Microvascular Function Research Articles

Impaired retinal micro-vascular function in patients with a systemic sclerosis

Abstract Background Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by widespread and progressive multi-organ fibrosis and vascular abnormalities. Endothelial dysfunction is an early manifestation of SSc and an important contributor to the progression and prognosis of the disease. Dynamic retinal vascular analysis (DVA) is a new method for non-invasive and precise determination of microvascular function. The primary aim was to assess micro- and macro-vascular function in patients with SSc. Methods In this study, vascular function was measured non-invasively with flicker-light induced vasodilation of retinal arterioles (FIDart) and branchial arterial flow-mediated vasodilation (FMD). Patients with SSc were prospectively enrolled in the study (n = 40; mean ± SD age 56±11 years, females 73 %) and compared with age- and sex-matched HC (n = 40; mean age 56±15 years, females 73%). Results Retinal microvascular function was significantly impaired in patients with SSc compared to matched HC (2.3±2.0% versus 3.1±1.9% respectively, p=0.04, figure 1). There was a trend for lower FMD in patients with SSc in comparison to HC (5.0± 3.2% versus 6.2±3.2% respectively, p=0.07). Conclusion Patients with SSc have severe impairment of retinal vascular function compared to matched HC. Thus, microvascular dysfunction in these patients is of systemic nature and retinal vessel analysis may serve as an important marker for SSc disease, severity and prognosis. These results set the stage for further studies on retinal function in SSc patients.Figure 1

Early improvement in left ventricular microvascular flow post sonothrombolysis is associated with better left ventricular systolic function in st elevation myocardial infarction patients

Abstract Background/Introduction Acute coronary syndromes are the main cause of death worldwide and the timely application of proper therapy is critical for patient outcome. However, even when state of the art treatment is implemented, significant no-reflow phenomenon may occur. In this scenario, sonothrombolysis, which consists of a continuous infusion of an ultrasound-enhancing agent associated with high-energy intermittent ultrasound impulses, may restore cardiac microcirculation and improve left ventricular (LV) systolic function. Purpose We aimed to evaluate LV segmental microvascular flow, LV mechanics and function in patients with ST-elevation myocardial infarction (STEMI) after sonothrombolysis therapy and evaluate whether an early (immediately post percutaneous coronary intervention – PCI or PCI+Sonothrombolysis) improvement in myocardial microvascular flow could predict better LV systolic function at 1-month. Methods STEMI patients receiving conventional treatment (PCI with or without previous fibrinolytic therapy) were randomized to sonothrombolysis (therapy group - TG) or conventional treatment (control group - CG). This study included 143 patients (interim analysis) who compose the HUBBLE I databank (High-intensity Ultrasonic impulses and microbuBBles to Limit the Extent of acute myocardial infarction I) and were randomized from two clinical trials (NCT04732091 and NCT02410330): CG, N=74 and TG, N=69 patients. There were 25 patients treated previously with fibrinolytic therapy (14 in CG and 11 in TG) and the percentage of left anterior descending artery as culprit vessel was similar between groups (59 vs. 54%, P=0.482). Sonothrombolysis was initiated after patient admission to the emergency room and continued after PCI for a total of 50 minutes. Echocardiography was carried out immediately after PCI or PCI+Sonothrombolysis and at 1-month for assessing LV ejection fraction (LVEF) and perfusion score index (PSI) in contrasted imaging and global longitudinal strain (GLS) in 2D imaging, that was presented in [module]. Results Demographic characteristics, cardiovascular risk factors and echocardiographic variables immediately after PCI or PCI+Sonothrombolysis were similar between groups (P>0.05). At 1-month follow up, TG presented higher LVEF (46.4±10.5 vs. 50.9±11.1%, P=0.018) and GLS (13.0±3.6 vs. 14.9±4.3%, P=0.008) and lower PSI (1.56±0.4 vs. 1.39±0.3, P=0.007) and number of segments with perfusion defects (5.8±3.7 vs. 4.6±3.3, P=0.050) compared with CG. There was a negative correlation between early PSI and 1-month LVEF (r=-0.701, p<0.0001). Conclusions The preliminary data indicates that sonothrombolysis can be an effective adjuvant treatment in STEMI patients previously treated or not with fibrinolytic therapy, contributing to a better myocardial microvascular flow and LV systolic performance. Early myocardial microvascular reperfusion improvement can predict whether cardiac function will improve in this setting.

Coronary microvascular dysfunction in heart failure: observations from the MICRO registry

Abstract Background Heart failure (HF) is one of the leading causes of hospitalization in the elderly. Coronary microvascular dysfunction (CMD), among other risk factors, is linked to the pathogenesis and clinical manifestations of HF. Purpose This abstract aims to summarize key findings from a comprehensive analysis of CMD in subgroups of HF, shedding light on its association with hemodynamic parameters. Methods Patients experiencing recurrent angina (CCS II-IV) and no relevant epicardial stenosis were enrolled in a prospective registry (MICRO). Epicardial and microvascular responses (pressure, resistance and flow) were assessed at rest and during adenosine and acetylcholine testing. The impact of an elevated left ventricular end-diastolic pressure (LVEDP) in the absence of clinical signs of HF was also investigated. Results Overall, 188 patients (63% (118) women, mean age 65±11 years) with angina and no epicardial stenosis were enrolled. Patients with HF (n=26) displayed lower hyperemic flow in response to endothelium-independent adenosine (5.2±3.1 vs. 7.3±4.4; P=0.004), lower coronary flow reserve (2.9±1.5 vs. 4.4±1.1; P<0.001) and microvascular resistance reserve (3.3±2.1 vs. 5.2±2.7; P<0.001), and increased microvascular resistance during adenosine-induced hyperemia (25±21 vs. 17±11; P=0.045). An increased LVEDP without clinical signs of HF was not associated with a lower coronary flow reserve (4.3±1.9 vs. 2.6±1.2; P=0.006) or microvascular resistance reserve (4.9±2.1 vs. 2.8±1.7; P=0.004). Microvascular resistance during acetylcholine (endothelium-dependent)-induced hyperemia was lower in HF patients (36.2±23.5 vs. 57.4±37.8; P=0.018). Conclusion(s) Patients with heart failure displayed signs of impaired microvascular endothelium-independent responses while endothelium-dependent reactivity appears to be maintained. An elevated LVEDP without clinical HF was not associated with impaired coronary microvascular function.

Assessment of cardiopulmonary exercise capacity in suspected heart failure with preserved ejection fraction: impact of coronary flow velocity reserve and body fat

Abstract Background and objectives Heart failure with preserved ejection fraction (HFpEF) has various pathophysiology including coronary microvascular dysfunction (CMD), obesity, and frailty. In the present study, we aimed to assess the cardiopulmonary exercise capacity according to coronary microvascular function and body composition in patients with suspected HFpEF. Methods Patients with chest symptoms with non-obstructive coronary artery disease (<50% stenosis) and preserved left ventricle (LV) ejection fraction (≥50%) were enrolled. LV end-diastolic pressure was measured during coronary angiography. All patients underwent body composition analysis, adenosine stress echocardiography with the evaluation of coronary blood flow, and cardiopulmonary exercise test assessing maximal oxygen consumption (VO2max). Coronary flow velocity reserve (CFvR) was defined as the ratio of peak to baseline mean diastolic velocity of coronary blood flow. Association between VO2max and CFvR as well as body composition was assessed. Results Of the 106 patients (mean age 63.5), 54 (50.9%) were women, 52.4% had hypertension, and 28.6% had diabetes. Baseline LV end-diastolic pressure was 15.3 ± 5.5 mmHg. Median Heart Failure Association-PEFF score was 3, while medial e’ velocity was 6.7 ± 2.0 cm/s and E/e’ was 9.6 (7.6 – 12.0). Mean diastolic velocity of coronary blood flow was 0.17 [interquartile range (IQR) 0.13 – 0.23] m/sec at baseline, while it increased to 0.46 [IQR 0.38 – 0.57] m/sec at peak, resulting in CFvR of 2.75 [IQR 2.10 – 3.67]. Eighteen (17.1%) patients had CMD (CFvR <2.0). VO2max was 23.1 ± 5.4 mL/kg/min with lower value in women (21.7 ± 4.8 vs. 24.5 ± 5.6 mL/kg/min, p = 0.007). CFvR was directly related to VO2max (r = 0.350, p <0.001). In body composition, skeletal muscle mass index, percent body fat, and visceral fat area were associated with VO2max. In multivariable analysis, age, visceral fat area or percent body fat, and CFvR were linearly correlated with VO2max, and estimated VO2max was well correlated with measured VO2max. Conclusions Cardiopulmonary exercise capacity represented by VO2max was correlated with CFvR and body composition including skeletal muscle mass index, percent body fat, and visceral fat area in patients with suspected HFpEF. VO2max could be estimated by CFvR and fat component in the body.

The relationship between coronary flow reserve and the TyG index in patients with gestational diabetes mellitus

Abstract Gestational diabetes mellitus (GDM) is a prevalent metabolic disorder characterized by glucose intolerance during pregnancy. The triglyceride glucose (TyG) index, a marker of insulin resistance, and coronary flow reserve (CFR), a measure of coronary microvascular function, are emerging as potential indicators of cardiovascular risk. This study aims to investigate the association between CFR and the TyG index in GDM patients. This cross-sectional study of 87 GDM patients and 36 healthy controls was conducted. The participants underwent clinical assessments, blood tests, and echocardiographic evaluations. The TyG index was calculated as ln(triglycerides × fasting glucose/2). CFR was measured using Doppler echocardiography during rest and hyperemia induced by dipyridamole. The study included 87 individuals in the GDM group and 36 individuals in the control group. There was no significant difference in age between the two groups (34.1 ± 5.3 years for GDM vs. 33.1 ± 4.9 years for the control, p = 0.364). The TyG index was significantly higher in the GDM group compared to the controls (p < 0.001) and CFR was lower in the GDM group (p < 0.001) as shown in Figure 1a and 1b. A negative and significant correlation between the TyG index and CFR was observed, which was demonstrated in Figure 2 (r = −0.624, p < 0.001). Linear regression revealed the TyG index as an independent predictor of reduced CFR. The study findings reveal a significant association between the TyG index and CFR in GDM patients, suggesting their potential role in assessing cardiovascular risk.TyG index and CFR of the groupsTyG and CFR correlation analysis

Microvascular blood flow disturbances predict poor outcome of revascularization in CLTI patients

Abstract Background We have recently established hypoxic microvascular remodelling as a critical pathomechanistic factor that limits oxygen diffusion to muscle in chronic limb threatening ischaemia (CLTI). Using animal models of experimental hind limb ischaemia we have also displayed the biological relevance of post-ischaemic microvascular remodelling in skeletal muscle. Our results indicate that differential microvascular changes associate to muscle damage and repair. The natural microvascular dynamics that inherently promote muscle recovery are defected in CLTI patients. Particularly, a progressive arterialization of capillaries in CLTI muscle differentiates the dynamics of the microvasculature from initially assisting muscle regeneration to aggravating ischaemic damage. Methods To establish the clinical relevance of the post-ischaemic microvascular changes in CLTI, we now have studied the effect of microvascular remodelling on the outcome of CLTI patients undergoing surgical or endovascular revascularization. Contrast enhanced ultrasound was used preoperatively to determine the microvascular status of CLTI patients (n=36) scheduled for immediate revascularization. Outcome events such as: hospitalization; reoperation; leg amputation; or death, were postoperatively followed from medical records up to 6 months after revascularization. Patients were grouped according to muscle capillary transit time (Tct) being either similar (n=18) or shorter (n=18) to that in the contralateral legs of the patients, and treatment outcomes were compared between groups. Results The results display consistent increases in postoperative event rates in all measured outcomes in the ShortTct group as compared to controls (at 1 month 8 vs. 2 events (rate ratio 4.00 (95%CI: 0.85-18.84, p=0.080)); at 3 months 13 vs. 4 events (rate ratio 3.25 (95%CI: 1.06-9.97, p=0.039)); at 6 months 17 vs. 9 events (rate ratio 1.89 (95%CI: 0.84-4.24, p=0.123))). For example, 5 vs. 0; 7 vs. 1; and 7 vs. 4 reoperations were detected in the ShortTct group as compared to controls at 1, 3 and 6 months, respectively. By 6 months after initial revascularization also 2 deaths were recorded in the ShortTct group as compared to no deaths in the controls. Conclusions Despite still small samples size in this study, these results suggest that microvascular blood flow disturbances, such as short preoperative muscle capillary transit time, can predict poor outcome of CLTI patients after revascularization. Importantly, the results also identify patients with microvascular blood flow disturbances a subgroup of CLTI patients that should likely receive more specialized care to improve outcomes. The results also call for immediate actions from the scientific community to improve clinical detection of microvascular alterations and to develop strategies to normalize microvascular function in CLTI patients.

Minimal coronary microvascular resistance: agreement between continuous and bolus thermodilution

Abstract Background Continuous thermodilution quantifies absolute microvascular resistance (Rµ, Woods units), the quintessential metric of microvascular function. Rµ is minimal during hyperaemia (Rµ,hyper) with increased Rµ,hyper suggestive of microvascular dysfunction. Bolus thermodilution measures the index of microcirculatory resistance (IMR), a dimensionless surrogate of Rµ,hyper. Purpose We compared Rµ,hyper measured by continuous thermodilution (invasive Rµ,hyper) with the gold standard [15O]H2O positron emission tomography (PET Rµ,hyper), and explored the correlation between invasive Rµ,hyper and uncorrected IMR. Methods The accuracy of invasive Rµ,hyper was assessed in a cohort of 24 patients in which both invasive and PET Rµ,hyper were measured (cohort 1). For both techniques, Rµ,hyper was assessed in both the left anterior descending artery (LAD) and the circumflex artery (LCX), corresponding to 46 measurement of Rµ,hyper in total (LAD=24, LCX=22). Agreement between invasive Rµ,hyper and IMR was evaluated in a cohort of 250 patients with angina and non-obstructive coronary arteries (ANOCA) evaluated in 3 European centres (cohort 2). All measurements in this cohort were performed in the LAD, with patients randomly assigned in a 1:1 ratio to undergo either bolus or continuous thermodilution first. Both techniques were performed by the same operator during the same procedure with a strict interval of 5 minutes between techniques. Results In cohort 1, invasive Rµ,hyper exhibited a strong correlation with PET Rµ,hyper (r=0.86 [95% CI 0.76-0.92], p<0.001), with excellent absolute agreement (ICC 0.82 [95% CI 0.70-0.90], p<0.001) (Figure 1). Furthermore, Passing-Bablok regression analysis found no significant systematic (intercept A: 54.53 [95% CI -18.95 to 120.96]) or proportional (slope B: 0.90 [95% CI 0.71 to 1.15]) bias between invasive Rµ,hyper and PET Rµ,hyper. However, in cohort 2, invasive Rµ,hyper exhibited no significant correlation with IMR (r=0.11 [95% CI -0.01 to 0.23], p=0.08) (Figure 2). Conclusion Invasive Rµ,hyper derived from continuous thermodilution exhibited excellent agreement with non-invasive Rµ,hyper measured by [15O]H2O PET, the current standard of reference. However, IMR exhibited no significant correlation with invasive Rµ,hyper in patients with stable coronary syndromes.Figure 1.PET vs invasive Rµ,hyperFigure 2.Invasive Rµ,hyper vs IMR

The influence of epicardial resistance on Microvascular Resistance Reserve (MRR)

Abstract Background The optimal index of microvascular function should be specific for the microvascular compartment. Yet, coronary flow reserve (CFR), despite being widely used to diagnose coronary microvascular dysfunction (CMD), is influenced by both epicardial and microvascular resistance. Conversely, microvascular resistance reserve (MRR) adjusts for fractional flow reserve (FFR), and thus is theoretically independent of epicardial resistance. Purpose We tested the hypothesis that MRR, unlike CFR, is not influenced by increasing epicardial resistance, and thus is a more specific index of microvascular function. Methods In a cohort of 16 patients that had undergone proximal left anterior descending artery stenting, we created four grades of artificial stenosis (no stenosis, mild, moderate, and severe) using a coronary angioplasty balloon inflated to different degrees within the stent. For each stenosis grade, we calculated CFR and MRR using continuous thermodilution (64 measurements of each) in order to assess their response to changing epicardial resistance. Results Graded balloon inflation resulted in a significant sequential decrease in mean FFR (no stenosis: 0.82 ±0.05; mild: 0.72 ±0.04; moderate: 0.61 ±0.05; severe: 0.48 ±0.09, p<0.001). This translated into a linear decrease in mean hyperaemic coronary flow (no stenosis: 170.5 ±66.8 ml/min; mild: 149.8 ±58.8 ml/min; moderate: 124.4 ±53.0 ml/min; severe: 94.0 ±45.2 ml/min, p<0.001) (Figure 1). CFR exhibited a marked linear decrease with increasing stenosis (no stenosis: 2.5 ±0.9; mild: 2.2 ±0.8; moderate: 1.8 ±0.7; severe: 1.4 ±0.6), corresponding to a decrease of 0.3 for a decrease in FFR of 0.1 (p<0.001). Conversely, MRR exhibited a minimal decrease across all stenosis grades (no stenosis: 3.0 ±1.0; mild: 3.0 ±1.0; moderate: 2.9 ±1.0; severe: 2.8 ±1.0), corresponding to a decrease of just 0.05 for a decrease in FFR of 0.1 (p<0.001) (Figure 1). Conclusion MRR, unlike CFR, is minimally influenced by epicardial resistance, and thus should be considered the most specific index of microvascular function.Figure 1.Absolute blood flow (Q) vs FFRFigure 2.MRR/CFR vs FFR

Coronary microvascular dysfunction in postmenopausal minipigs with multiple risk factors

Abstract Background Coronary microvascular angina occurs in both men and women, however, the majority of patients are postmenopausal women with multiple cardiovascular risk factors, such as diabetes mellitus (DM), chronic kidney disease (CKD) and dyslipidemia. No treatment is available for coronary microvascular dysfunction, requiring more in depth knowledge on the mechanisms underlying this syndrome in this expanding group of patients. Purpose Here we studied microvascular function in vivo and and in vitro in isolated small coronary arteries, in post-menopausal miniswine with multiple cardiovascular risk factors. Methods DM (streptozotocin), hypercholesterolemia (HC, high fat, high sugar diet), CKD (renal artery embolization) and menopause (ovariectomy, OVX) were induced in 5 adult female minipigs (1.5-2 years old, ~40kg, DM+HC+CKD+OVX) for 6 months, while 11 healthy age- and weight-matched female minipigs on normal pig chow served as controls (Normal). At sacrifice, coronary flow reserve (CFR) in response to intracoronary infusion of adenosine was measured under anesthesia. Isolated small coronary arteries were used to study the endothelium-dependent response to bradykinin in the presence and absence of eNOS blockade with LNAME, and cyclooxygenase inhibition by indomethacin, and endothelium-independent response to the nitric oxide (NO) donor, SNAP. Results 6 months of sustained hyperglycemia (17.5±1.0 in DM+HC+CKD+OVX vs 8.2±0.9 mmol/l in Normal, P<0.05 by t-test), hypercholesterolemia (15.4±2.0 vs 1.7±0.1 mmol/l, P<0.05), renal dysfunction (NGAL: 205±72 vs 67±5 ng/ml, P<0.05) and low progesterone levels (13.1±5.7 in DM+HC+CKD+OVX vs 92.0±30.0 nmol/l in Normal, P=0.1) were accompanied by systemic inflammation (TNFα: 62±7 vs 47±1 pg/ml, P<0.05). CFR was significantly reduced in DM+HC+CKD+OVX as compared to the healthy animals (panel A). Coronary small arteries from DM+HC+CKD+OVX animals showed impaired endothelium-dependent vasodilation to bradykinin (panel B), which was mediated by a loss of NO (panels C & D). The loss of NO was partly compensated for by activation of the cyclooxygenase pathway, as indomethacin blunted the dilation to bradykinin in the DM+HC+CKD+OVX animals, but had no effect on the dilation to bradykinin in Normals (panels C & D). Endothelium-independent dilation to SNAP was also impaired in DM+HC+CKD+OVX animals, indicating blunted vascular smooth muscle responsiveness to nitric oxide (panel E). Conclusion Postmenopausal minipigs with multiple risk factors, displayed severe coronary microvascular dysfunction as evidenced by a significantly reduced coronary flow reserve and both reduced NO sensitivity/ production, indicating endothelial and smooth muscle cell dysfunction. Loss of NO-mediated vasodilation was partially compensated by activation of cyclooxygenase pathway. Such perturbations may contribute to reduced myocardial perfusion that is often observed in post-menopausal women with multiple cardiovascular risk factors.

Assessment of coronary microvascular function with absolute coronary fl ow measurements

Abstract Background Reliable assessment of microvascular function is essential, both in research setting and clinical practice. New techniques, such as continuous coronary thermodilution, are very promising and could revolutionize the field. However, there is a need for proper validation before widespread use is possible. Purpose The goals of this study were: 1. to validate the potential of saline infusion to generate maximum hyperemia in vivo. 2. to validate absolute blood flow (ABF) measured with continuous coronary thermodilution at higher (40-50 ml/min) infusion speeds 3. To assess the safety of higher infusion speeds. Methods Fourteen closed-chest sheep underwent ABF measurements with increasing saline infusion speeds with and without adenosine. Another seven open-chest sheep underwent these measurements with epicardial doppler flow probes on both the left anterior descending artery and left circumflex coronary artery. Maximal hyperemia was defined as maximal flow after 45 seconds of proximal occlusion. The principles of laboratory animal care and all national regulations were followed. Results 20 ml/min of saline infusion induced lower hyperemic coronary flow (140 vs 191 ml/min, p=0.0165) and lower coronary flow reserve (CFR) (1.82 vs 3.21, p= <0.0001) than coronary occlusion. In contrast, 30 ml/min resulted in flow (196 vs 192 ml/min, p=0.8292) and CFR (2.77 vs 3.21, p=0.1107) that were not different from post-occlusion. There was a significant flow overestimation bias (Bland-Altman: Bias ± SD: -73.09 ± 30.52, 95% Limits of agreement: -132.9 to -13.27) with 40-50ml/min of saline. Occasionally, higher saline infusion rates resulted in ischemic ECG-changes and ventricular fibrillation (9.5% at 50 ml/min). Conclusions Continuous saline infusion of 30ml/min, but not 20 ml/min, induced maximal hyperemia. ABF measured with saline infusion speeds of 40-50 ml/min was not accurate nor safe, and should therefore be avoided.

Effectiveness of household-level interventions for reducing the impact of air pollution on health outcomes – a systematic review

Background and aimSeveral air pollution mitigation initiatives have been researched worldwide to see how efficient they are at reducing air pollution and the related health benefits. The effectiveness of these interventions for improving health outcomes is key for scaling up and increasing uptake of same by policymakers and people. We aimed to synthesize scientific evidence about the effectiveness of household-level interventions on air quality and health outcomes using a systematic approach.MethodsComprehensive strategy was used to carry out a literature search in PubMed, Cochrane, and Google scholar by two independent investigators using keywords and Medical Subject Heading terms. Research articles published till the year 2021 focusing on interventions for improvement in air quality and health were selected using pre-specified eligibility criteria. All abstracts for inclusion were reviewed independently by two reviewers. In case of doubt, the articles were included for full-text review. Disagreements were resolved by discussion with the third investigator. The quality of the studies and risk of bias was assessed using the Joanna Briggs Institute critical appraisal tool and Cochrane Risk of Bias tool, version 2.0. Effect estimates were reported using odds ratio, relative risks, difference in mean, and percentage changes with 95% confidence intervals. PRISMA guidelines were used to conduct and report the systematic review. The review was registered in PROSPERO (CRD42022295393).ResultsThe search resulted in the identification of 46,809 studies and 18 of them were finally included in the review using eligibility criteria. The household-level interventions were categorized mainly into air purifiers/electric heater use, cookstove use, and behavioural change interventions. These interventions resulted in a decrease in the number of daytime asthma attacks by 33%, an increase in FEV1 by 4.4%, −1.4% and 0.8% overall percent change in microvascular and lung function. PM2.5 was the most commonly reported air pollutant, its concentrations reduced in the range between 31% and 53% across the studies.ConclusionOur review provided consistent evidence for the effectiveness of household-level interventions thus associated with improvements in cardiovascular and respiratory symptoms.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=295393, identifier, CRD42022295393

Endothelial Beta 1 Integrins are Necessary for Microvascular Function and Glucose Uptake.

Microvascular insulin delivery to myocytes is rate limiting for the onset of insulin-stimulated muscle glucose uptake. The structural integrity of capillaries of the microvasculature is regulated, in part, by a family of transmembrane adhesion receptors known as integrins, which are composed of an α and β subunit. The integrin β1 (itgb1) subunit is highly expressed in endothelial cells (EC). EC itgb1 is necessary for the formation of capillary networks during embryonic during development and its knockdown blunts the reactive hyperemia that manifests during ischemia reperfusion. We investigated the contribution of EC itgb1 in microcirculatory function and glucose uptake with emphasis in skeletal muscle. We hypothesized that loss of EC itgb1 would impair microvascular hemodynamics and glucose uptake during insulin stimulation, creating 'delivery'-mediated insulin resistance. An itgβ1 knockdown mouse model was developed to avoid lethality of embryonic gene knockout and the deteriorating health resulting from early post-natal inducible gene deletion. Mice with (itgb1fl/flSCLcre) and without (itgb1fl/fl) tamoxifen inducible stem cell leukemia cre recombinase (SLCcre) expression at 10 days post cre induction had comparable exercise tolerance and pulmonary and cardiac functions. Using robust in vivo experimental platforms (i.e., intravital microscopy and hyperinsulinemic-euglycemic clamp), we show that itgb1fl/flSCLcre mice compared to itgb1fl/fl littermates have, i) deficits in capillary flow rate, flow heterogeneity, and capillary density; ii) impaired insulin-stimulated glucose uptake despite sufficient transcapillary insulin efflux; and iii) reduced insulin-stimulated glucose uptake due to perfusion-limited glucose delivery. Thus, EC itgb1 is necessary for microcirculatory function and to meet the metabolic challenge of insulin stimulation.

Changes in the reactive hyperemia index after continuous and interval exercise.

High-intensity interval exercise (HIIE) is more effective than moderate-intensity interval exercise (MICE) for improving macrovascular function (e.g., flow-mediated dilation), but less is known regarding the effect of HIIE on microvascular function. We used peripheral artery tonometry to measure the reactive hyperemia index (RHI) and examine the acute effects of HIIE and MICE on microvascular function. Ten healthy participants (50% men, age: 26 ± 5 years, mass: 75.6 ± 15.1 kg, height: 170 ± 10 cm, body mass index: 26.0 ± 3.1 kg∙m-2) performed single bouts of HIIE and MICE cycling on separate occasions. The MICE protocol was 20 min at 60% of maximum power output. The HIIE protocol was a 12-min warm up at 50% of maximum power output immediately followed by an 8-min Tabata protocol where participants alternated between cycling at ⩾ 100% max power (20 sec) and rest (10 sec). The RHI was measured before, immediately after, and 1 h after exercise and compared by two-way repeated measures analysis of variance (condition [MICE, HIIE] and time [pre-, post-, and 1-h postexercise]). Compared to baseline, RHI increased 1 h after MICE only (p = 0.02). Heart rate was higher during MICE at 5 and 10 min (p = 0.02) and higher during HIIE at min 20 (p < 0.01). Within a sample of healthy adults, the RHI was improved 1 h after a single session of MICE but not HIIE. Future research is needed to determine the significance of the differential effects of exercise regimens on the macro- and microvasculature.

Association Between Coronary Microvascular Dysfunction and Exercise Capacity in Dilated Cardiomyopathy.

Aerobic exercise capacity is an independent predictor of mortality in dilated cardiomyopathy (DCM), but the central mechanisms contributing to exercise intolerance in DCM are unknown. Characterize coronary microvascular function in DCM and determine if cardiovascular magnetic resonance (CMR) measures are associated with aerobic exercise capacity. Prospective case-control comparison of adults with DCM and matched controls. Adenosine-stress perfusion CMR to assess cardiac structure, function and automated inline myocardial blood flow quantification, and cardiopulmonary exercise testing (CPET) to determine peak VO2, were performed. Pre-specified multivariable linear regression, including key clinical and cardiac variables, was undertaken to identify independent associations with peak VO2. Sixty-six patients with DCM (mean age 61 years, 71% male) were propensity-matched to 66 controls (mean age 59 years, 71% male) based on age, sex, body mass index and diabetes. DCM patients had markedly lower peak VO2 (19.8±5.5 versus 25.2±7.3mL/kg/min; P<0.001). The DCM group had greater left ventricular (LV) volumes, lower systolic function, and had more fibrosis compared to controls. In the DCM group, there was similar rest but lower stress myocardial blood flow (1.53±0.49 versus 2.01±0.60mL/g/min; P<0.001) and lower MPR (2.69±0.84 versus 3.15±0.84; P=0.002). Multivariable linear regression demonstrated that LV ejection fraction, extracellular volume fraction and MPR, were independently associated with percentage predicted peak VO2 in DCM (R2=0.531, P<0.001). In comparison to controls, DCM patients have lower stress myocardial blood flow and MPR. In DCM, MPR, LV ejection fraction and fibrosis are independently associated with aerobic exercise capacity.

Oxidative stress initiates hemodynamic change in CKD-induced heart disease.

Chronic kidney disease (CKD) predisposes to cardiac remodeling and coronary microvascular dysfunction. Studies in swine identified changes in microvascular structure and function, as well as changes in mitochondrial structure and oxidative stress. However, CKD was combined with metabolic derangement, thereby obscuring the contribution of CKD alone. Therefore, we studied the impact of CKD on the heart and combined proteome studies with measurement of cardiac function and perfusion to identify processes involved in cardiac remodeling in CKD. CKD was induced in swine at 10-12weeks of age while sham-operated swine served as controls. 5-6months later, left ventricular (LV) function and coronary flow reserve were measured. LC-MS-MS-based proteomic analysis of LV tissue was performed. LV myocardium and kidneys were histologically examined for interstitial fibrosis and oxidative stress. Renal embolization resulted in mild chronic kidney injury (increased fibrosis and urinary NGAL). PV loops showed LV dilation and increased wall stress, while preload recruitable stroke work was impaired in CKD. Quantitative proteomic analysis of LV myocardium and STRING pre-ranked functional analysis showed enrichments in pathways related to contractile function, reactive oxygen species, and extracellular matrix (ECM) remodeling, which were confirmed histologically and associated with impaired total anti-oxidant capacity. H2O2 exposure of myocardial slices from CKD, but not normal swine, impaired contractile function. Furthermore, in CKD, mitochondrial proteins were downregulated suggesting mitochondrial dysfunction which was associated with higher basal coronary blood flow. Thus, mild CKD induces alterations in mitochondrial proteins along with contractile proteins, oxidative stress and ECM remodeling, that were associated with changes in cardiac function and perfusion.

Chronic stress in adulthood results in microvascular dysfunction and subsequent depressive-like behavior

Depression is a prevalent mental disorder characterized by unknown pathogenesis and challenging treatment. Recent meta-analyses reveal an association between cardiovascular risk factors and an elevated risk of depression. Despite this, the precise role of vascular injury in depression development remains unclear. In this investigation, we assess vascular system function in three established animal models of depression— chronic unpredictable mild stress (CUMS), chronic social defeat stress (CSDS) and maternal separation (MS)—utilizing ultrasonography and laser Doppler measurement. All three model animals exhibit anhedonia and despair-like behavior. However, significant microvascular dysfunction (not macrovascular) is observed in animals subjected to CUMS and CSDS models, while such dysfunction is absent in the MS model. Statistical analysis further indicates that microcirculation dysfunction is not only associated with depression-like behavior but is also intricately involved in the development of depression in the CUMS and CSDS models. Furthermore, our study has proved for the first time that endothelial nitric oxide synthase-deficient (eNOS+/−) mice, which is a classic model of vascular endothelial injury, showed depression-like behavior which occurred two months later than microvascular dysfunction. Notably, the mitigation of microvascular dysfunction successfully reverses depression-like behavior in eNOS+/− mice by enhancing nitric oxide production. In conclusion, this study unveils the pivotal role of microvascular dysfunction in the onset of depression induced by chronic stress in adulthood and proposes that modulating microvascular function may serve as a potential intervention in the treatment of depression.

Artificial intelligence in assessing cardiovascular diseases and risk factors via retinal fundus images: A review of the last decade

AbstractCardiovascular diseases (CVDs) are the leading cause of death globally. The use of artificial intelligence (AI) methods—in particular, deep learning (DL)—has been on the rise lately for the analysis of different CVD‐related topics. The use of fundus images and optical coherence tomography angiography (OCTA) in the diagnosis of retinal diseases has also been extensively studied. To better understand heart function and anticipate changes based on microvascular characteristics and function, researchers are currently exploring the integration of AI with noninvasive retinal scanning. There is great potential to reduce the number of cardiovascular events and the financial strain on healthcare systems by utilizing AI‐assisted early detection and prediction of cardiovascular diseases on a large scale. A comprehensive search was conducted across various databases, including PubMed, Medline, Google Scholar, Scopus, Web of Sciences, IEEE Xplore, and ACM Digital Library, using specific keywords related to cardiovascular diseases and AI. The study included 87 English‐language publications selected for relevance, and additional references were considered. This article provides an overview of the recent developments and difficulties in using AI and retinal imaging to diagnose cardiovascular diseases. It provides insights for further exploration in this field. Researchers are trying to develop precise disease prognosis patterns in response to the aging population and the growing global burden of CVD. AI and DL are revolutionizing healthcare by potentially diagnosing multiple CVDs from a single retinal image. However, swifter adoption of these technologies in healthcare systems is required.This article is categorized under: Application Areas &gt; Health Care Technologies &gt; Artificial Intelligence

Coronary Physiological Indexes to Evaluate Myocardial Ischemia in Patients With Aortic Stenosis Undergoing Valve Replacement

BackgroundThe evaluation of myocardial ischemia in patients with aortic valve stenosis (AS) with concomitant coronary artery disease (CAD) and possible microvascular dysfunction (MVD) is challenging because fractional flow reserve (FFR) and the resting full-cycle ratio (RFR) have not been validated in this clinical setting. ObjectivesThe objectives of this study in patients with AS and CAD were 1) to describe the relationship between hyperemic and resting indexes, 2) to investigate the acute and long-term effects of aortic valve replacement (AVR) on epicardial indexes and microvascular function, 3) to assess the impact of these changes on clinical decision making, and 4) to determine FFR/RFR ischemia cutoff points in AS. MethodsIn this prospective multicentric study, we performed serial measurements of FFR and RFR and evaluated MVD by means of coronary flow reserve, the index of microvascular resistance, and microvascular resistance reserve in patients with severe AS and intermediate to severe CAD before and 6 months after AVR. Patients underwent myocardial perfusion single-photon emission computed tomography before AVR. ResultsIn total, 146 coronary lesions in 116 patients were included. Before AVR, we observed high FFR/RFR discordance according to standard cutoff values (FFR negative [>0.80]/RFR positive [≤0.89] in 42.3% [68/137] of these lesions). Acutely after AVR, FFR decreased significantly (−0.0120 ± 0.0192; P = 0.0045), whereas RFR remained stable (0.0140 ± 0.0673; P = 0.3089). Six months after AVR, FFR decreased (−0.0279 ± 0.0368), whereas RFR increased significantly (+0.0410 ± 0.0487) (P < 0.0001 for both), resulting in 21.5% (21/98) and 39.8% (39/98) of lesions crossing traditional FFR and RFR cutoff lines, respectively. Left ventricular mass decreased significantly (153.68 ± 44.22 g before vs 134.66 ± 37.26 g after; P < 0.0001). MVD was frequently observed at baseline (32.1% abnormal index of microvascular resistance and 68.6% abnormal microvascular resistance reserve) with all microvascular parameters improving after AVR. The most accurate cutoffs to predict ischemia were FFR ≤0.83 and RFR ≤0.85 with comparable accuracy (75%-80%). ConclusionsIn patients with severe AS and CAD, FFR ≤0.83 and RFR ≤0.85 appear to predict myocardial ischemia more accurately. Six months after AVR, FFR decreases, whereas RFR increases significantly with a simultaneous decrease of left ventricular mass and an improvement of microvascular function.

Acute impact of inorganic nitrate supplementation after ischemia and during small muscle mass exercise in postmenopausal females: A pilot study.

Menopause is associated with reduced endothelial-dependent vasodilation and increased cardiovascular disease (CVD) risk. Dietary nitrate, a non-pharmacological approach, may increase vasodilatory capacity consequentially reducing CVD risk. We investigated macro- and microvascular function after acute nitrate supplementation in postmenopausal females (PMF). Vascular function was studied with flow-mediated vasodilation (FMD) and near-infrared post occlusive reactive hyperemia (PORH). Incremental handgrip exercise was performed to investigate blood flow and tissue oxygenation. We hypothesized acute dietary nitrate would not impact resting endothelial measures but would increase post ischemic vasodilation and incremental exercise blood flow. Late-phase PMF (n = 12) participated in a randomized crossover design with 140 mL of nitrate-rich (NR) beetroot juice or nitrate-poor black currant juice. Testing included a 5-min FMD, a 3-min ischemic exercise FMD, and incremental exercise at 10%, 15%, and 20% maximal voluntary contraction to measure blood flow and pressure responses. A p ≤ 0.05 was considered significant. One-way ANOVA indicated lower resting pressures, but no change to FMD, or PORH in either protocol. Two-way repeated measures ANOVA indicated NR supplementation significantly reduced mean arterial pressure at rest and during incremental exercise at all intensities without changes to blood flow. Acute nitrate is effective for resting and exercising blood pressure management in PMF.

Impaired Endothelial And Microvascular Functions In Obese Patients: Analysis Of Blood Flow In The Femoral Artery During Passive Leg Movements

Impaired Endothelial And Microvascular Functions In Obese Patients: Analysis Of Blood Flow In The Femoral Artery During Passive Leg Movements