Measures Of Microvascular Function Research Articles

Functional improvement of non-infarct related coronary artery stenosis by extensive LDL-C reduction with a PCSK9 antibody: the FITTER trial, microvascular function analysis

Abstract Background Atherosclerosis and microvascular dysfunction are closely linked. Moreover, impaired microvascular function is strongly associated with increased risk on major adverse cardiac events. In patients presenting with acute coronary syndrome (ACS), microvascular function is reduced. PCSK9-inhibitors have shown to reduce plaque burden and lipid load in epicardial vessels and might exhibit similar results on microvascular vessels, thereby improving microvascular function. The FITTER trial offers the unique opportunity to test this hypothesis. Methods The FITTER trial is a multi-center, randomized, double blind, placebo controlled clinical trial for patients presenting with ACS and multi-vessel disease (MVD). After treatment of the culprit lesion, fractional flow reserve (FFR) measurement of non-infarct related artery (non-IRA) lesions was performed. Patients with intermediate, non-critical lesions (FFR: 0.67-0.85) were included in this trial. For exploratory purpose, additional physiological assessment of the non-IRA included coronary flow reserve (CFR) and microvascular resistance index (IMR) measurements. Microvascular function was evaluated using a pressure- and temperature-sensitive guidewire and a bolus thermodilution method. Participants were randomized and treated for 12 weeks with either evolocumab or placebo in addition to high-intensity statin therapy. Staged reevaluation was done at 12 weeks. After repeated physiology testing, PCI was performed if deemed necessary. Pre-defined exploratory analysis includes the absolute and relative difference in change between CFR and IMR from baseline to follow up in the non-IRA. PCSK9 inhibition might result in a relatively larger increase of CFR and larger decrease of IMR. Results Between March 2020 and August 2023, a total of 150 patients were included in the trial. In 61 patients (88.5% male, age 65.3 ± 9.1 years, 23.0% STEMI, 70.5% non-STEMI, 6.6% UAP) successful baseline and follow-up measurements of microvascular function were performed. Complete results will be available at the beginning of March 2024. The primary- and secondary endpoints will be submitted for late-breaking clinical trials selection. The results of this abstract will include a per vessel analysis of coronary artery microvascular function. Conclusion The FITTER trial will provide new insights on the potential of extensive LDL-C reduction with a PCSK9 antibody on microvascular coronary artery function in patients presenting with ACS and MVD.

Traditional cardiovascular risk factors and coronary microvascular disease in women and men- a single center study

Abstract Introduction Coronary microvascular dysfunction (CMD) is a common, often missed, cause for effort intolerance and angina symptoms, and is associated with adverse clinical outcomes. Risk factors for the development of CMD have not been fully elucidated, and studies examining sex associated differences in traditional cardiovascular risk factors (TCRs) for obstructive coronary artery disease (CAD) in patients with CMD have yielded conflicting results. Although several non-invasive methods for the evaluation of CMD exist, currently, catheter-based invasive assessment is the gold standard for the diagnosis of coronary microvascular dysfunction. Purpose To examine the association between TCR and CMD and sex associated differences in TCR, in a prospective cohort of patients undergoing invasive microvascular function evaluation in a large tertiary medical center. Methods In this single center, prospective registry, we enrolled patients with non-obstructive CAD undergoing clinically indicated invasive assessment of coronary microvascular function between November 2019 and March 2023. Measurements of microvascular function included CFR, IMR, RRR as well as FFR. Pathologic CFR was defined as <2.5 or <2. Associations between coronary microvascular dysfunction, traditional cardiovascular risk factors, and sex were assessed using univariate and multivariate regression models. Results Overall, 245 patients with non-obstructive CAD were included in the analysis (62.9% female; median age 68 (interquartile range [IQR]: 59,75). Microvascular dysfunction was diagnosed in 141 patients (57.5%). The prevalence of microvascular dysfunction was similar in women and men in the entire cohort (59.0% vs. 57.0%; p=0.77). In 41 patients diagnosed with functional microvascular dysfunction there were more women than men (70.7% vs. 29%). When using a threshold of CFR<2.5 no association was found between traditional risk factors for coronary atherosclerosis and CMD regardless of whether CMD was structural or functional. In women, but not in men, older age and the presence of previous ischemic heart disease were associated with lower coronary flow reserve (CFR) (β=-0.29; p<0.01 and β=-0.15; p=0.05, respectively) and lower resistive reserve ratio (RRR) (β=-0.28; p<0.01 and β=-0.17; p=0.04, respectively). When using a threshold of <2.0 for CFR similar results were found. Conclusion The prevalence of TCRs was similar in patients with and without CMD. In women, older age and previous IHD were associated with lower CFR and RRR values while no association between TCRs and indices of CMD was found in men. It is likely that there are other, currently unknown risk factors for CMD as well as unique risk factors for each of its endotypes, beyond TCRs. It is unclear which parameter of microvascular dysfunction is the most accurate, and whether different parameters should be used in women and men. Large-scale multi-center studies to further evaluate these issues are needed.Variables associated with CMDStudy inclusion process

Pilot Assessment of Piezoelectric Transducers as a Cost-Effective Alternative to EndoPAT

Introduction: Current microvascular assessments may not be practical or accessible requiring experienced personnel and/or ongoing equipment costs. Piezoelectric transducers can reliably obtain finger blood pressure waves, similar to peripheral arterial tonometry devices; thus, they could be used to estimate microvascular function. We aimed to validate piezoelectric transducers as an alternative measure of microvascular function compared to EndoPAT. Methods: Twenty-five adults (aged 20–64 years) completed reactive hyperemia (5 min forearm circulatory occlusion and 3 min recovery) with piezoelectric transducers on the middle fingers and EndoPAT probes on the index fingers. Average area under the curve (AUC) of the pulse wave signal for the occluded and control arms was determined at baseline, every 30 s post-occlusion, and 10 s around the peak response. Microvascular function index (MFI) was calculated as the ratio of AUC post-occlusion to AUC baseline in the test arm, then normalized to the same ratio in the control arm. MFI at each time point was correlated with the reactive hyperemia index (RHI) from the EndoPAT. Results: The greatest significance was found between RHI and MFI at 10 s around the peak response (Spearman’s r = 0.67, p = 0.0002; Pearson’s r = 0.76, p = 0.00001). Conclusion: MFI is a reusable and user-friendly microvascular function assessment that could provide better access to vascular health screening.

Microvascular Dysfunction and Whole-Brain White Matter Connectivity: The Maastricht Study.

Microvascular dysfunction is involved in the development of various cerebral disorders. It may contribute to these disorders by disrupting white matter tracts and altering brain connectivity, but evidence is scarce. We investigated the association between multiple biomarkers of microvascular function and whole-brain white matter connectivity. Cross-sectional data from The Maastricht Study, a Dutch population-based cohort (n=4326; age, 59.4±8.6 years; 49.7% women). Measures of microvascular function included urinary albumin excretion, central retinal arteriolar and venular calibers, composite scores of flicker light-induced retinal arteriolar and venular dilation, and plasma biomarkers of endothelial dysfunction (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and von Willebrand factor). White matter connectivity was calculated from 3T diffusion magnetic resonance imaging to quantify the number (average node degree) and organization (characteristic path length, global efficiency, clustering coefficient, and local efficiency) of white matter connections. A higher plasma biomarkers of endothelial dysfunction composite score was associated with a longer characteristic path length (β per SD, 0.066 [95% CI, 0.017-0.114]) after adjustment for sociodemographic, lifestyle, and cardiovascular factors but not with any of the other white matter connectivity measures. After multiple comparison correction, this association was nonsignificant. None of the other microvascular function measures were associated with any of the connectivity measures. These findings suggest that microvascular dysfunction as measured by indirect markers is not associated with whole-brain white matter connectivity.

Biomarkers of microvascular dysfunction and cerebral white matter connectivity: The Maastricht Study

AbstractBackgroundMicrovascular dysfunction may contribute to the development of various cerebral disorders, including cognitive dysfunction, dementia, and certain forms of depression. The suggested mechanism through which microvascular dysfunction contributes to these disorders is by disrupting white matter tracts and altering brain connectivity, but evidence is scarce. We investigated the association between multiple biomarkers of microvascular function and cerebral white matter connectivity.MethodWe used cross‐sectional data from The Maastricht Study, a Dutch population‐based cohort (n = 4,326, mean±SD age 59.4±8.6 years, 49.7% women). Measures of microvascular function included urinary albumin excretion, central retinal arteriolar and venular calibers (CRAE and CRVE), a composite score of flicker light‐induced retinal arteriolar and venular dilation response, and a composite score of plasma biomarkers of endothelial dysfunction (soluble intercellular adhesion molecule‐1 (sICAM‐1), soluble vascular cell adhesion molecule‐1 (sVCAM‐1), soluble E‐selectin (sE‐selectin) and von Willebrand factor (vWF)). White matter connectivity was calculated from 3T diffusion MRI to quantify the number (average node degree) and organization (characteristic path length, global efficiency, clustering coefficient and local efficiency) of cerebral white matter connections.ResultA higher endothelial dysfunction composite score was associated with a longer characteristic path length (beta per SD: 0.066 (95% confidence interval: 0.017; 0.114)) after adjustment for sociodemographic, lifestyle and cardiovascular factors, but not with any of the other white matter connectivity measures. All other measures of microvascular dysfunction were not associated with any of the connectivity measures after adjustments.ConclusionThe present study suggests that microvascular dysfunction, as quantified by a set of various measures, is not consistently associated with cerebral white matter connectivity. Only a composite score of plasma biomarkers of endothelial dysfunction was associated with a longer characteristic path length, with a longer characteristic path length being indicative for a topographically less integrated and less efficient cerebral network. Future cross‐sectional and longitudinal studies are needed to further understand the role of microvascular dysfunction in the development of cerebral disorders.

The diagnostic value of left-anterior-descending artery velocity assessed by transthoracic Doppler echocardiography for microvascular dysfunction in stenotic left-anterior-descending artery

Abstract Background Index of microcirculatory resistance (IMR) has been used as a clinical measure of microvascular function. Transthoracic Doppler echocardiography (TDE) can provide information on the functional status of coronary artery circulation. This study aims to assess the diagnostic value of left-anterior-descending artery (LAD) flow velocity by TDE for microvascular dysfunction. Methods Consecutive patients who were scheduled for elective percutaneous coronary intervention (PCI) for LAD lesions were prospectively enrolled in the single tertiary-care center between April 2020 and July 2021. Pre-PCI LAD diastolic peak velocity (DPV) by TDE at rest and hyperemia were measured. By invasive coronary angiography, quantitative coronary angiography and invasive wire-based physiological indices including fractional flow reserve (FFR) and index of microcirculatory resistance (IMR) were measured. Results A total of 104 patients were studied. Median FFR and IMR values were 0.70 (0.60–0.74) and 20.68 (14.92–31.69), respectively. No significant relationship was observed between FFR and IMR. The prevalence of microvascular dysfunction defined as IMR≥25 was 39.4%. Basal DPV was 25 (20–33) cm/sec, and hyperemic DPV was 51 (41–67) cm/sec. In lesions with IMR≥25, reference diameter (RD) was significantly greater [2.63 (2.22–3.19) mm vs 2.39 (2.09–2.66) mm, p=0.019], basal DPV was lower [26 (18–29) cm/sec vs 29 (22–37) cm/sec, p=0.022)] and hyperemic DPV was lower [49 (19–54) cm/sec vs 56 (42–70) cm/sec, p=0.023] compared to lesions with IMR<25. ROC analysis showed basal DPV and RD are significant predictors of IMR≥25 [basal DPV: AUC 0.633 (0.525–0.742), best cutoff 29cm/sec RD: AUC 0.636 (0.523–0.750), best cutoff 2.84mm]. Multivariable logistic regression analysis showed basal DPV<29cm/sec and RD>2.84mm are independent predictors for IMR≥25 [Odds ratio: 3.08 (1.22–7.78), p=0.017; odds ratio 4.40 (1.55–12.50), p=0.005]. Conclusion Basal DPV by non-invasive pre-PCI TDE and reference diameter can predict lesions with coexisting microvascular dysfunction in LAD territory with functionally significant lesions without the need of vasodilator-induced hyperemia and a wire-based invasive physiological measurement. Funding Acknowledgement Type of funding sources: None.

Aortic stiffness and aortic-brachial stiffness mismatch as markers of renal dysfunction in hypertension

Purpose The dismal combination of hypertension and chronic kidney disease potentiates both cardiovascular disease and loss of renal function. Research points to the importance of arterial and left ventricular stiffening in this process but few studies have compared aspects of central and peripheral hemodynamics in relation to renal function in hypertension. Materials and methods We investigated 107 hypertensive individuals with renal function ranging from normal to severe dysfunction with pulse wave analysis to obtain central blood pressures (BP), augmentation index, carotid-femoral and carotid-radial pulse wave velocity (cfPWV, crPWV), aortic-to-brachial stiffness mismatch (cfPWV/crPWV), endothelial function by forearm flow-mediated vasodilation and myocardial microvascular function by subendocardial viability ratio, and indices of left ventricular structure (left ventricular mass index and relative wall thickness, RWT) and diastolic function (left atrial volume index, E/A, and E/é). Results Mean age was 58 years, BP 149/87 mm Hg, 9% had cardiovascular disease, and 31% were on antihypertensive treatment. Mean estimated glomerular filtration rate (eGFR) was 74 (range 130–21) ml/min × 1.73 m2. Whereas cfPWV and cfPWV/crPWV were independently related to eGFR (r = −0.20, p = 0.002, r = −0.16, p = 0.01), central diastolic BP (r = 0.21, p = 0.04), RWT (r = −0.34, p = 0.001), E/é (r = −0.39, p < 0.001) and E/A (r = 0.27, p = 0.01) were related to eGFR in bivariate correlations, but these findings were not retained in multivariate analyses. Remaining markers of hypertensive heart disease and measures of microvascular function were not related to eGFR. Conclusion Increased aortic stiffness and aortic-to-brachial stiffness mismatch are independently related to reduced eGFR in hypertensive patients, suggesting an important role for aortic stiffness in the evolution of hypertension-mediated renal dysfunction. Aortic stiffness and aortic-brachial stiffness mismatch may be useful early markers to find hypertensive patients at risk for decline in renal function.

Mechanistic study of the effect of Endothelin SNPs in microvascular angina - Protocol of the PRIZE Endothelin Sub-Study.

Microvascular angina is a common cause of ischemia with non-obstructive coronary arteries (INOCA) and limited therapeutic options are available to those affected. Endothelin-1 (ET-1) is a potent vasoconstrictor implicated in the pathophysiology of microvascular angina. A large randomised, double blinded, placebo controlled crossover trial, the PRecIsion medicine with ZibotEntan in microvascular angina (PRIZE) trial is currently underway, investigating an endothelin receptor antagonist - Zibotentan, as a new drug treatment for microvascular angina. The trial uses a 'precision medicine' approach by preferential selection of those with higher ET-1 expression conferred by the PHACTR1 minor G allele single nucleotide polymorphism (SNP). The incidence of this SNP occurs in approximately one third of the population therefore a considerable number of screened patients will be ineligible for randomisation and the treatment phase of the trial. In the PRIZE Endothelin (ET) Sub-Study, patients screened out of the PRIZE trial will be genotyped for other genetic variants in the ET-1 pathway. These will be correlated with phenotypic characteristics including exercise tolerance, angina severity and quantitative measures of microvascular function on cardiovascular MRI as well as mechanistic data on endothelin pathway signalling. The study will provide a comprehensive genotype and phenotype bio-resource identifying novel ET-1 genotypes to inform the potential wider use of endothelin receptor antagonists for this indication.

Development and feasibility of quantitative dynamic cardiac imaging for mice using μSPECT

BackgroundDespite growing interest in coronary microvascular disease (CMVD), there is a dearth of mechanistic understanding. Mouse models offer opportunities to understand molecular processes in CMVD. We have sought to develop quantitative mouse imaging to assess coronary microvascular function. MethodsWe used 99mTc-sestamibi to measure myocardial blood flow in mice with MILabs U-SPECT+ system. We determined recovery and crosstalk coefficients, the influx rate constant from blood to myocardium (K1), and, using microsphere perfusion, constraints on the extraction fraction curve. We used 99mTc and stannous pyrophosphate for red blood cell imaging to measure intramyocardial blood volume (IMBV) as an alternate measure of microvascular function. ResultsThe recovery coefficients for myocardial tissue (RT) and left ventricular arterial blood (RA) were 0.81 ± 0.16 and 1.07 ± 0.12, respectively. The assumption RT = 1 − FBV (fraction blood volume) does not hold in mice. Using a complete mixing matrix to fit a one-compartment model, we measured K1 of 0.57 ± 0.08 min−1. Constraints on the extraction fraction curve for 99mTc-sestamibi in mice for best-fit Renkin–Crone parameters were α = 0.99 and β = 0.39. Additionally, we found that wild-type mice increase their IMBV by 22.9 ± 3.3% under hyperemic conditions. ConclusionsWe have developed a framework for measuring K1 and change in IMBV in mice, demonstrating non-invasive µSPECT-based quantitative imaging of mouse microvascular function.

Influences on myocardial perfusion in non-obstructive coronary disease: an observational quantitative perfusion mapping study

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This study was supported by a Clinical Training Research Fellowship (K. Knott) from the British Heart Foundation and directly and indirectly from the Biomedical Research Centre at University College London Hospitals and Barts Heart Centre. Background Cardiovascular magnetic resonance (CMR) with automated inline perfusion mapping permits rapid fully automated non-invasive myocardial blood flow (MBF, ml/g/min). Understanding the microvascular component of MBF would help optimize epicardial coronary artery disease detection and potentially serve as an independent diagnostic / therapeutic target. Purpose To explore MBF influences at stress and rest in patients with unobstructed epicardial coronary arteries. Methods 242 participants (mean age 56.9 years) from 5 European centers with unobstructed epicardial coronary arteries and no myocardial scar underwent adenosine vasodilator perfusion mapping at stress and rest. The factors influencing MBF were determined using univariate and multivariate linear regression analyses. Results Mean rest perfusion was 0.91+/-0.24ml/g/min. Rest perfusion was higher in females (0.97+/-0.22ml/g/min vs 0.83 +/- 0.24ml/g/min) and lower in patients on beta blockers. Mean stress MBF was 2.53+/-0.82ml/g/min. Factors independently associated with reduced stress MBF were increasing age, diabetes, increasing left ventricular mass (LVMi) and the use of beta blockers. The predicted stress MBF can be obtained from the equation MBF = 2.66–0.015(age-60)–0.013(LVMi-57)-0.405(diabetes)–0.365(beta blocker). This means stress MBF falls 10% over 19 years and that diabetes drops the MBF by the equivalent of being 27 years older. These changes are large: for example, a 70-year-old diabetic would have 30% lower stress MBF than a 35 year-old non-diabetic. Conclusions In the absence of obstructive epicardial coronary disease, stress MBF falls with age, diabetes, increased LV mass and beta-blockers. These data may help develop normal reference ranges, input to other modelling (eg CT FFR), and they advance perfusion mapping as a measure of microvascular function. Abstract Figure. Summary of the determinants of perfusion

Putting the muscle back in microcirculation: From firefighters to near-infrared spectroscopy.

Putting the muscle back in microcirculation: From firefighters to near-infrared spectroscopy.

Clinical Associations of Vascular Stiffness, Microvascular Dysfunction, and Prevalent Cardiovascular Disease in a Black Cohort: The Jackson Heart Study.

BackgroundMeasures of vascular dysfunction are related to adverse cardiovascular disease (CVD) outcomes in non‐Hispanic, White populations; however, data from Black individuals are limited. We aimed to investigate the associations between novel hemodynamic measures and prevalent CVD in a sample of Black individuals.Methods and ResultsAmong older Black participants of the Jackson Heart Study, we assessed noninvasive vascular hemodynamic measures using arterial tonometry and Doppler ultrasound. We assessed 5 measures of aortic stiffness and wave reflection (carotid‐femoral pulse wave velocity, pulse wave velocity ratio, forward pressure wave amplitude, central pulse pressure, and augmentation index), and 2 measures of microvascular function (baseline and hyperemic brachial flow velocity). Using multivariable logistic regression models, we examined the relations between vascular hemodynamic measures and prevalent CVD. In models adjusted for traditional CVD risk factors, higher carotid‐femoral pulse wave velocity (odds ratio [OR],1.25; 95% CI, 1.01–1.55; P=0.04), lower augmentation index (OR, 0.84; 95% CI, 0.70–0.99; P=0.05), and lower hyperemic brachial flow velocity (OR, 0.77; 95% CI, 0.65–0.90; P=0.001) were associated with higher odds of CVD. After further adjustment for hypertension treatment, lower augmentation index (OR, 0.84; 95% CI, 0.70–0.99; P=0.04) and hyperemic brachial flow velocity (OR, 0.79; 95% CI, 0.67–0.94; P=0.006), but not carotid‐femoral pulse wave velocity (OR, 1.23; 95% CI, 0.99–1.051; P=0.06), were associated with higher odds of CVD.ConclusionsIn a sample of older Black individuals, more severe microvascular damage and aortic stiffness were associated with prevalent CVD. Further research on hemodynamic mechanisms that contribute to cardiovascular risk among older Black individuals is merited.

A Mendelian Randomization Study Provides Evidence That Adiposity and Dyslipidemia Lead to Lower Urinary Albumin-to-Creatinine Ratio, a Marker of Microvascular Function.

Urinary albumin-to-creatinine ratio (ACR) is a marker of diabetic nephropathy and microvascular damage. Metabolic-related traits are observationally associated with ACR, but their causal role is uncertain. Here, we confirmed ACR as a marker of microvascular damage and tested whether metabolic-related traits have causal relationships with ACR. The association between ACR and microvascular function (responses to acetylcholine [ACH] and sodium nitroprusside) was tested in the SUMMIT study. Two-sample Mendelian randomization (MR) was used to infer the causal effects of 11 metabolic risk factors, including glycemic, lipid, and adiposity traits, on ACR. MR was performed in up to 440,000 UK Biobank and 54,451 CKDGen participants. ACR was robustly associated with microvascular function measures in SUMMIT. Using MR, we inferred that higher triglyceride (TG) and LDL cholesterol (LDL-C) levels caused elevated ACR. A 1 SD higher TG and LDL-C level caused a 0.062 (95% CI 0.040, 0.083) and a 0.026 (95% CI 0.008, 0.044) SD higher ACR, respectively. There was evidence that higher body fat and visceral body fat distribution caused elevated ACR, while a metabolically "favorable adiposity" phenotype lowered ACR. ACR is a valid marker for microvascular function. MR suggested that seven traits have causal effects on ACR, highlighting the role of adiposity-related traits in causing lower microvascular function.

The oral glucose tolerance test-derived incremental glucose peak is associated with greater arterial stiffness and maladaptive arterial remodeling: The Maastricht Study

BackgroundDaily glucose variability may contribute to vascular complication development irrespective of mean glucose values. The incremental glucose peak (IGP) during an oral glucose tolerance test (OGTT) can be used as a proxy of glucose variability. We investigated the association of IGP with arterial stiffness, arterial remodeling, and microvascular function, independent of HbA1c and other confounders.MethodsIGP was calculated as the peak minus baseline plasma glucose value during a seven-point OGTT in 2758 participants (age: 60 ± 8 years; 48% women) of The Maastricht Study, an observational population-based cohort. We assessed the cross-sectional associations between IGP and arterial stiffness (carotid-femoral pulse wave velocity [cf-PWV], carotid distensibility coefficient [carDC]), arterial remodeling (carotid intima-media thickness [cIMT]; mean [CWSmean] and pulsatile [CWSpuls] circumferential wall stress), and microvascular function (retinal arteriolar average dilatation; heat-induced skin hyperemia) via multiple linear regression with adjustment for age, sex, HbA1c, cardiovascular risk factors, lifestyle factors, and medication use.ResultsHigher IGP was independently associated with higher cf-PWV (regression coefficient [B]: 0.054 m/s [0.020; 0.089]) and with higher CWSmean (B: 0.227 kPa [0.008; 0.446]). IGP was not independently associated with carDC (B: − 0.026 10−3/kPa [− 0.112; 0.060]), cIMT (B: − 2.745 µm [− 5.736; 0.245]), CWSpuls (B: 0.108 kPa [− 0.054; 0.270]), retinal arteriolar average dilatation (B: − 0.022% [− 0.087; 0.043]), or heat-induced skin hyperemia (B: − 1.380% [− 22.273; 19.513]).ConclusionsIGP was independently associated with aortic stiffness and maladaptive carotid remodeling, but not with carotid stiffness, cIMT, and microvascular function measures. Future studies should investigate whether glucose variability is associated with cardiovascular disease.

Serum Phosphate and Microvascular Function in a Population-Based Cohort.

Higher serum phosphate is associated with cardiovascular events and all-cause mortality. Explanations of this association have focused on large vessel calcification and stiffness. Studies suggest that a higher serum phosphate induces microvascular dysfunction, but relationships in humans with direct measures of microvascular function are lacking. We performed a cross-sectional analysis of 3189 community-living participants that underwent skin capillaroscopy, laser-Doppler flowmetry, and flicker light-induced retinal vessel responses. We used linear regression to assess the association between serum phosphate and each microvascular outcome. The primary outcome was skin capillary recruitment during postocclusive peak reactive hyperemia by capillaroscopy. Secondary outcomes included capillary recruitment during venous congestion, heat-induced skin hyperemic response, flicker light-induced retinal arteriolar, and venular dilation. The mean age of the cohort was 59±8 years, 48% were women, 7% had an eGFR <60 ml/min per 1.73 m2, and the mean serum phosphate concentration was 3.2±0.5 mg/dl. A 1 mg/dl higher serum phosphate was independently associated with a 5.0% lower postocclusive capillary recruitment (95% CI, -10.0% to -0.1%). Results were similar for capillary recruitment with venous congestion (-4.5%; 95% CI, -9.8% to 0.7%). A 1 mg/dl higher serum phosphate was also independently associated with a 0.23% lower retinal venular dilation in response to flicker light (95% CI, -0.44% to -0.02%). A higher serum phosphate was not associated with change in flicker light-induced retinal arteriolar dilation or heat-induced skin hyperemic response, however a higher serum phosphate was associated with a lower heat-induced skin hyperemic response among men (-149% [95% CI, -260 to -38] per 1 mg/dl higher serum phosphate) but not women (P interaction, 0.01). Higher serum phosphate concentrations, even within the normal range, are associated with microvascular dysfunction in community-living individuals. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_09_20_CJN02610319.mp3.

Reactive Hyperemia is Decreased in Black Subjects with Heart Failure Despite Equal Prescription of Guideline-Directed Medical Therapy

Background Impaired vascular function in Black Americans contributes to a higher risk of heart failure compared to other race/ethnicities. Augmentation of digital pulse volume amplitude (PVA) in response to hyperemia is a novel measure of microvascular function that is partially nitric oxide dependent, and is related to adverse cardiovascular events. We sought to examine augmentation of digital PVA in blacks and whites with heart failure to determine if guideline-directed medical therapy (GDMT) ameliorates racial differences in vascular function. Methods We assessed vascular function in 139 subjects with heart failure with reduced ejection fraction. Using digital pulse amplitude tonometry (EndoPAT), we estimated the reactive hyperemia index (RHI). Generalized linear models were used to determine if race was predictive of the RHI after adjustment for age, sex, blood pressure, diabetes, body mass index, lipid profile, serum creatinine, and number of vasodilator drugs as GDMT. Results Compared with whites, blacks were younger (51 ± 4 vs. 59 ± 11 years, P Figure ). Conclusion Black race is associated with impaired microvascular vasodilatory function, despite equal prescription of GDMT. Whether the vascular impairment seen in Blacks is associated with increased risk for adverse clinical outcomes in HF warrants further investigation.

Measurement of microvascular function in patients presenting with thrombolysis for ST elevation myocardial infarction, and PCI for non-ST elevation myocardial infarction.

In this prospective study, we compared the invasive measures of microvascular function in two subsets: patients with pharmacoinvasive thrombolysis for STEMI, and patients undergoing percutaneous coronary intervention (PCI) for NSTEMI. The study consisted of 17 patients with STEMI referred for cardiac catheterisation post thrombolysis, and 20 patients with NSTEMI. Coronary physiological indexes were measured in each patient before and after PCI. The median pre-PCI index of microcirculatory function (IMR) at baseline was significantly higher in the STEMI group than the NSTEMI group (26 units vs. 15 units, p = 0.02). Following PCI, IMR decreased in both groups (STEMI 20 units vs. NSTEMI 14 units, p = 0.10). There was an inverse correlation between post PCI IMR and left ventricular ejection fraction (LVEF) (r = -0.52, p = 0.001). Furthermore, post PCI IMR was an independent predictor of index admission LVEF in the total population (β = -0.388, p = 0.02). Invasive measures of microvascular function are inferior in a pharmacoinvasive STEMI group compared to a clinically stable NSTEMI group. In the STEMI population, the IMR following coronary intervention appears to predict LVEF.

Doppler Versus Thermodilution-Derived Coronary Microvascular Resistance to Predict Coronary Microvascular Dysfunction in Patients With Acute Myocardial Infarction or Stable Angina Pectoris

Coronary microvascular resistance is increasingly measured as a predictor of clinical outcomes, but there is no accepted gold-standard measurement. We compared the diagnostic accuracy of 2 invasive indices of microvascular resistance, Doppler-derived hyperemic microvascular resistance (hMR) and thermodilution-derived index of microcirculatory resistance (IMR), at predicting microvascular dysfunction. A total of 54 patients (61 ± 10 years) who underwent cardiac catheterization for stable coronary artery disease (n = 10) or acute myocardial infarction (n = 44) had simultaneous intracoronary pressure, Doppler flow velocity and thermodilution flow data acquired from 74 unobstructed vessels, at rest and during hyperemia. Three independent measurements of microvascular function were assessed, using predefined dichotomous thresholds: (1) coronary flow reserve (CFR), the average value of Doppler- and thermodilution-derived CFR; (2) cardiovascular magnetic resonance (CMR) derived myocardial perfusion reserve index; and (3) CMR-derived microvascular obstruction. hMR correlated with IMR (rho = 0.41, p <0.0001). hMR had better diagnostic accuracy than IMR to predict CFR (area under curve [AUC] 0.82 vs 0.58, p <0.001, sensitivity and specificity 77% and 77% vs 51% and 71%) and myocardial perfusion reserve index (AUC 0.85 vs 0.72, p = 0.19, sensitivity and specificity 82% and 80% vs 64% and 75%). In patients with acute myocardial infarction, the AUCs of hMR and IMR at predicting extensive microvascular obstruction were 0.83 and 0.72, respectively (p = 0.22, sensitivity and specificity 78% and 74% vs 44% and 91%). We conclude that these 2 invasive indices of coronary microvascular resistance only correlate modestly and so cannot be considered equivalent. In our study, the correlation between independent invasive and noninvasive measurements of microvascular function was better with hMR than with IMR.

Automated Measurement of Microvascular Function Reveals Dysfunction in Systemic Sclerosis: A Cross-sectional Study.

The aim of our study was to determine whether an automated capture and analysis system could detect differences in structure and function of sublingual microvessels in patients with systemic sclerosis (SSc) compared to healthy controls. Intravital microscopy of the sublingual microcirculation was automatically captured and analyzed in 40 patients with SSc and 10 age-matched healthy controls. Total and perfused microvascular density were lower in patients with SSc compared with controls (total microvascular density: 2471 ± 134 µm/mm2 vs 3067 ± 197 µm/mm2, p = 0.020; perfused microvascular density: 1708 ± 92 µm/mm2 vs 2192 ± 144 µm/mm2, p = 0.009). However, the relative percentage of perfused to total microvascular density was similar between SSc and controls (72 ± 2% vs 71 ± 2%, respectively, p = 0.429). Mean red blood cell (RBC) fraction, which indicates the longitudinal tube hematocrit of microvessel segments, was lower in patients with SSc compared with controls (69 ± 1% vs 77 ± 1%, respectively, p < 0.001). Perfused boundary region (PBR), a marker of endothelial glycocalyx barrier properties, was higher in patients with SSc compared with controls (2.1 ± 0.0 µm vs 1.9 ± 0.0 µm, respectively, p = 0.012), suggestive of a dysfunctional glycocalyx. There was an inverse association of PBR with perfused microvascular density (r = -0.40, p = 0.004) and RBC fraction (r = -0.80, p < 0.001). Our results indicate that automated capture and analysis of sublingual microvessel segments produces detailed, objective microvascular structural and functional data that have allowed us to distinguish patients with SSc from controls. These data suggest that microvascular structural and functional abnormalities present in patients with SSc could be at least partly due to a dysfunctional glycocalyx.

PP.20.01] REPRODUCIBILITY OF DIFFERENT MEASURES OF ENDOTHELIAL FUNCTION

Objective: Brachial artery flow-mediated dilatation (FMD) to determine endothelial function is an investigator-demanding method. Impaired endothelial function as measured by FMD is known to be associated with cardiovascular risk factors. Local thermal hyperaemia (LTH) of the skin measured with a laser Doppler flow imager is less demanding and may serve as an alternative. We investigated the reproducibility of LTH and its correlation with FMD. In addition, the association of FMD with post-occlusive dermal hyperaemia (PORH), a widely used measure of microvascular function, was assessed. Design and method: FMD, LTH and PORH were measured in 27 healthy men (8 smokers) on two occasions, one week apart, at the same time of the day. FMD, measured with ultra-sound, was expressed as the maximal percentage increase in brachial artery diameter during reactive hyperaemia. LTH peak was defined as the maximal dermal blood flow (DBF) response within the first ten minutes and LTH plateau as the average DBF response during the last five minutes of 35 heating in arbitrary units (a.u.), measured with a laser Doppler flow imager. PORH Peak and AUC were measured at the volar site of the left forearm just under the pressure cuff, using a laser speckle imager. Results: Coefficients of variation (n = 27) of the LTH peak and plateau response were 18% and 21%, of the PORH peak and area under the curve (AUC) response both 13% and of the FMD response 21%. The LTH peak and plateau response and FMD response were not correlated, whereas the PORH AUC was correlated with FMD (r = 0.46, p < 0.05) and PORH Peak correlated with LTH Plateau (r = 0.58, p < 0.05). Conclusions: The reproducibility of the LTH plateau response and FMD response were almost equal in this study. In addition, as LTH and FMD did not correlate, these responses appear to provide different information. PORH, however, correlated partly with both LTH and FMD and should be further investigated as a possible alternative for FMD in long-term outcome studies.