Impaired Microvascular Function Research Articles

Biomarkers of endothelial glycocalyx damage are associated with microvascular dysfunction in resuscitated septic shock patients

BackgroundMicrovascular dysfunction plays a central role in organ dysfunction during septic shock. Endothelial glycocalyx (eGC) damage could contribute to impaired microcirculation. The aim was to assess whether several eGC-damaged biomarkers are associated with microvascular dysfunction in resuscitated septic shock patients. MethodsThis cross-sectional study included resuscitated septic shock patients (N = 31), and a group of healthy individuals (N = 20). The eGC damage biomarkers measured were syndecan-1 (SDC-1), soluble CD44 (CD44s), hyaluronic acid (HYAL) in blood sample; sulfated glycosaminoglycans (GAGs) in urine sample; and thrombomodulin (TBML) in blood sample as biomarker of endothelial cell damage. Microcirculation was assessed through sublingual videocapillaroscopy using the GlycoCheck™, which estimated the perfused vascular density (PVD); the perfused boundary region (PBR), an inverse parameter of the eGC thickness; and the microvascular health score (MVHS). We defined a low MVHS (<50th percentile in septic patients) as a surrogate for more impaired microvascular function. ResultsThe SDC-1, CD44s, TBML and GAGs levels were correlated with impaired microvascular parameters (PVD of vessels with diameter < 10 μm, MVHS and flow-adjusted PBR); p < 0.05 for all comparisons, except for GAGs and flow-adjusted PBR. The SDC-1 [78 ng/mL (interquartile range (IQR) 45–336) vs. 48 ng/mL (IQR 9–85); p = 0.052], CD44s [796ρg/mL (IQR 512–1995) vs. 526ρg/mL (IQR 287–750); p = 0.036], TBML [734ρg/mL (IQR 237–2396) vs. 95ρg/mL (IQR 63–475); p = 0.012] and GAGs levels [0.42 ρg/mg (IQR 0.04–1.40) vs. 0.07 ρg/mg (IQR 0.02–0.20); p = 0.024]; were higher in septic patients with more impaired sublingual microvascular function (low MVHS vs. high MVHS). ConclusionSDC-1, CD44s, TBML and GAGs levels were associated with impaired microvascular function in resuscitated septic shock patients.

Risk Factors for Bone Fractures in Patients With Comorbid Pathology

Patients with heart failure (HF) have elevated levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), leading to macrophage activation, impaired microvascular function, changes in muscle contraction and fibrosis development. In addition, these proinflammatory cytokines promote bone resorption, thereby increasing the incidence of bone fractures. The aim of the study is to evaluate the effect of tumor necrosis factor-alpha receptor types 1 and 2 (TNF-α-SR1 and TNF-α-SR2) on fracture probability in individuals with osteoporosis who have concurrent chronic heart failure (HF) and type 2 diabetes mellitus (T2DM). The study was conducted on 178 women aged 50 to 65 years. Among these women, 48 were in group 1 and had both heart failure and type 2 diabetes. Group 2 included 93 patients with osteoporosis and heart failure and group 3 included 37 women with osteoporosis, heart failure and type 2 diabetes. Thirty-five postmenopausal women without any clinical and instrumental signs of cardiovascular pathology or osteoporosis were selected as the control group. The levels of TNF-α-SR1 and TNF-α-SR2 receptors in patient groups 1-3 were significantly higher (p&lt;0.01) than in the control group, as were their concentrations. In addition, it was found that the levels of both receptors were significantly higher in group 3 than in patients in groups 1 and 2. To evaluate the levels of TNF-α-SR1 and TNF-α-SR2, the data were divided into four quartiles (Q1-Q4) based on the increase in the concentrations of these markers. For TNF-α-SR2, an increasing risk gradient was observed, with the odds ratio (OR) for osteoporosis events increasing from 1.4 to 12.83, but the risk was statistically significant only for Q3-Q4. For Q4 TNF-α-SR1 levels, a significant increase in the risk of an adverse osteoporosis outcome at 36 months was also found (OR=5.25, p=0.038). In addition, the use of loop diuretics was found to be a predictor of high risk of osteoporotic fractures in patients with chronic HF (JR=6.29, 95% CI=1.45-17.26, p=0.015). Postmenopausal women with chronic HF and elevated levels of soluble TNF-α-SR1 and TNF-α-SR2 receptors are at higher risk for osteoporosis and adverse disease progression. In addition, the use of loop diuretics in these individuals is associated with an increased risk of osteoporotic fractures.

Association between cardiovascular risk profile and impaired microvascular function in a Swedish middle-aged cohort (the SCAPIS study)

Abstract Aims The aim was to investigate the relationship between microvascular function, cardiovascular risk profile, and subclinical atherosclerotic burden. Methods and results The study enrolled 3809 individuals, 50–65 years old, participating in the population-based observational cross-sectional Swedish CArdioPulmonary bioImage Study. Microvascular function was assessed in forearm skin using an arterial occlusion and release protocol determining peak blood oxygen saturation (OxyP). Cardiovascular risk was calculated using the updated Systematic Coronary Risk Evaluation [SCORE2; 10-year risk of fatal and non-fatal cardiovascular disease (CVD) events]. The OxyP was compared with coronary artery calcification score (CACS) and to plaques in the carotid arteries. Individuals with OxyP values in the lowest quartile (Q1; impaired microvascular function) had a mean SCORE2 of 5.8% compared with 3.8% in those with the highest values of OxyP (Q4), a relative risk increase of 53%. The risk of having a SCORE2 &amp;gt; 10% was five times higher for those in Q1 (odds ratio: 4.96, 95% confidence interval: 2.76–8.93) vs. Q4 when adjusting for body mass index and high-sensitivity C-reactive protein. The OxyP was lower in individuals with CACS &amp;gt; 0 and in those with both carotid plaques and CACS &amp;gt; 0, compared with individuals without subclinical atherosclerotic burdens (87.5 ± 5.6% and 86.9 ± 6.0%, vs. 88.6 ± 5.8%, P &amp;lt; 0.01). Conclusion In a population without CVD or diabetes mellitus, impaired microvascular function is associated with cardiovascular risk profiles such as higher SCORE2 risk and CACS. We suggest that OxyP may serve as a microcirculatory functional marker of subclinical atherosclerosis and CVD risk that is not detected by structural assessments.

Diagnostic value of angiography-derived index of microcirculatory resistance (AMR) for coronary microcirculatory dysfunction (CMD) and its prognostic significance in patients with chronic coronary syndromes in the smoking population.

This study aims to analyze the prognostic significance of angiographic microvascular resistance (AMR) derived from functional coronary angiography in diagnosing coronary microvascular dysfunction (CMD) among patients with chronic coronary syndrome (CCS), particularly focusing on the prognostic significance of CMD in smokers. Additionally, this study assesses the prognostic significance of the diagnostic accuracy of the AMR index for CMD in CCS patients within the smoking population. Seventy-five CCS patients were studied for IMR measurement between June 2018 and December 2020, classified into CMD and non-CMD groups. Pearson correlation analyzed AMR and IMR relationship, while ROC curves determined AMR's predictive value for CMD with optimal cutoff value. An additional 223 CCS patients were included for AMR measurements. The study's primary endpoint was MACE occurrence, followed up through telephone calls. COX one-way analysis and Kaplan-Meier analysis evaluated the association between AMR and MACE risk. In the study, 52% of patients were diagnosed with CMD, and the AUC under the AMR curve for predicted IMR ≥ 25 was 0.90 (95% CI: 0.79-0.95). The CMD group had a higher proportion of female patients, smokers, and those with hypertension and diabetes mellitus compared to the non-CMD group (all P < .05). The CMD group exhibited higher AMR values than the non-CMD group (3.20 ± 0.5 vs 1.95 ± 0.45, P < .01), with a significant correlation between AMR and IMR (R2 = 0.81, P < .001). The ROC curve illustrated AMR's effectiveness in diagnosing CMD in CCS patients, using IMR as the gold standard, with the optimal cutoff value of AMR = 2.6mmHgs/cm (sensitivity: 90.5%, specificity: 81.5%). Patients with AMR ≥ 2.6mmHgs/cm had a higher risk of MACE events (HR = 6.00; 95% CI: 1.59-22.67). AMR in patients with CCS was significantly correlated with IMR and demonstrated good diagnostic accuracy. AMR ≥ 2.6 mm Hg*s/cm was associated with an increased risk of MACE occurrence and served as a valuable prognostic factor. In patients with CCS, AMR has a high diagnostic performance, In patients with CCS who smoke, impaired coronary microvascular function as assessed by AMR is significant and is an independent predictor of MACE.

Increased Subclinical Coronary Artery Pathology in Type 2 Diabetes With Albuminuria.

Diabetes affects the kidneys, and presence of albuminuria reflects widespread vascular damage and is a risk factor for cardiovascular disease (CVD). Still, the pathophysiological association between albuminuria and CVD remains incompletely understood. Recent advantages in non-invasive imaging enable functional assessment of coronary artery pathology and present an opportunity to explore the association between albuminuria and CVD. In this cross-sectional study, we evaluated the presence of sub-clinical coronary artery pathology in people with type 2 diabetes, free of overt CVD. Using multimodal imaging, we assessed the coronary microcalcification activity (18F-sodium fluoride positron emission tomography/computed tomography (PET/CT), plaque inflammation (64Cu- DOTATATE PET/CT) and myocardial flow reserve (82Rubidium PET/CT). The study population consisted of 90 participants, stratified by albuminuria; 60 had historic or current albuminuria (urine albumin creatinine ratio (UACR) ≥ 30 mg/g)), and 30 had normoalbuminuria (UACR < 30 mg/g). We demonstrated that any albuminuria (historic or current) was associated with a more severe phenotype, in particularly higher levels of microcalcifications and impaired myocardial microvascular function, however, coronary inflammation activity was similar in people with and without albuminuria. Our findings establish a potential underlying mechanism connecting cardiovascular and kidney diseases and could indicate the initial stages of the cardiorenal syndrome.

Impaired retinal micro-vascular function in patients with atrial fibrillation

BackgroundCardiovascular (CV) risk factors and CV diseases, in particular heart failure, are strongly associated with impaired microvascular retinal endothelial function. Whether atrial fibrillation (AF) contributes to vascular dysfunction is not clear. Therefore, the aim of this study was to investigate the impact of AF on retinal microvascular function. MethodsIn this study, vascular function was measured non-invasively with flicker-light induced vasodilatation of retinal arterioles (FIDart%). Patients with a history of AF and risk factors for heart failure (HF) or heart failure (n = 69; age 67.9 ± 9.2 years, 71% male, 35% HFrEF, 56% paroxysmal, 25% persistent, 19% permanent AF), as well as age, sex and ejection fraction matched patients with absent history of AF (n = 66; age 63.4 ± 10.6 years, 67% male, 47% HFrEF) were included. Patients with AF were further divided into those with paroxysmal AF (in sinus rhythm – AFSR: n = 38, age 71.4 ± 9.2, 73% male), and those with AF at the time of the study visit. ResultsRetinal microvascular function was impaired in patients with AF compared to patients without AF (FIDart% 1.1% [0.3–2.8] vs. 2.7% [1.3–5.1], p < 0.001). Patients currently in AF have poorer retinal microvascular function (FIDart% 0.8% [0.1–1.9) compared to patients with a history of AF but currently in SR at the time of retinal function measurement (1.5% [0.6–4.9] p = 0.017). In patients with AF, impaired retinal vascular function was independently associated with larger left atrial volume (mean 49.8 ± 18.4), even after correction for confounding factors in different models (SCR = -0. 251 to −0.256, p = 0.035–0.01). ConclusionsAF in patients with heart failure is associated with impaired vascular function, even if currently in sinus rhythm. The association of retinal microvascular dysfunction with left atrial volume, a surrogate for elevated cardiac filling pressures, may further highlight the important interplay between the vasculature and elevated filling pressures in the development of AF.

Association between global sleep quality and coronary microvascular function in male physicians with occupational burnout.

Occupational burnout has been associated with an increased risk of coronary heart disease, although the mechanisms involved are elusive. We investigated whether poor global sleep quality is associated with impaired coronary microvascular function in male physicians, a professional group at increased risk for burnout. Study participants were 30 male physicians with clinical burnout and 30 controls without burnout defined by the Maslach Burnout Inventory. Global sleep quality was measured with the Pittsburgh Sleep Quality Index (PSQI). Endothelium-dependent (cold pressor test) and endothelium-independent (adenosine challenge) coronary microvascular function were quantified with myocardial perfusion positron emission tomography. In multivariable analyses, the interaction between burnout and the PSQI global score was regressed on measures of coronary microvascular function, adjusting for age, body mass index, physical activity, alcohol consumption, and main effects of burnout and PSQI score. The prevalence of poor sleepers (PSQI score > 5) was 40% in the burnout group and 10% in the control group. Adjusting for covariates, burnout-by-global PSQI score interactions were observed for myocardial blood flow (MBF) at rest (r partial = -.30, p = .025), endothelium-dependent coronary flow reserve (r partial = -.26, p = .062), MBF response (r partial = -.30, p = .028), and hyperemic MBF (r partial = -.34, p = -.012). The global PSQI score was inversely associated with these MBF measures in the burnout group relative to the control group. No significant interactions emerged for endothelium-independent MBF. In male physicians with occupational burnout, poor global sleep quality was associated with reduced endothelium-dependent coronary microvascular function, suggesting a mechanism by which burnout may affect cardiovascular health.

Abstract 17076: The Relationship Between Impaired Microvascular Function, Cardiovascular Risk Profile and Subclinical Atherosclerotic Burden in a Swedish Middle-Aged Cohort

Introduction: Microvascular function is associated with cardiovascular risk factors and deteriorates in individuals with cardiovascular disease. Hypothesis: The aim of this study was to investigate the relationship between microvascular function, cardiovascular risk profile and subclinical atherosclerotic burden. Methods: The study enrolled 3809 randomly selected individuals, 50-65 years old, participating in the population-based observational cross-sectional Swedish CArdioPulmonary bioImage Study (SCAPIS). Microvascular function was measured in forearm skin using an arterial occlusion and release protocol determining the peak blood oxygen saturation, OxyP. Cardiovascular risk was calculated using the updated Systematic Coronary Risk Evaluation (SCORE2; 10-year risk of fatal and non-fatal CVD events). OxyP was compared with Coronary artery calcification score (CACS) and plaques in the carotid arteries. Results: Individuals with OxyP values in the lowest quartile (Q1; impaired microvascular function), had a mean SCORE2 of 5.8% compared to 3.8% in those with the highest values of OxyP (Q4), a relative risk increase of 53%. In the low-risk SCORE2 level (&lt;5% risk), 19.0% of the individuals have impaired microvascular function as compared to 48.1% in the high-risk SCORE2 level (&gt;10% risk). OxyP was lower in individuals with coronary artery calcification (CACS&gt;0) and those with both carotid plaque and CACS&gt;0, as compared to individuals without subclinical atherosclerotic burden (CACS=0 and no carotid plaque; 87.5 ±5.6 % and 86.9 ±6.0 % vs 88.6 ± 5.8 %, p &lt; 0.01). Conclusion: In a population without cardiovascular disease or diabetes mellitus, impaired microvascular function is associated with higher SCORE2 risk and CACS&gt;0. Hence, assessment of microvascular function may be a useful tool for accurate cardiovascular risk prediction, in addition to imaging assessment of atherosclerosis in the coronary and carotid arteries.

Abstract 13787: Restricted Coronary Flow Reserve of Mental Stress Induced Myocardial Ischemia in Angina and No Obstructive Coronary Artery Disease

Background: The myocardial blood flow (MBF) mechanism in mental stress-induced myocardial ischemia (MSIMI) in angina with no obstructive coronary artery disease (ANOCA) population is unknown. Methods: 13-NH 3 cardiac PET-CT was utilized to assess MBF and perfusion changes under mental stress (ms) and adenosine stress (as) in ANOCA subjects and gender- and age-matched healthy controls. MSIMI was defined as an increase in perfusion defect score of ≥3 points. Results: Among the 126 participants enrolled, ANOCA women showed a significantly higher prevalence of MSIMI compared to the healthy controls (36/84 vs. 1/42, p &lt;0.001). Perfusion defects under ms occurred synchronously however more pronounced in the left anterior descending and right coronary artery territories, consistent with a significantly higher MBF hyperemia in the left circumflex territory. MBF ms shows a close correlation with rate-pressure product (RPP ms ) ( p &lt;0.05 in ANOCA&amp;MSIMI+, ANOCA&amp;MSIMI-, and control groups with r pearson ranging from 0.39-0.65). Although no differences existed in absolute MBF ms values between groups, there were notable increasing trends among the three groups in corrected MBF, which reflected blood flow supply-demand balance (ANOCA&amp;MSIMI+: 0.96±0.23 vs. control group: 1.10±0.29, p =0.020), and in coronary flow reserve (CFR) (ANOCA&amp;MSIMI+: 2.41±0.75 vs. control group: 2.89±0.77, p =0.016). Furthermore, after adjusting for confounding factors, only subjects in ANOCA&amp;MSIMI+ group did not exhibit a corresponding increase in MBF ms matching MBF as . Conclusion: Restricted CFR, indicating impaired coronary microvascular function, and mismatch between myocardial blood supply and demand together constitute the pathogenic mechanism of MSIMI in ANOCA population. More researches are still needed in exploring the brain-heart interaction in MSIMI.

Impaired coronary microvascular reactivity in youth with bipolar disorder.

Cardiovascular disease (CVD) is excessively prevalent and premature in bipolar disorder (BD), even after controlling for traditional cardiovascular risk factors. The increased risk of CVD in BD may be subserved by microvascular dysfunction. We examined coronary microvascular function in relation to youth BD. Participants were 86 youth, ages 13-20 years (n = 39 BD, n = 47 controls). Coronary microvascular reactivity (CMVR) was assessed using quantitative T2 magnetic resonance imaging during a validated breathing-paradigm. Quantitative T2 maps were acquired at baseline, following 60-s of hyperventilation, and every 10-s thereafter during a 40-s breath-hold. Left ventricular structure and function were evaluated based on 12-15 short- and long-axis cardiac-gated cine images. A linear mixed-effects model that controlled for age, sex, and body mass index assessed for between-group differences in CMVR (time-by-group interaction). The breathing-paradigm induced a significant time-related increase in T2 relaxation time for all participants (i.e. CMVR; β = 0.36, p < 0.001). CMVR was significantly lower in BD v. controls (β = -0.11, p = 0.002). Post-hoc analyses found lower T2 relaxation time in BD youth after 20-, 30-, and 40 s of breath-holding (d = 0.48, d = 0.72, d = 0.91, respectively; all pFDR < 0.01). Gross left ventricular structure and function (e.g. mass, ejection fraction) were within normal ranges and did not differ between groups. Youth with BD showed evidence of subclinically impaired coronary microvascular function, despite normal gross cardiac structure and function. These results converge with prior findings in adults with major depressive disorder and post-traumatic stress disorder. Future studies integrating larger samples, prospective follow-up, and blood-based biomarkers are warranted.

Diverging role of epicardial adipose tissue across the entire heart failure spectrum.

Epicardial adipose tissue (EAT) is a metabolically highly active tissue modulating numerous pathophysiological processes. The aim of this study was to investigate the association between EAT thickness and endothelial function in patients with heart failure (HF) across the entire ejection fraction spectrum. A total of 258 patients with HF with an ejection fraction across the entire spectrum [HF with reduced ejection fraction (HFrEF), n=168, age 60.6±11.2years; HF with preserved ejection fraction (HFpEF), n=50, mean age 65.1±11.9years; HF with mildly reduced ejection fraction (HFmrEF), n=32, mean age 65±12] were included. EAT was measured with transthoracic echocardiography. Vascular function was assessed with flicker-light-induced vasodilation of retinal arterioles (FIDart%) and flow-mediated dilatation (FMD%) in conduit arteries. Patients with HFrEF have less EAT compared with patients with HFpEF (4.2±2 vs. 5.3±2mm, respectively, P<0.001). Interestingly, EAT was significantly associated with impaired microvascular function (FIDart%; r=-0.213, P=0.012) and FMD% (r=-0.186, P=0.022), even after multivariate correction for confounding factors (age, body mass index, hypertension, and diabetes; standardized regression coefficient (SRC)=-0.184, P=0.049 for FIDart% and SRC=-0.178, P=0.043 for FMD%) in HFrEF but not in HFpEF. Although less EAT is present in HFrEF than in HFpEF, only in HFrEF EAT is associated with vascular dysfunction. The diverging role of EAT in HF and its switch to a functionally deleterious tissue promoting HF progression provide the rationale to specifically target EAT, in particular in patients with reduced ejection fraction.

Unraveling the pathophysiology of lower-limb postthrombotic syndrome in adolescents: a proof-of-concept study.

A better understanding of the pathophysiology of pediatric postthrombotic syndrome (PTS) is needed to develop strategies to treat this condition. We investigated calf pump function, exercise capacity, balance in power output, and changes in limb muscle oxygen saturation (SmO2) and fluid content during exercise in 10 pediatric patients with unilateral lower-limb PTS, and in age- and sex-matched controls (1:1-1:2 ratio). Outcomes were investigated usingbioimpedance spectroscopy, torque-sensing pedals, and near-infrared spectroscopy during incremental- and constant-load cycling tests. The median age at participation was 17years (25th-75th percentile, 15-18 years); 68% of participants were females. The median CAPTSure score in the affected leg of affected participants was 35 points (25th-75th percentile, 24-46 points), indicating moderate/severe PTS; 20% of patients had a history of central venous catheter-related thrombosis. Increasing PTS severity was associated with higher calf pump venous volume and higher ejection volume, leading to compensated calf pump performance. We found no evidence of PTS impact on exercise capacity. Leg contribution to power output was similar in affected and unaffected legs. However, the PTS-affected legs showed lower SmO2 during active cycling and recovery with increasing PTS severity, indicating impaired microvascular function in the muscle. These findings suggest that PTS severity is associated with impaired blood flow, presumably from elevated venous pressure during and after exercise. The fact that microvascular function is impaired in young patients with PTS underscores the relevance of developing strategies to mitigate the effects of this chronic vascular disease to minimize its deleterious effects as children grow older.

A novel, microvascular evaluation method and device for early diagnosis of peripheral artery disease and chronic limb-threatening ischemia in individuals with diabetes.

A novel transdermal arterial gasotransmitter sensor (TAGS) has been tested as a diagnostic tool for lower limb microvascular disease in individuals with and without diabetes mellitus (DM). The TAGS system noninvasively measures hydrogen sulfide (H2S) emitted from the skin. Measurements were made on the forearm and lower limbs of individuals from three cohorts, including subjects with DM and chronic limb-threatening ischemia, to evaluate skin microvascular integrity. These measurements were compared with diagnosis of peripheral artery disease (PAD) using the standard approach of the toe brachial index. Other measures of vascular health were made in some subjects including fasting blood glucose, hemoglobin A1c, plasma lipids, blood pressure, estimated glomerular filtration, and body mass index. The leg:arm ratio of H2S emissions correlated with risk factors for microvascular disease (ie, high-density lipoprotein levels, estimated glomerular filtration rate, systolic blood pressure, and hemoglobin A1c). The ratios were significantly lower in symptomatic DM subjects being treated for chronic limb-threatening ischemia (n= 8, 0.48± 0.21) compared with healthy controls (n= 5, 1.08± 0.30; P= .0001) and with asymptomatic DM subjects (n= 4, 0.79± 0.08; P= .0086). The asymptomatic DM group ratios were also significantly lower than the healthy controls (P= .0194). Using ratios of leg:arm transdermal H2S measurement (17 subjects, 34 ratios), the overall accuracy to identify limbs with severe PAD had an area under the curve of the receiver operating curve of 0.93. Ratios of transdermal H2S measurements are lower in legs with impaired microvascular function, and the decrease in ratio precedes clinically apparent severe microvascular disease and diabetic ulcers. The TAGS instrument is a novel, sensitive tool that may aid in the early detection and monitoring of PAD complications and efforts for limb salvage.

Sex differences in the development of coronary microvascular diseases in type-2 diabetes: possible role of gap junction protein connexin-40

Type-2 diabetes (T2D) increases the risk of cardiovascular diseases 2-4 folds in both sexes compared to non-diabetic individuals. However, more than 50% of female patients who experience chest pain have coronary microvascular disease (CMD) instead of obstructive CAD. On the other hand, 20% of men with chest pain have CMD. CMD is characterized by reduced coronary flow reserve, and coronary flow is regulated by the change in capillary density and vessel diameter. Gap junction protein connexin-40 (Cx40) plays a significant role in coronary microvascular function by controlling endothelium-dependent relaxation (EDR), cardiac endothelial cell (CEC) migration and capillary density. We hypothesized that T2D differentially affects the CX-40 expression and function in male and female coronary artery (CA) and causes CMD. The objective of this study is to identify the molecular mechanisms underlining the development of T2D-induced CMD in male and female mice.T2D mice were generated by a combination of high-fat diet feeding and a low-dose of streptozotocin (75 mg/kg, i.p.). The oral glucose tolerance was conducted at 4-, 8-, 12-, and 16 weeks after diabetes induction. Coronary flow velocity reserve (CFVR) was used to assess coronary microvascular function in mice. Coronary endothelial function was determined by 1) capillary density measurement in the left ventricle and 2) isometric tension experiment in small CAs (3rd order). CECs from male and female mice were isolated to conduct molecular biological experiments.There was no significant difference in CFVR and capillary density between control male and female mice. However, T2D mice of both sexes showed significant differences in the properties of EDR, CFVR and capillary density. T2D male mice exhibited a significant attenuation of EDR accompanied by impaired endothelium-derived nitric oxide(EDNO)-dependent relaxation and endothelium-dependent hyperpolarization (EDH)-mediated relaxation. On the contrary, there is no difference in EDR between control and diabetic female mice. Capillary density was reduced in T2D mice of both sexes compared to the respective controls. Our RNA sequencing data in CECs revealed that Cx40 is one of the genes which contributes to diabetes-mediated CMD. Systemic Cx40-KO male mice showed reduced EDR, EDH-mediated relaxation and capillary density compared to wild type control. T2D reduced the expression of Cx40 and overexpression of Cx40 restored EDR in CAs and increased capillary density in T2D male mice.T2D impaired coronary microvascular function in both sexes. However, the cause of reduced CFVR was different between diabetic male and female mice. In T2D females, capillary rarefaction was a primary cause of reduced CFVR. In contrast, attenuated EDNO- and EDH-mediated relaxation, reduced capillary density and downregulation of Cx40 contributed to decreased CFVR in T2D male mice. Future studies are required to establish the role of Cx40 in the development of CMD in T2D females. Supported by NIH R01HL142214 and DOD W81XWH2110472 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

MP27-08 RADIAL TYPE LOW-INTENSITY EXTRACORPOREAL SHOCKWAVE THERAPY (LI-ESWT) AS NOVEL THERAPY TO ENHANCE MICROCIRCULATION IN AGING RAT PENIS

You have accessJournal of UrologyCME1 Apr 2023MP27-08 RADIAL TYPE LOW-INTENSITY EXTRACORPOREAL SHOCKWAVE THERAPY (LI-ESWT) AS NOVEL THERAPY TO ENHANCE MICROCIRCULATION IN AGING RAT PENIS Saager Chawla, Yong Sun Choi, Bae Woongjin, Samuel Sorkhi, Jae Hak Jeong, Tung-Chin Hsieh, and M. Raj Rajasekaran Saager ChawlaSaager Chawla More articles by this author , Yong Sun ChoiYong Sun Choi More articles by this author , Bae WoongjinBae Woongjin More articles by this author , Samuel SorkhiSamuel Sorkhi More articles by this author , Jae Hak JeongJae Hak Jeong More articles by this author , Tung-Chin HsiehTung-Chin Hsieh More articles by this author , and M. Raj RajasekaranM. Raj Rajasekaran More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003255.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Physiological aging is associated with the impairment of microvascular function in several organs, including the penis. Low-intensity extracorporeal shock-wave therapy (Li-ESWT) is a non-invasive intervention for the restoration of the pathological alterations of penile tissue. However, the effect of ESWT on penile microvascular function is still unclear. In addition, most previous studies have employed focused ESWT, which is known to target deeper organs, while radial ESWT is more superficial. Thus, our objective is to evaluate the effect of radial type Li-ESWT (targeting superficial penile tissue) on microvascular perfusion (MVP) in an aging rat model and elucidate a possible mechanism of action. METHODS: We anesthetized male rats (n=5; age 15-18 months) and subjected them to radial type Li-ESWT (Fig A-C) while monitoring penile hemodynamics via Laser Speckle Contrast imaging techniques immediately before and after Li-ESWT. The penile shaft was positioned beneath the ESWT applicator (HNT MEDICAL Co., Ltd, Seoul, Korea; Fig B). A level 1 intensity (L1i) (0.12 mJ/mm2) ESWT session for 500 counts at 120 HZ (Fig C) was chosen to increase blood penile microvascular perfusion (PMP). Baseline and peak PMP was assessed by the PeriCam PSI system (Perimed AB, Järfälla, Sweden). This technique quantifies PMP in arbitrary perfusion units (AU) and displays a real-time perfusion image. To assess the involvement of the nitric oxide (NO) pathway, an intracavernosal injection of L-NAME (NO synthase inhibitor) was given [200 µg/kg], and the response to ESWT was recorded again after 15 minutes. RESULTS: ESWT produced a 2-fold increase in PMP (mean±SEM) from baseline (68.456±9.021 AU) to max (163.742±11.787 AU). In addition, the L-NAME injection (n=4) resulted in a ∼40-50% decrease (from 185.293±20.604 AU to 101.008±13.077 AU) in ESWT-induced MVP response. CONCLUSIONS: Our results suggest ESWT is a novel, non-invasive intervention to improve penile circulation and treat erectile and sexual dysfunction following cancer treatment, possibly by improving penile hemodynamics and preventing penile hypoxia and fibrosis. Our findings suggest that the Li-ESWT-induced increase in MVP is mediated by the NO pathway, and future studies are warranted to confirm its efficacy in human subjects. Source of Funding: UCSD Academic Senate © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e365 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Saager Chawla More articles by this author Yong Sun Choi More articles by this author Bae Woongjin More articles by this author Samuel Sorkhi More articles by this author Jae Hak Jeong More articles by this author Tung-Chin Hsieh More articles by this author M. Raj Rajasekaran More articles by this author Expand All Advertisement PDF downloadLoading ...

Factors Associated with Impaired Resistive Reserve Ratio and Microvascular Resistance Reserve

Coronary microvascular dysfunction (CMD) is described as an important subset of ischemia with no obstructive coronary artery disease. Resistive reserve ratio (RRR) and microvascular resistance reserve (MRR) have been proposed as novel physiological indices evaluating coronary microvascular dilation function. The aim of this study was to explore factors associated with impaired RRR and MRR. Coronary physiological indices were invasively evaluated in the left anterior descending coronary artery using the thermodilution method in patients suspected of CMD. CMD was defined as a coronary flow reserve <2.0 and/or index of microcirculatory resistance ≥25. Of 117 patients, 26 (24.1%) had CMD. RRR (3.1 ± 1.9 vs. 6.2 ± 3.2, p < 0.001) and MRR (3.4 ± 1.9 vs. 6.9 ± 3.5, p < 0.001) were lower in the CMD group. In the receiver operating characteristic curve analysis, RRR (area under the curve 0.84, p < 0.001) and MRR (area under the curve 0.85, p < 0.001) were both predictive of the presence of CMD. In the multivariable analysis, previous myocardial infarction, lower hemoglobin, higher brain natriuretic peptide levels, and intracoronary nicorandil were identified as factors associated with lower RRR and MRR. In conclusion, the presence of previous myocardial infarction, anemia, and heart failure was associated with impaired coronary microvascular dilation function. RRR and MRR may be useful to identify patients with CMD.

Microcirculation dynamics in systemic vasculitis: evidence of impaired microvascular response regardless of cardiovascular risk factors.

Systemic vasculitides (SVs) are a highly inflammatory group of diseases characterized by significant cardiovascular (CV) mortality. Microvascular damage closely linked with accelerated atherosclerosis and thrombosis represents a core pathophysiological mechanism contributing to the excess CV risk of patients with SVs. Skin represents an easily accessible tissue facilitating non-invasive microvascular study. In this study we aimed to investigate microcirculation dynamics and associate them with disease-related factors in patients with SVs. We assessed skin microcirculation using laser speckle contrast imaging (LSCI) and vascular reactivity by the post-occlusive reactive hyperaemia (PORH) protocol in a meticulously selected group of patients with SVs without CV disease and compared them to controls, matched for age, sex, BMI and smoking status. Sixty individuals were included in the study, 30 patients and 30 controls. Patients with SVs presented a lower peak magnitude during reperfusion phase (median [interquartile range] 207 [60.1] vs 143.7 [41.0] laser speckle perfusion units, P < 0.001) and lower percentage cutaneous vascular conductance increase (mean (s.d.) 190.0 [49.6]% vs 149.6 [48.9]%, P = 0.002) as compared with controls. Importantly, microvascular damage was correlated with disease duration (P < 0.001, r = -0.563 and P < 0.001, r = 0.442, respectively). For the first time we have shown that patients with SVs exhibit impaired microvascular function and blunted reactivity after occlusion, as this was demonstrated by the LSCI technique. Therefore, skin microcirculation may be a useful, non-invasive method in patients with SVs for the early detection of microvascular dysfunction, which is closely related to the high CV risk that these patients bear.

Quantitative myocardial perfusion during stress using CMR is impaired in healthy Middle Eastern immigrants without CV risk factors

Middle Eastern immigrants constitute a growing proportion of the European population and compared to native Swedes are more insulin resistant, which can contribute to atherosclerosis. Quantitative first pass perfusion (qFPP) using cardiovascular magnetic resonance (CMR) can detect early signs of cardiovascular disease (CVD). The aim was to study if myocardial perfusion differs between healthy male Middle Eastern immigrants and native male Swedes. Eighteen Iraqi- and twelve Swedish born controls, all males, never smokers with no CVD risk factors were included. Global myocardial perfusion at rest and stress was assessed using qFPP and by phase-contrast CMR imaging of coronary sinus flow. Quantitative first pass perfusion analysis (mean ± SD) demonstrated no difference at rest between Iraqi and Swedish males (0.8 ± 0.2 vs 1.0 ± 0.4 ml/min/g, P = 0.38) but lower perfusion during adenosine in Iraqi males (2.9 ± 0.7 vs 3.5 ± 0.7 ml/min/g, P = 0.02). Myocardial perfusion assessed by coronary sinus flow demonstrated similar results with no difference in resting perfusion between groups (0.7 ± 0.2 vs 0.8 ± 0.2 ml/min/g, P = 0.21) but a lower perfusion during adenosine in the Iraqi group (3.0 ± 0.2 vs 3.7 ± 0.6 ml/min/g, P = 0.01. Myocardial perfusion during adenosine stress was lower in healthy Iraqi immigrants compared to Swedish controls suggesting impaired microvascular function and risk of underestimating CVD risk in healthy individuals of Middle Eastern origin.

Peripheral microvascular function is linked to cardiac involvement on CMR in systemic sclerosis-related pulmonary arterial hypertension patients

Abstract Background Systemic sclerosis (SSc) is characterized by vasculopathy, inflammation and fibrosis, and carries one of the worst prognosis in patients who also develop pulmonary arterial hypertension (PAH). Although PAH is a known prognosticator, SSc-PAH patients demonstrate disproportionately high morbidity and mortality, presumably due to cardiac involvement. Purpose To determine the pathophysiology of cardiac involvement in SSc, cardiovascular magnetic resonance (CMR) measures of perfusion, inflammation and fibrosis were compared between SSc-PAH and idiopathic PAH (IPAH) patients. In addition, the correlation between myocardial involvement on CMR and known markers of peripheral microvascular function was assessed. Methods Consecutive patients with SSc-PAH and IPAH of similar age and gender, consecutively underwent CMR imaging, and nailfold capillaroscopy (NC) with post-occlusive reactivity hyperaemia-test (PORH-test). CMR imaging included T2 mapping (inflammation), pre- and postcontrast T1 mapping to calculate the extracellular volume fraction (ECV, fibrosis), and adenosine-stress perfusion imaging to measure the relative myocardial upslope (microvascular perfusion), all measurements were performed on the left ventricle. These CMR markers were related to peripheral microvascular function by NC and PORH-test. Results Twenty SSc-PAH patients (71 [62–77] years, 14% male) and 5 IPAH patients (69 [47–77] years, 20% male) were included. SSc-PAH patients had higher ECV and T2 values than IPAH patients. NC showed lower average capillary density and reduced recruitment of capillaries after PORH in SSc-PAH patients, corresponding to impaired microvascular structure and function. Both higher ECV and T2 values correlated with lower average capillary density (r=−0.454 and −0.583, respectively, p&amp;lt;0.05 for both). Additionally, higher T2 values and lower relative myocardial upslope correlated with worse peripheral microvascular function measured by PORH-test (r=−0.471 and r=0.421, respectively, p&amp;lt;0.05 for both). Conclusion SSc-PAH patients showed higher markers of cardiac fibrosis and inflammation, compared to IPAH patients. These markers correlated well with worse peripheral microvascular function, suggesting that SSc-driven inflammation and vasculopathy concurrently affect peripheral microcirculation and the heart. This may have important therapeutic implications, for which future studies are warranted evaluating the role of anti-inflammatory/anti-fibrotic therapy. Funding Acknowledgement Type of funding sources: None.

Coexistent diabetes is associated with the presence of adverse phenotypic features in patients with hypertrophic cardiomyopathy

Abstract Background Type 2 diabetes mellitus (DM) is associated with worsened clinical outcomes in hypertrophic cardiomyopathy (HCM) patients. The reasons for this adverse prognostic association are incompletely understood. Although distinct entities both HCM and DM share common features of impaired myocardial energetics and coronary microvascular function. Purpose We sought to test the hypothesis that co-existent diabetes is associated with greater reductions in myocardial energetics and perfusion, and higher scar burden in HCM. Research design and methods Seventy-five age- and sex-matched participants with concomitant HCM and DM (HCM-DM, n=20), isolated HCM (n=20), isolated DM (n=20) and healthy volunteers (HV, n=15) underwent 31phosphorus magnetic resonance spectroscopy and cardiovascular magnetic resonance imaging. The HCM groups were matched for HCM phenotype. The DM groups were matched for diabetes treatment, duration, HbA1c, body mass index and hypertension comorbidity. Results ESC sudden cardiac death risk scores were comparable between the HCM groups (HCM: 2.2±1.5%, HCM-DM: 1.9±1.2%; p=NS) and sarcomeric mutations were equally common. HCM-DM had the highest NT-proBNP levels (HV: 42 ng/L [IQR: 35–66], DM: 118 ng/L [IQR: 53–187], HCM: 298 ng/L [IQR: 157–837], HCM-DM: 726 ng/L [IQR: 213–8695]; p&amp;lt;0.0001). Left-ventricular ejection fraction, mass and wall thickness were similar between the HCM groups. HCM-DM displayed a greater degree of fibrosis burden with higher scar percentage, and lower global longitudinal strain compared to the isolated HCM. PCr/ATP was similarly decreased in the HCM-DM and DM (HV: 2.17±0.49, DM: 1.61±0.23, HCM: 1.93±0.38, HCM-DM: 1.54±0.27; p=0.0003). HCM-DM had the lowest stress myocardial blood flow (HV: 2.06±0.42 ml/min/g, DM: 1.78±0.45 ml/min/g, HCM: 1.74±0.44 ml/min/g, HCM-DM: 1.39±0.42 ml/min/g; p=0.004). Conclusions We show for the first time that HCM patients with DM comorbidity display greater reductions in myocardial energetics, perfusion, contractile function and higher myocardial scar burden and serum NT-proBNP levels compared to patients with isolated HCM despite similar LV mass and wall thickness and presence of sarcomeric mutations. These adverse phenotypic features may be important components of the adverse clinical manifestation attributable to a combined presence of HCM and DM. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Diabetes UK