are widely used in combination to distinguish ischemic from non-ischemic coronary stenoses. Recent studies have shown that simultaneous measurements of FFR(myo) and CFR are recommended to dissociate conduit epicardial coronary stenoses from distal resistance microvascular disease. In this study, a more comprehensive diagnostic parameter, named as lesion flow coefficient, c, is proposed. The coefficient, c, which accounts for mean pressure drop, Delta p, mean coronary flow, Q, and percentage area stenosis, can be used to assess the hemodynamic severity of a coronary artery stenoses. Importantly, the contribution of viscous loss and loss due to momentum change for several lesion sizes can be distinguished using c. FFR(myo), CFR and c were calculated for pre-angioplasty, intermediate and post-angioplasty epicardial lesions, without microvascular disease. While hyperemic c decreased from 0.65 for pre-angioplasty to 0.48 for post-angioplasty lesion with guidewire of size 0.35 mm, FFR(myo) increased from 0.52 to 0.87, and CFR increased from 1.72 to 3.45, respectively. Thus, reduced loss produced by momentum change due to lower percentage area stenosis decreased c. For post-angioplasty lesion, c decreased from 0.55 to 0.48 with the insertion of guidewire. Hence, increased viscous loss due to the presence of guidewire decreased c compared with a lesion without guidewire. Further, c showed a linear relationship with FFR(myo), CFR and percentage area stenosis for pre-angioplasty, intermediate and post-angioplasty lesion. These baseline values of c were developed from fluid dynamics fundamentals for focal lesions, and provided a single hemodynamic endpoint to evaluate coronary stenosis severity.

Delineating the guide-wire flow obstruction effect in assessment of fractional flow reserve and coronary flow reserve measurements.

Hemodynamic analysis was conducted to determine uncertainty in clinical measurements of coronary flow reserve (CFR) and fractional flow reserve (FFR) over pathophysiological conditions in a patient group with coronary artery disease during angioplasty. The vasodilation-distal perfusion pressure (CFR-p(rh)) curve was obtained for 0.35- and 0.46-mm guide wires. Our hypothesis is that a guide wire spanning the lesions elevates the pressure gradient and reduces the flow during hyperemic measurements. Maximal CFR-p(rh) was uniquely determined by the intersection of measured CFR and calculated p(rh) of native and residual epicardial lesions in patients without microvascular disease, during angioplasty. Extrapolation of the linear curve gave a zero-coronary flow mean pressure (p(zf)) of approximately 20 mmHg and a corresponding p(rh) of 55 mmHg in the native lesions, which coincided with the level that causes ischemia in human hearts. On this linear curve, values of CFR and FFRmyo (pathophysiological condition) and CFRg and FFRmyog (in the presence of the guide wire) were obtained in native and residual lesions. A strong linear correlation was found between CFR and CFRg [CFR = CFRg x 0.689 + 1.271 (R2= 0.99) for 0.46 mm and CFR = CFRg x 0.757 + 1.004 (R2= 0.99) for 0.35 mm] and between FFRmyo and FFRmyog [FFRmyo = FFRmyog x 0.737 + 0.263 (R2= 0.99) for 0.46 mm and FFRmyo = FFRmyog x 0.790 + 0.210 (R2= 0.99) for 0.35 mm]. This study establishes a strong correlation between CFR and CFRg and between FFRmyo and FFRmyog, which could be used to obtain the true state of occlusion in the coronary artery during angioplasty.