Prognostic Significance of Coronary Microvascular Dysfunction in Patients With Heart Failure With Preserved Ejection Fraction.

BACKGROUND: The prognostic impact of coronary microvascular dysfunction (CMD) has been scarcely addressed in heart failure with preserved ejection fraction (HFpEF). This study investigated the prevalence and prognostic significance of CMD as measured by a novel pressure wire-free coronary angiography-derived index of microcirculatory resistance (caIMR) on clinical outcomes. METHODS: Patients diagnosed with HFpEF from 2019 to 2021 were enrolled retrospectively. caIMR was used to quantify microvascular function, and patients were categorised into 2 groups based on their caIMR. The primary end points were composite of all-cause death and heart failure rehospitalisation. RESULTS: Of 137 HFpEF patients, CMD (defined as caIMR ≥ 25) was present in 88 patients (64.2%). Forty-five patients (32.8%) experienced composite events during a mean follow-up of 15 months. Compared with patients with caIMR < 25, those with caIMR ≥ 25 had a notably higher incidence of composite events (16.3% vs 42.0%; P = 0.002). On survival analysis, patients with caIMR ≥ 25 demonstrated a worse prognosis than those with caIMR < 25 for composite events (P = 0.006). Patients with caIMR ≥ 25 in multiple coronary arteries showed a trend to worse outcome than those with caIMR ≥ 25 in a single coronary artery (log-rank P = 0.056). In adjusted analysis, caIMR ≥ 25 was independently predictive of adverse outcomes (adjusted hazard ratio 2.93, 95% confidence interval [CI] 1.28-6.70; P = 0.010). caIMR displayed a significant predictive power for adverse event prediction (area under the receiver operating characteristic curve 0.767, 95% CI 0.677-0.858; P < 0.001). CONCLUSIONS: CMD is highly prevalent and is an independent predictor of adverse outcomes in HFpEF patients. Assessment of CMD may identify high-risk patients early for intensified treatment and risk-factor management.

Clinical Value of Computational Angiography-derived Fractional Flow Reserve in Stable Coronary Artery Disease.

The utilization of FFR remains low. Our study evaluated the per-vessel prognostic value of computational pressure-flow dynamics-derived FFR (caFFR) among patients with stable coronary artery disease. A total of 3329 vessels from 1308 patients were included and analysed. They were stratified into ischaemic (caFFR ≤ 0.8) and non-ischaemic (caFFR > 0.8) cohorts, and the associations between PCI and outcomes were evaluated. The third cohort comprised all included vessels, and the associations between treatment adherent-to-caFFR (PCI in vessels with caFFR ≤ 0.8 and no PCI in vessels with caFFR > 0.8) and outcomes were evaluated. The primary outcome was VOCE, defined as a composite of vessel-related cardiovascular mortality, non-fatal myocardial infarction, and repeat revascularization. PCI was associated with a lower 3-year risk of VOCE in the ischaemic cohort (HR, 0.44; 95% CI, 0.26-0.74; P = 0.002) but not in the non-ischaemic cohort. The risk of VOCE was lower in the adherent-to-caFFR group (n = 2649) (HR, 0.69; 95% CI, 0.48-0.98; P = 0.039). A novel index that uses coronary angiography images to estimate FFR may have substantial clinical value in guiding management among patients with stable coronary artery disease.

Prognostic impact of coronary microvascular dysfunction assessed by caIMR in overweight with chronic coronary syndrome patients.

Objective: Coronary microvascular dysfunction (CMD) may associate with adverse cardiovascular events in obese patients. Coronary angiography-derived index of microcirculatory resistance (caIMR) is proposed as a less-invasive and pressure-wire-free index to assess CMD. We aimed to investigate the impact of coronary microvascular function assessed by caIMR in patients with overweight and chronic coronary syndrome (CCS). Methods: CCS patients who underwent coronary angiography between 2015 to 2018 were included. Overweight was defined as BMI≥24.0kg/m². Impaired coronary microvascular function was defined as caIMR≥25U. The patients were classified according to BMI and caIMR. The primary endpoint was major adverse cardiac events (MACE). Kaplan-Meier and Cox regression analyses evaluated the association between caIMR and MACE. Results: Two hundred and eighty-two CCS patients were enrolled. Among these, 169 (59.93%) were overweight. Impaired coronary microvascular function was higher in overweight patients than in patients with normal weight (49.70% vs. 38.05%; P=0.035). During 35 months of follow-up, 33 MACE had occurred. Among the total CCS population, MACE was higher in patients with high caIMR than in low caIMR (18.11% vs. 6.45%, P=0.003). In subgroups analysis, MACE was higher in overweight patients with high caIMR than low caIMR (20.24% vs. 7.06%, P=0.014), while there were no significant differences in normal-weight patients. Multivariate Cox analysis demonstrated that caIMR≥25 was independently associated with MACE in overweight patients (HR, 2.87; 95% CI, 1.12-7.30; P=0.027) but not in the normal-weight patients. In addition, caIMR showed a significant predictive value for adverse outcomes in overweight patients and provided an incremental prediction when added to a prediction model with BMI. Conclusions: Impaired coronary microvascular function assessed by caIMR was common and is an independent predictor of MACE in overweight patients with CCS.

A comparison of passive and active wall mechanics between elastic and muscular arteries of juvenile and adult rats.

The elastic abdominal aorta and muscular femoral artery are susceptible to aneurysm and atherosclerosis, respectively. The vessel wall mechanics should be an important element for the difference. The objective of the study is to demonstrate a comparison of vessel wall mechanics between elastic and muscular arteries of juvenile and adult rats to show the changes of mechanical properties relevant to aging. The passive and active mechanical tests, theoretical analysis, and histological evaluation were carried out to investigate mechanical properties of vessel walls in the abdominal aorta and carotid and femoral arteries of young and adult rats. There are stiffening femoral artery, unchanged carotid artery, and distensible abdominal aorta in adult rats as compared with the young. The opening angle has values of 54 ± 13°, 82 ± 13°, and 94 ± 13° in the abdominal aorta and carotid and femoral arteries of adult rats, respectively, as well as 80 ± 22°, 93 ± 19°, and 100 ± 23° in the young. The findings are explained by the significantly reduced width of collagen fibers in the abdominal aorta, relatively unchanged width in the carotid artery, and significantly increased width in the femoral artery of adult rats as compared with the young. In conjunction with available literatures, we concluded that inconsistency for nonlinear age-related changes of artery wall mechanics occurs between arteries of different types, which may be a risk factor for the occurrence of abdominal aorta aneurysm and femoral artery atherosclerosis.

[Experimental measurement and modeling analysis of active and passive mechanical properties of arterial vessel wall].

Coronary artery diseases (CAD) have always been serious threats to human health. The measurement, constitutive modeling, and analysis of mechanical properties of the blood vessel wall can provide a tool for disease diagnosis, stent implantation, and artificial artery design. The vessel wall has both active and passive mechanical properties. The passive mechanical properties are mainly determined by elastic and collagen fibers, and the active mechanical properties are determined by the contraction of vascular smooth muscle cells (VSMC). Substantial studies have shown that, the two-layer model of the vessel wall can feature the mechanical properties well, and the circumferential, axial and radial strain and stress are of great significance in arterial wall mechanics. This study reviewed recent investigations of mechanical properties of the vessel wall. Challenges and opportunities in this area are discussed relevant to the clinical treatment of coronary artery diseases.

Coronary Angiography-Derived Diastolic Pressure Ratio.

AIMS: Based on the aortic pressure waveform, a specially designed computational fluid dynamic (CFD) method was proposed to determine coronary angiography-derived diastolic pressure ratio (caDPR) without using invasive pressure wire. The aim of the study is to retrospectively assess diagnostic performance of the caDPR in the catheterization laboratory, based on a previous multicenter trial for online assessment of coronary angiography-derived FFR (caFFR). METHODS AND RESULTS: Patients with diagnosis of stable or unstable angina pectoris were enrolled in six centers. Wire-derived FFR was measured in coronary arteries with 30-90% diameter stenosis. Offline caDPR was assessed in blinded fashion against wire-derived FFR at an independent core laboratory. A total of 330 patients who met the inclusion/exclusion criteria were enrolled from June 26 to December 18, 2018. Offline computed caDPR and wire-derived FFR were compared in 328 interrogated vessels. The caDPR with a cutoff value of 0.89 shows diagnostic accuracy of 87.7%, sensitivity of 89.5%, specificity of 86.8%, and AUC of 0.940 against the wire-derived FFR with a cutoff value of 0.80. CONCLUSIONS: Using wired-based FFR as the standard reference, there is good diagnostic performance of the novel-CFD-design caDPR. Hence, caDPR could enhance the hemodynamic assessment of coronary lesions.

Sickle Cell Anemia Mediates Carotid Artery Expansive Remodeling That Can Be Prevented by Inhibition of JNK (c-Jun N-Terminal Kinase).

OBJECTIVE: Sickle cell anemia (SCA) causes chronic inflammation and multiorgan damage. Less understood are the arterial complications, most evident by increased strokes among children. Proteolytic mechanisms, biomechanical consequences, and pharmaceutical inhibitory strategies were studied in a mouse model to provide a platform for mechanistic and intervention studies of large artery damage due to sickle cell disease. Approach and Results: Townes humanized transgenic mouse model of SCA was used to test the hypothesis that elastic lamina and structural damage in carotid arteries increased with age and was accelerated in mice homozygous for SCA (sickle cell anemia homozygous genotype [SS]) due to inflammatory signaling pathways activating proteolytic enzymes. Elastic lamina fragmentation observed by 1 month in SS mice compared with heterozygous littermate controls (sickle cell trait heterozygous genotype [AS]). Positive immunostaining for cathepsin K, a powerful collagenase and elastase, confirmed accelerated proteolytic activity in SS carotids. Larger cross-sectional areas were quantified by magnetic resonance angiography and increased arterial compliance in SS carotids were also measured. Inhibiting JNK (c-jun N-terminal kinase) signaling with SP600125 significantly reduced cathepsin K expression, elastin fragmentation, and carotid artery perimeters in SS mice. By 5 months of age, continued medial thinning and collagen degradation was mitigated by treatment of SS mice with JNK inhibitor. CONCLUSIONS: Arterial remodeling due to SCA is mediated by JNK signaling, cathepsin proteolytic upregulation, and degradation of elastin and collagen. Demonstration in Townes mice establishes their utility for mechanistic studies of arterial vasculopathy, related complications, and therapeutic interventions for large artery damage due to SCA.

Vertebral Artery Stenoses Contribute to the Development of Diffuse Plaques in the Basilar Artery.

Vertebral artery (VA) stenosis is relevant to a high early risk of recurrent stroke and basilar artery (BA) is the most common intracranial site of atherosclerotic lesions. It is important to show predictive risk factors for transient ischemic attack (TIA) or posterior infarctions. The aim of the study is to investigate morphometry and hemodynamics in intracranial vertebral and basilar arteries of health and diseased patients to enhance the risk assessment. Based on the geometrical model reconstructed from CTA images in 343 patients, a transient three-dimensional computational model was used to determine the hemodynamics. Patients were classified in symmetric, asymmetric, hypoplastic, and stenotic groups while patients in the stenotic group were divided into unilateral, bilateral, bifurcation, and tandem stenotic sub-groups. Patients in bilateral, bifurcation, and tandem stenotic sub-groups had significantly lower basilar artery diameters than other groups. Patients in the stenotic group had significantly higher surface area ratio (SAR) of high time-averaged wall shear stress gradient (TAWSSG) and higher incidence of TIAs or posterior infarctions than other groups while patients in the tandem stenotic sub-group had the highest values (SAR-TAWSSG of 57 ± 22% and TIAs or posterior infarction incidence of 54%). The high SAR-TAWSSG is predisposed to induce TIAs or posterior infarction.

Coronary Angiography-Derived Index of Microvascular Resistance.

A coronary angiography-derived index of microvascular resistance (caIMR) is proposed for physiological assessment of microvasular diseases in coronary circulation. The aim of the study is to assess diagnostic performance of caIMR, using wire-derived index of microvascular resistance (IMR) as the reference standard. IMR was demonstrated in 56 patients (57 vessels) with stable/unstable angina pectoris and no obstructive coronary arteries in three centers using the Certus pressure wire. Based on the aortic pressure wave and coronary angiograms from two projections, the caIMR was computed and assessed in blinded fashion against the IMR at an independent core laboratory. Diagnostic accuracy, sensitivity, specificity, positive predictive value and negative predictive value of the caIMR with a cutoff value of 25 were 84.2% (95% CI: 72.1% to 92.5%), 86.1% (95% CI: 70.5% to 95.3%), 81.0% (95% CI: 58.1% to 94.6%), 88.6% (95% CI: 76.1% to 95.0%), and 77.3% (95% CI: 59.5% to 88.7%) against the IMR with a cutoff value of 25. The receiver-operating curve had area under the curve of 0.919 and the correlation coefficient equaled to 0.746 between caIMR and wire-derived IMR. Hence, caIMR could eliminate the need of a pressure wire, reduce technical error, and potentially increase adoption of physiological assessment of microvascular diseases in patients with ischemic heart disease.

Cardiac wall mechanics analysis in hypertension-induced heart failure rats with preserved ejection fraction.

Although cardiac wall mechanics is of importance for understanding heart failure with preserved ejection fraction (HFpEF), there is a lack of relevant mechanics studies. The aim of this study was to analyze the changes in stress and strain in the left ventricle (LV) in hypertension-induced HFpEF rats. Based on experimental measurements in DSS rats fed with high-salt (HS) and low-salt (LS) diets, LV stress and strain were computed throughout the cardiac cycle using Continuity software. HS-feeding increased myofiber stress and strain along both the transmural and longitudinal directions at the end-diastolic state but resulted in a lower absolute value of strain and relatively unchanged stress at the end-systolic state. Moreover, the end-diastolic stress and strain decreased with increasing radial position from the endocardial towards the epicardial walls despite negligible changes along the longitudinal direction. The changes in LV wall mechanics characterized the elevated diastolic LV stiffness and slow LV relaxation in HS-fed rats of HFpEF. These findings denote that a vicious cycle of increased stress and strain and diastolic dysfunction can prompt the development of HFpEF.

Bifurcation Asymmetry of Small Coronary Arteries in Juvenile and Adult Mice.

Background: Microvascular bifurcation asymmetry is of significance for regulation of coronary flow heterogeneity during juvenile and adult growth. The aim of the study is to investigate the morphometric and hemodynamic variation of coronary arterial bifurcations in mice of different ages. Methods: Pulsatile blood flows were computed from a Womersley-type model in the reconstructed left coronary arterial (LCA) trees from Micro-CT images in normal mice at ages of 3 weeks, 6 weeks, 12 weeks, 5-6 months, and >8 months. Diameter and flow ratios and bifurcation angles were determined in each bifurcation of the LCA trees. Results: The blood volume and inlet flow rate of LCA trees increase and decrease during juvenile and adult growth, respectively. As vessel diameters decrease, the increased ratios of small to large daughter vessel diameters (Ds /Dl ) result in more uniform flows and lower velocities. There are significant structure-functional changes of LCA trees in mice of >8 months compared with mice of < 8 months. As Ds /Dl increases, the variation trend of bifurcation angle during juvenile growth is different from that during adult growth. Conclusions: Although inlet flows are different in adult vs. juvenile mice, the adult still have uniform flow and low velocity. This is accomplished through a decrease in diameter. The design ensures ordered dispersion of red cells through asymmetric branching patterns into the capillaries.

The Interplay of Rogue and Clustered Ryanodine Receptors Regulates Ca2+ Waves in Cardiac Myocytes.

Ca2+ waves in cardiac myocytes can lead to arrhythmias owing to delayed after-depolarisations. Based on Ca2+ regulation from the junctional sarcoplasmic reticulum (JSR), a mathematical model was developed to investigate the interplay of clustered and rogue RyRs on Ca2+ waves. The model successfully reproduces Ca2+ waves in cardiac myocytes, which are in agreement with experimental results. A new wave propagation mode of "spark-diffusion-quark-spark" is put forward. It is found that rogue RyRs greatly increase the initiation of Ca2+ sparks, further contribute to the formation and propagation of Ca2+ waves when the free Ca2+ concentration in JSR lumen ([Ca2+]lumen) is higher than a threshold value of 0.7 mM. Computational results show an exponential increase in the velocity of Ca2+ waves with [Ca2+]lumen. In addition, more CRUs of rogue RyRs and Ca2+ release from rogue RyRs result in higher velocity and amplitude of Ca2+ waves. Distance between CRUs significantly affects the velocity of Ca2+ waves, but not the amplitude. This work could improve understanding the mechanism of Ca2+ waves in cardiac myocytes.

Effects of rogue ryanodine receptors on Ca2+ sparks in cardiac myocytes.

Ca2+ sparks and Ca2+ quarks, arising from clustered and rogue ryanodine receptors (RyRs), are significant Ca2+ release events from the junctional sarcoplasmic reticulum (JSR). Based on the anomalous subdiffusion of Ca2+ in the cytoplasm, a mathematical model was developed to investigate the effects of rogue RyRs on Ca2+ sparks in cardiac myocytes. Ca2+ quarks and sparks from the stochastic opening of rogue and clustered RyRs are numerically reproduced and agree with experimental measurements. It is found that the stochastic opening Ca2+ release units (CRUs) of clustered RyRs are regulated by free Ca2+ concentration in the JSR lumen (i.e. [Ca2+]lumen). The frequency of spontaneous Ca2+ sparks is remarkably increased by the rogue RyRs opening at high [Ca2+]lumen, but not at low [Ca2+]lumen. Hence, the opening of rogue RyRs contributes to the formation of Ca2+ sparks at high [Ca2+]lumen. The interplay of Ca2+ sparks and Ca2+ quarks has been discussed in detail. This work is of significance to provide insight into understanding Ca2+ release mechanisms in cardiac myocytes.

A comparison of postoperative morphometric and hemodynamic changes between saphenous vein and left internal mammary artery grafts.

There is higher long-term failure of the saphenous vein graft (SVG) compared with the left internal mammary artery (LIMA) graft, which is affected by the hemodynamic environment. A comprehensive analysis of postoperative structure-function changes is important to study the atherogenesis in the SVG A comparison of morphometric and hemodynamic parameters was carried out between LIMA grafts and SVGs and between different time points postoperatively. Various parameters were obtained from the image reconstruction and flow simulation in patients, who underwent CT exams for ~1 year, 5 and 10 years after revascularization. Morphometric data showed a decrease in lumen size in the entire SVG and anastomosis of different patients in a sequence of ~1 year, 5 and 10 years postoperatively despite negligible changes of LIMA size. Computational results indicated the fourfold increased surface area ratio (SAR) of low time-averaged wall shear stress (TAWSS) in the SVG and anastomosis at postoperative 10 years than that at postoperative ~1 year. The SAR of high TAWSS gradient (TAWSSG) at the distal anastomosis between SVG and coronary arteries was significantly higher (14 ± 9% vs. 6 ± 8%) than that in the LIMA group at postoperative ~1 year. There were strong correlations between morphometric and hemodynamic parameters in the SVG and distal anastomosis at various time points postoperatively, which showed deterioration relevant to persistent diffuse diseases at postoperative ~10 years.

Intraspecific scaling laws are preserved in ventricular hypertrophy but not in heart failure.

It is scientifically and clinically important to understand the structure-function scaling of coronary arterial trees in compensatory (e.g., left and right ventricular hypertrophy, LVH and RVH) and decompensatory vascular remodeling (e.g., congestive heart failure, CHF). This study hypothesizes that intraspecific scaling power laws of vascular trees are preserved in hypertrophic hearts but not in CHF swine hearts. To test the hypothesis, we carried out the scaling analysis based on morphometry and hemodynamics of coronary arterial trees in moderate LVH, severe RVH, and CHF compared with age-matched respective control hearts. The scaling exponents of volume-diameter, length-volume, and flow-diameter power laws in control hearts were consistent with the theoretical predictions (i.e., 3, 7/9, and 7/3, respectively), which remained unchanged in LVH and RVH hearts. The scaling exponents were also preserved with an increase of body weight during normal growth of control animals. In contrast, CHF increased the exponents of volume-diameter and flow-diameter scaling laws to 4.25 ± 1.50 and 3.15 ± 1.49, respectively, in the epicardial arterial trees. This study validates the predictive utility of the scaling laws to diagnose vascular structure and function in CHF hearts to identify the borderline between compensatory and decompensatory remodeling.

Interplay of Proximal Flow Confluence and Distal Flow Divergence in Patient-Specific Vertebrobasilar System.

Approximately one-quarter of ischemic strokes involve the vertebrobasilar arterial system that includes the upstream flow confluence and downstream flow divergence. A patient-specific hemodynamic analysis is needed to understand the posterior circulation. The objective of this study is to determine the distribution of hemodynamic parameters in the vertebrobasilar system, based on computer tomography angiography images. Here, the interplay of upstream flow confluence and downstream flow divergence was hypothesized to be a determinant factor for the hemodynamic distribution in the vertebrobasilar system. A computational fluid dynamics model was used to compute the flow fields in patient-specific vertebrobasilar models (n = 6). The inlet and outlet boundary conditions were the aortic pressure waveform and flow resistances, respectively. A 50% reduction of total outlet area was found to induce a ten-fold increase in surface area ratio of low time-averaged wall shear stress (i.e., TAWSS ≤ 4 dynes/cm2). This study enhances our understanding of the posterior circulation associated with the incidence of atherosclerotic plaques.