Early Microvascular Dysfunction Research Articles

Progress in molecular mechanisms of coronary microvascular dysfunction.

Coronary microvascular dysfunction is a high-risk factor for many cardiovascular events. However, because of multiple risk factors and limited understanding about its underlying pathophysiological mechanisms, it was easily misdiagnosed. Therefore, its clinical diagnosis and treatment were greatly restricted. Coronary microcirculation refers to microvessels that play an important role in the physiological regulation of myocardial perfusion and regulating blood flow distribution, fulfilling myocardial metabolic needs and moderating peripheral vascular resistance. In coronary microvascular dysfunction, vascular endothelial celldamage is a critical link. The main feature of early coronary microvascular dysfunction is the impairment of endothelial cell proliferation, adhesion, migration, apoptosis, and secretion. Moreover, coronary microvascular dysfunction risk factors include hyperglycemia, lipid metabolism disorders, ischemia-reperfusion injury, aging, and hypertension, similar to coronary atherosclerosis. There are various mechanisms by which these risk factors harm endothelial function and cause microcirculatory disturbances. Therefore, we reviewed coronary microvascular dysfunction's risk factors and pathogenesis in this article.

Nailfold capillaroscopy reveals early peripheral microcirculation abnormalities in children affected by heterozygous familial hypercholesterolemia.

nailfold capillaroscopy (NCF) is a non-invasive imaging technique to seek peripheral microcirculation abnormalities in children and adults. Familial hypercholesterolemia is a genetic disorder caused by mutations capable of increasing blood levels of low-density lipoproteins cholesterol (LDL-C), thus triggering early atherosclerosis. The study aims at evaluating peripheral microcirculation in children with heterozygous familial hypercholesterolemia (HeFH) by means of NFC in comparison with healthy peers and at searching for possible correlations between these abnormalities and patients' lipid panel. thirty-six HeFH patients were enrolled (13 males and 23 females. Mean age 8±3years; age range 3-13years). They had increased levels of total cholesterol (237.9±34.2mg/dl) and LDL-C (154.2±37.6mg/dl). Both values were ≥95th gender and age specific centile. All the subjects in the study underwent NFC. In 69.4% of HeFH children nailfold capillaries were tortuous (p<0.00001 compared to healthy controls). In 41.6% the number of capillaries was markedly reduced (<7 capillaries/mm). The mean number of capillaries was 8.4±2.6/mm in HeFH and 12.2±1.4/mm in healthy controls (p<0.00001). In 100% of the sample size capillary blood flow was slowed down (p<0.00001). In 50% of the sample size a blood "sludge" phenomenon was seen (p<0.00001). No gender differences were detected. Sludge phenomenon was seen only in those with LDL-C over 99th centile (p<0.00001). NCF allows the identification of an early peripheral microvascular dysfunction in HeFH children which is similar to that already seen in atherosclerotic disease. Prompt identification of these capillary abnormalities may be crucial in implementing early prevention measures.

Finding the Road to Rome in Cardiac Allograft Vasculopathy Imaging Surveillance.

Finding the Road to Rome in Cardiac Allograft Vasculopathy Imaging Surveillance.

Spectroscopy detects skeletal muscle microvascular dysfunction during onset of sepsis in a rat fecal peritonitis model

Sepsis is a dysregulated host inflammatory response to infection potentially leading to life-threatening organ dysfunction. The objectives of this study were to determine whether early microvascular dysfunction (MVD) in skeletal muscle can be detected as dynamic changes in microvascular hemoglobin (MVHb) levels using spectroscopy and whether MVD precedes organ histopathology in septic peritonitis. Skeletal muscle of male Sprague–Dawley rats was prepared for intravital microscopy. After intraperitoneal injection of fecal slurry or saline, microscopy and spectroscopy recordings were taken for 6 h. Capillary red blood cell (RBC) dynamics and SO2 were quantified from digitized microscopy frames and MVHb levels were derived from spectroscopy data. Capillary RBC dynamics were significantly decreased by 4 h after peritoneal infection and preceded macrohemodynamic changes. At the same time, low-frequency oscillations in MVHb levels exhibited a significant increase in Power in parts of the muscle and resembled oscillations in RBC dynamics and SO2. After completion of microscopy, tissues were collected. Histopathological alterations were not observed in livers, kidneys, brains, or muscles 6 h after induction of peritonitis. The findings of this study show that, in our rat model of sepsis, MVD occurs before detectable organ histopathology and includes ~ 30-s oscillations in MVHb. Our work highlights MVHb oscillations as one of the indicators of MVD onset and provides a foundation for the use of non-invasive spectroscopy to continuously monitor MVD in septic patients.

Analysis of Microvasculature in Children Recovered from COVID-19 Using Swept-Source OCT/OCTA Technology

ABSTRACT Purpose To analyze structural and vascular changes of the retina and choroid in pediatric patients with coronavirus disease 2019 (COVID-19) using optical coherence tomography (OCT)/OCT angiography (OCTA). Methods This comparative cross-sectional study consists of the COVID-19 group including pediatric COVID-19 patients and the control group including healthy children. Vessel density (VD), central macular thickness,, and choroidal thickness (ChT) measurements were performed using swept-source OCT/OCTA 12 weeks after the recovery from COVID-19. Results The mean VD measurements in the central fovea and nasal quadrants of all three retinal layers and choriocapillaris showed insignificantly lower values in the COVID-19 group when compared to the control group (0:002 < p < 0:05 for all). Similar to VD measurements, insignificant lower ChT measurements were obtained in the central fovea and nasal points in the COVID-19 group. Conclusion OCTA can be used as a non-invasive and valid biomarker in the assessment of early microvascular dysfunction associated with COVID-19.

Early Microvascular Dysfunction: Is the Vasa Vasorum a "Missing Link" in Insulin Resistance and Atherosclerosis.

The arterial vasa vasorum is a specialized microvasculature that provides critical perfusion required for the health of the arterial wall, and is increasingly recognized to play a central role in atherogenesis. Cardio-metabolic disease (CMD) (including hypertension, metabolic syndrome, obesity, diabetes, and pre-diabetes) is associated with insulin resistance, and characteristically injures the microvasculature in multiple tissues, (e.g., the eye, kidney, muscle, and heart). CMD also increases the risk for atherosclerotic vascular disease. Despite this, the impact of CMD on vasa vasorum structure and function has been little studied. Here we review emerging information on the early impact of CMD on the microvasculature in multiple tissues and consider the potential impact on atherosclerosis development and progression, if vasa vasorum is similarly affected.

Lower endothelium-dependent microvascular function in adult breast cancer patients receiving radiation therapy

PurposeCancer patients with a history of radiotherapy are at an increased risk of ischemic heart disease. Preclinical animal studies demonstrate markedly impaired acetylcholine (ACh)-mediated endothelium-dependent vasorelaxation within days to weeks post-irradiation, however, whether microvascular function is affected in the intact human circulation during cancer radiation therapy has yet to be determined.Materials and methodsUsing laser-Doppler flowmetry, microvascular endothelium-dependent and independent responses were evaluated through iontophoresis of acetylcholine (ACh) (part 1, n = 7) and sodium nitroprusside (SNP) (part 2, n = 8), respectively, in women currently receiving unilateral chest adjuvant radiation therapy for breast cancer. Measurements were performed at the site of radiation treatment and at a contralateral control, non-radiated site. Cutaneous vascular conductance (CVC) was calculated by normalizing for mean arterial pressure.Results and ConculsionsIn part 1, patients received an average radiation dose of 2104 ± 236 cGy. A significantly lower peak ACh-mediated endothelium-dependent vasodilation was observed within the radiated microvasculature when compared to non-radiated (radiated: 532 ± 167%, non-radiated 1029 ± 263%; P = 0.02). In part 2, the average radiation dose received was 2251 ± 196 cGy. Iontophoresis of SNP elicited a similar peak endothelium-independent vasodilator response in radiated and non-radiated tissue (radiated: 179 ± 58%, non-radiated: 310 ± 158; P = 0.2). The time to 50% of the peak response for ACh and SNP was similar between radiated and non-radiated microvasculature (P < 0.05). These data provide evidence of early endothelium-dependent microvascular dysfunction in cancer patients currently receiving chest radiation and provide the scientific premise for future work evaluating coronary endothelial function and vasomotor reactivity using more detailed and invasive procedures.

Clinical relevance of combining Thermography with Nailfold Capillaroscopy to improve differentiation between primary and secondary Raynaud’s Phenomenon

Objectives: Early microvascular damage and dysfunction are clinically mirrored in Raynaud’s phenomenon (RP). Currently, nailfold capillaroscopy (NC) is applied to differentiate between primary RP (PRP) and secondary RP (PRP), associated with connective tissue disease. However, abnormal morphology can also be caused due to age-related changes and cardiovascular disease. Thermography (TG) is a non-invasive technique which enables quantification of cutaneous vascular function. An approach using both NC and TG could improve the differentiation between PRP and SRP. Methods: Thirty RP patients (PRP, n = 21; SRP, n = 9) underwent nailfold capillaroscopy and thermography. Morphologic features were scored and patients were categorized according to the guidelines of EULAR Study group on Microcirculation in Rheumatic Diseases. TG of the hand was performed before, directly and ten minutes after a cold challenge test. Baseline images and rewarming curves were analyzed. Results: Capillary abnormalities with NC were found in all SRP patients (9/9) and in 48% (10/21) of PRP patients. Out of 10 PRP patients with altered capillary morphology, 9 (90%) had a cardiovascular disease. For all patients mean temperature was significantly higher 10 minutes after cold induction than before (p &lt; 0,01). The gradient of the rewarming curve was significantly lower in patients with SRP compared to PRP patients (p = 0.015). Conclusions: Nailfold capillaroscopy and thermography can reliably be used to measure microvascular damage and dysfunction. Additional thermography can assist in differentiating between PRP and SRP, especially in elderly patients or in presence of a cardiovascular disease. Keywords: Raynaud’s phenomenon; Nailfold capillaroscopy; Thermography

MICROVASCULAR DYSFUNCTION IN NON-DIABETIC HYPERTENSIVE PATIENTS IS RELATED TO DYSLIPIDAEMIA AND GLUCOSE INTOLERANCE: RESULTS FROM THE DOXAZOSIN RAMIPRIL STUDY

Objective: Microvascular dysfunction relates to increased cardiovascular risk in type 2 diabetes and in the metabolic syndrome. Disturbances in microvascular function are multifactorial, and both low HDL-cholesterol (HDL) and glucose intolerance are important mediators. However, their importance in relation to microvascular function in non-diabetic hypertension is not well studied. Design and method: 71 patients with untreated hypertension (mean BP 154/93 mm Hg) without coronary heart disease were included. The subendocardial viability ratio (SEVR) was calculated by pulse wave analysis (SphygmoCor). Skin microvascular function was assessed by laser Doppler fluxmetry and iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP), and by local heating. Glucose tolerance was estimated by the triglyceride (TG) glucose index (TyG, ln [fasting plasma glucose (mg/dL) x triglycerides (mg/dL)/2]), and by the TG/HDL ratio. Results: Fasting LDL-cholesterol (LDL), HDL and TG 3.48 ± 0.92, 1.40 ± 0.40 and 0.96 [0.61–1.33] mmol/L, respectively. Mean glucose was 5.40 ± 0.55 mmol/L, TyG 6.74 ± 0.59, and median TG/HDL ratio 0.65 [0.43–1.18]. Ach peak flux (mean 42.4 ± 29.8 PU) related to HDL (r = 0.27, P = 0.025). Peak flux by local heating (85.4 ± 43.7 PU) related to HDL (r = 0.29, P = 0.017) and inversely to the LDL/HDL ratio (r = –0.29, P = 0.019). Ach peak flux was inversely related to log(TG/HDL) ratio (r = –0.29, P = 0.016) and tended to relate to TyG (r = –0.23, P = 0.065), while responses to SNP and local heating did not. SEVR (mean 169 ± 29 %) was inversely related to LDL (r = –0.25; P = 0.041), but not to HDL (r = –0.05; P = 0.69). SEVR did not relate to TyG or to log(TG/HDL) ratio. Conclusions: Skin microvascular dysfunction was related to low HDL and to glucose intolerance, whereas coronary microvascular dysfunction was related to increased LDL. Maximum reactive hyperaemia by local heating is a robust method to evaluate skin microvascular function in non-diabetic hypertension. As for patients with type 2 diabetes and the metabolic syndrome, early microvascular dysfunction can be detected in non-diabetic hypertensive patients, and predict cardiovascular risk.

Early myocardial damage and microvascular dysfunction in asymptomatic patients with systemic sclerosis: A cardiovascular magnetic resonance study with cold pressor test.

PurposeCardiac involvement in Systemic Sclerosis (SSc) is increasingly recognized as a mayor cause of morbidity and mortality. The aim of present study is to investigate the early stages of cardiac involvement in SSc by Cardiovascular magnetic resonance (CMR), combining the non-invasive detection of myocardial inflammation and fibrosis using T2 and T1 mapping techniques and the assessment of microcirculatory impairment through perfusion response to cold pressor test (CPT).Methods40 SSc patients (30 females, mean age: 42.1 years) without cardiac symptoms and 10 controls underwent CMR at 1.5 T unit. CMR protocol included: native and contrast-enhanced T1 mapping, T2 mapping, T2-weighted, cineMR and late gadolinium enhancement (LGE) imaging. Microvascular function was evaluated by comparing myocardial blood flow (MBF) on perfusion imaging acquired at rest and after CPT. Native myocardial T1 and T2 relaxation times, extracellular volume fraction (ECV), T2 signal intensity ratio, biventricular volumes and LGE were assessed in each patient.ResultsSSc patients had significantly higher mean myocardial T1 (1029±32ms vs. 985±18ms, p<0.01), ECV (30.1±4.3% vs. 26.7±2.4%, p<0.05) and T2 (50.1±2.8ms vs. 47±1.5ms, p<0.01) values compared with controls. No significant differences were found between absolute MBF values at rest and after CPT; whereas lower MBF variation after CPT was observed in SSc patients (+33 ± 14% vs. +44 ± 12%, p<0.01). MBF variation had inverse correlation with native T1 values (r: -0.32, p<0.05), but not with ECV.ConclusionsMyocardial involvement in SSc at preclinical stage increases native T1, T2 and ECV values, reflecting inflammation and fibrosis, and reduces vasodilatory response to CPT, as expression of microvascular dysfunction.

Association of Markers of Microvascular Dysfunction With Prevalent and Incident Depressive Symptoms: The Maastricht Study.

The etiology of late-life depression (LLD) is still poorly understood. Microvascular dysfunction (MVD) has been suggested to play a role in the etiology of LLD, but direct evidence of this association is scarce. The aim of this study was to investigate whether direct and indirect markers of early microvascular dysfunction are associated with prevalent and incident LLD in the population-based Maastricht Study cohort. We measured microvascular dysfunction at baseline by use of flicker light-induced retinal vessel dilation response (Dynamic Vessel Analyzer), heat-induced skin hyperemic response (laser- Doppler flowmetry), and plasma markers of endothelial dysfunction (endothelial dysfunction; sICAM-1 [soluble intercellular adhesion molecule-1], sVCAM-1 [soluble vascular adhesion molecule-1], sE-selectin [soluble E-selectin], and vWF [Von Willebrand Factor]). Depressive symptoms were assessed with the 9-item Patient Health Questionnaire (PHQ-9) at baseline and annually over 4 years of follow-up (n=3029; mean age 59.6±8.2 years, 49.5% were women, n=132 and n=251 with prevalent and incident depressive symptoms [PHQ-9≥10]). We used logistic, negative binominal and Cox regression analyses, and adjusted for demographic, cardiovascular, and lifestyle factors. Retinal venular dilatation and plasma markers of endothelial dysfunction were associated with the more prevalent depressive symptoms after full adjustment (PHQ-9 score, RR, 1.05 [1.00-1.11] and RR 1.06 [1.01-1.11], respectively). Retinal venular dilatation was also associated with prevalent depressive symptoms (PHQ-9≥10; odds ratio, 1.42 [1.09-1.84]), after full adjustment. Retinal arteriolar dilatation and plasma markers of endothelial dysfunction were associated with incident depressive symptoms (PHQ-9≥10; HR, 1.23 [1.04-1.46] and HR, 1.19 [1.05-1.35]), after full adjustment. These findings support the concept that microvascular dysfunction in the retina, and plasma markers of endothelial dysfunction is involved in the etiology of LLD and might help in finding additional targets for the prevention and treatment of LLD.

Deletion of Thioredoxin-Interacting Protein (TXNIP) Abrogates High Fat Diet-induced Retinal Leukostasis, Barrier Dysfunction and Microvascular Degeneration in a Mouse Obesity Model.

We have shown that a high fat diet (HFD) induces the activation of retinal NOD-like receptor protein (NLRP3)-inflammasome that is associated with enhanced expression and interaction with thioredoxin-interacting protein (TXNIP). Here, the specific contribution of TXNIP and the impact of HFD on retinal leukostasis, barrier dysfunction and microvascular degeneration were investigated. Wild-type (WT) and TXNIP knockout (TKO) mice were fed with normal diet or 60% HFD for 8–18 weeks. TXNIP was overexpressed or silenced in human retinal endothelial cells (REC). At 8 weeks, HFD significantly induced retinal leukostasis and breakdown of the blood–retina barrier in WT mice, but not in TKO mice. In parallel, HFD also induced retinal expression of adhesion molecules and cleaved IL-1β in WT mice, which were also abrogated in TKO mice. In culture, TXNIP overexpression induced NLRP3, IL-1β, and adhesion molecules expression, while TXNIP silencing inhibited them. Blocking the IL-1β receptor significantly suppressed TXNIP-induced expression of NLRP3-inflammasome and adhesion molecules in HREC. Ex-vivo assay showed that leukocytes isolated from WT-HFD, but not from TKO-HFD, induced leukostasis and cell death. At 18 weeks, HFD triggered development of degenerated (acellular) capillaries and decreased branching density in WT but not in TKO mice. Together, HFD-induced obesity triggered early retinal leukostasis and microvascular dysfunction at least in part via TXNIP-NLRP3-inflammasome activation.

Renal perfusion parameters measured by contrast-enhanced ultrasound in healthy dogs demonstrate a wide range of variability in the long-term.

Contrast-enhanced ultrasound may be helpful for detecting early renal microvascular damage and dysfunction in dogs. However, before this noninvasive imaging method can be tested as an early-stage screening tool in clinical patients, an improved understanding of long-term variation in healthy animals is needed. In this prospective, secondary, longitudinal, serial measurements study, variability of contrast-enhanced ultrasound renal perfusion parameters was described for eight healthy dogs, using seven time points and a period of 83weeks. Dogs were sedated with butorphanol (0.4mg/kg), and contrast-enhanced ultrasound of each kidney was performed after an intravenous bolus injection of a microbubble contrast agent (0.04mL/kg). Time-intensity curves were created from regions-of-interest drawn in the renal cortex and medulla. Intensity-related parameters representing blood volume and time-related parameters representing blood velocity were determined. A random-effects model using restricted maximum likelihood was used to estimate variance components. Within-dog coefficient of variation was defined as the ratio of the standard deviation over the mean. Time-related parameters such as time-to-peak, rise and fall time had lowest within-dog variability. Intensity-related parameters such as peak enhancement, wash-in and wash-out area under the curve, total area under the curve, and wash-in and washout rates had high within-dog variability (coefficient of variation>45%). Authors therefore recommend the use of time-related parameters for future studies of renal perfusion. Within-dog variability for bilateral kidney measurements was extremely low, therefore contrast-enhanced ultrasound may be particularly useful for detecting unilateral changes in renal perfusion. Future studies are needed to compare contrast-enhanced ultrasound findings in healthy dogs versus dogs with renal disease.

Microvascular Dysfunction, Inflammation and Tissue Injury in Polymicrobial Sepsis

Sepsis is an overwhelming systemic inflammatory response to infection that may lead to multiple organ failure and shock. One of the characteristics of sepsis is early microvascular dysfunction. In our rat model of polymicrobial sepsis, microvascular dysfunction is detected as early as 3 hours after infection (Bateman et al., Am J Physiol Heart Circ Physiol, 2001). The objective of this study was to examine the timing of microvascular dysfunction in the context of tissue injury and inflammation. Sepsis was induced in male Sprague‐Dawley rats with an intraperitoneal injection of a fecal slurry. Control animals were injected with normal saline. The septic and control animals were then prepared for intravital video microscopy (IVVM) of the right extensor digitorum longus (EDL) muscle. The microvasculature was examined for changes in hemodynamics and erythrocyte oxygen saturation using dual wavelength IVVM for a period of 4 or 6 hours after the injection of the fecal slurry. The data were set aside for future analysis and comparisons were made to our existing hemodynamic data in order to further characterize our sepsis model. Completion of IVVM observations was followed by perfusion fixation and organ collection. Hematoxylin and eosin‐stained sections were graded for pathological and inflammatory changes normalized to tissues collected from naïve control animals. Livers from septic and control animals were both marked by mild leukocyte infiltration in the 4‐hour and 6‐ hour groups, while erythrocyte trapping within the microvasculature did not rise above naïve levels and parenchymal cell architecture was not altered. The EDL muscles from septic animals did not exhibit increased inflammatory cell infiltration. Immunohistochemical labelling of brain sections for rat MHC class II did not show signs of inflammatory microglial activation in coronal slices spanning the entire brain in the septic animals from the 4‐hour and 6‐hour groups. Intravenous injection of Evans Blue prior to perfusion fixation also indicated that the blood‐brain barrier was not broken. On the other hand, septic rats had evidence of increased dye leakage in the liver and kidneys, which was not observed in the saline‐injected animals. Evans Blue leakage was not observed in the intact EDL muscles of either group. The findings of this study suggest that microvascular dysfunction occurs before detectable organ injury in our rat fecal‐induced peritonitis model of sepsis.Support or Funding InformationCollaborative Health Research Projects ( CHRP )This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Abstract P344: Nuclear Factor E2-related Factor 2 (nrf2) Causes Early Microvascular Endothelial Dysfunction and Increased Adma by Activation of the Cox2/tp Receptor Pathway in Mice Infused With Angiotensin II for Three Days

Background: Activation of Nrf2 by tert-buthylhydroquinone (tBHQ) prevents hypertension, oxidative stress, endothelial dysfunction and ADMA in mice infused with angiotensin II (Ang II) for 12 days. However, Nrf2 activation with bardoxolone methyl increased cardiovascular events in diabetic patients within one week. Since we found that tBHQ activated cyclooxygenase (COX)-2 within 3 days, we tested the hypothesis that short-term tBHQ administration to Ang II infused mice increases microvascular dysfunction via COX dependent of PGs and TxA 2 that activate thromboxane-prostanoid receptors (TP-Rs). Methods: Mesenteric resistance arterioles(MRAs)were isolated from mice infused for 3 days with ANG II (400 ng/kg/min) or vehicle and given oral tBHQ (0.1% of water) or vehicle (n=6 mice/group). Endothelial derived relaxation factor (EDRF) was assessed by a myograph and NO and ROS by RatioMaster TM . Results: Compared to vehicle, Ang II infused mice given tBHQ had increased (P&lt;0.05) conscious mean arterial pressure (135±6 vs 115±7 mmHg), urinary 8-Iso prostane (1.5±0.4 vs 1.1±0.2ng/mg creatinine), and decreased EDRF (17± 3 vs 23± 2%) and NO (0.23 ± 0.02 vs 0.35 ± 0.02 Δunits), and enhanced ( P&lt;0.05, ) cellular ROS (0.27 ± 0.02 vs 0.12 ± 0.03 Δunits), mitochondria ROS (0.24 ± 0.02 vs 0.1 ± 0.02 Δunit) and microvascular asymmetric dimethylarginine (ADMA, 77 ± 6 vs 55 ± 7 nmol/mg protein). All these effects of tBHQ were prevented in COX-1 knockout mice drinking parecoxib (COX-2 inhibitor) and in TPR and Nrf2 knockout mice. Conclusions: Activation of Nrf2 increases short term Ang II-induced increases in BP, oxidative stress, ADMA and endothelial dysfunction. These depend on signaling via COX 1 + 2 and TP receptors. Our studies reveal novel dual effects of Nrf2 in Ang II infused mice: increased BP, ROS, ADMA and endothelial dysfunction within 3 days secondary to activation of COX/TPR signaling follow by the opposite effects of Nrf2 on BP, ADMA and vascular function within 12 days. Therefore, blockade of COX-2/TPRs pathway during initiation of Nrf2 therapy may prevent the devastating early adverse effects that have prevented its use in hypertension or diabetes.

Adenosine stress CMR T1-mapping detects early microvascular dysfunction in patients with type 2 diabetes mellitus without obstructive coronary artery disease

BackgroundType 2 diabetes mellitus (T2DM) is associated with coronary microvascular dysfunction in the absence of obstructive coronary artery disease (CAD). Cardiovascular magnetic resonance (CMR) T1-mapping at rest and during adenosine stress can assess coronary vascular reactivity. We hypothesised that the non-contrast T1 response to vasodilator stress will be altered in patients with T2DM without CAD compared to controls due to coronary microvascular dysfunction.MethodsThirty-one patients with T2DM and sixteen matched healthy controls underwent CMR (3 T) for cine, rest and adenosine stress non-contrast T1-mapping (ShMOLLI), first-pass perfusion and late gadolinium enhancement (LGE) imaging. Significant CAD (>50% coronary luminal stenosis) was excluded in all patients by coronary computed tomographic angiography.ResultsAll subjects had normal left ventricular (LV) ejection and LV mass index, with no LGE. Myocardial perfusion reserve index (MPRI) was lower in T2DM than in controls (1.60 ± 0.44 vs 2.01 ± 0.42; p = 0.008). There was no difference in rest native T1 values (p = 0.59). During adenosine stress, T1 values increased significantly in both T2DM patients (from 1196 ± 32 ms to 1244 ± 44 ms, p < 0.001) and controls (from 1194 ± 26 ms to 1273 ± 44 ms, p < 0.001). T2DM patients showed blunted relative stress non-contrast T1 response (T2DM: ΔT1 = 4.1 ± 2.9% vs. controls: ΔT1 = 6.6 ± 2.6%, p = 0.007) due to a blunted maximal T1 during adenosine stress (T2DM 1244 ± 44 ms vs. controls 1273 ± 44 ms, p = 0.045).ConclusionsPatients with well controlled T2DM, even in the absence of arterial hypertension and significant CAD, exhibit blunted maximal non-contrast T1 response during adenosine vasodilatory stress, likely reflecting coronary microvascular dysfunction. Adenosine stress and rest T1 mapping can detect subclinical abnormalities of the coronary microvasculature, without the need for gadolinium contrast agents. CMR may identify early features of the diabetic heart phenotype and subclinical cardiac risk markers in patients with T2DM, providing an opportunity for early therapeutic intervention.

The clinical implications of recent studies on the structure and function of the retinal microvasculature in diabetes.

The retinal blood vessels provide the opportunity to study early structural and functional changes in the microvasculature prior to clinically significant microvascular and macrovascular complications of diabetes. Advances in digital retinal photography and computerised assessment of the retinal vasculature have provided more objective and precise measurements of retinal vascular changes. Clinic- and population-based studies have reported that these quantitatively measured retinal vascular changes (e.g. retinal arteriolar narrowing and venular widening) are associated with preclinical structural changes in other microvascular systems (e.g. infarct in the cerebral microcirculation), as well as diabetes and diabetic complications, suggesting that they are markers of early microvascular dysfunction. In addition, there are new retinal imaging techniques to further assess alterations in retinal vascular function (e.g. flicker-induced vasodilatory response, blood flow and oxygen saturation) in diabetes and complications that result from the effects of chronic hyperglycaemia, inflammation and endothelial dysfunction. In this review, we summarise the latest findings on the relationships between quantitatively measured structural and functional retinal vascular changes with diabetes and diabetic complications. We also discuss clinical implications and future research to evaluate whether detection of retinal vascular changes has additional value beyond that achieved with methods currently used to stratify the risk of diabetes and its complications.

Early microvascular dysfunction in cerebral small vessel disease is not detectable on 3.0 Tesla magnetic resonance imaging: a longitudinal study in spontaneously hypertensive stroke-prone rats

BackgroundHuman cerebral small vessel disease (CSVD) has distinct histopathologic and imaging findings in its advanced stages. In spontaneously hypertensive stroke-prone rats (SHRSP), a well-established animal model of CSVD, we recently demonstrated that cerebral microangiopathy is initiated by early microvascular dysfunction leading to the breakdown of the blood–brain barrier and an activated coagulatory state resulting in capillary and arteriolar erythrocyte accumulations (stases). In the present study, we investigated whether initial microvascular dysfunction and other stages of the pathologic CSVD cascade can be detected by serial magnetic resonance imaging (MRI).FindingsFourteen SHRSP and three control (Wistar) rats (aged 26–44 weeks) were investigated biweekly by 3.0 Tesla (3 T) MRI. After perfusion, brains were stained with hematoxylin–eosin and histology was correlated with MRI data. Three SHRSP developed terminal CSVD stages including cortical, hippocampal, and striatal infarcts and macrohemorrhages, which could be detected consistently by MRI. Corresponding histology showed small vessel thromboses and increased numbers of small perivascular bleeds in the infarcted areas. However, 3 T MRI failed to visualize intravascular erythrocyte accumulations, even in those brain regions with the highest densities of affected vessels and the largest vessels affected by stases, as well as failing to detect small perivascular bleeds.ConclusionSerial MRI at a field strength of 3 T failed to detect the initial microvascular dysfunction and subsequent small perivascular bleeds in SHRSP; only terminal stages of cerebral microangiopathy were reliably detected. Further investigations at higher magnetic field strengths (7 T) using blood- and flow-sensitive sequences are currently underway.

What is the ideal biological marker in diagnosis of diabetic neuropathies?

What is the ideal biological marker in diagnosis of diabetic neuropathies?

Clinical and Functional Correlates of Early Microvascular Dysfunction After Heart Transplantation

Microvascular dysfunction is emerging as a strong predictor of outcome in heart transplant recipients. At this time, the determinants and consequences of early microvascular dysfunction are not well established. The objective of the study was to determine the risk factors and functional correlates associated with early microvascular dysfunction in heart transplant recipients. Sixty-three heart transplant recipients who had coronary physiology assessment, right heart catheterization, and echocardiography performed at the time of their first annual evaluation were included in the study. Microvascular dysfunction was assessed using the recently described index of microcirculatory resistance. The presence of microvascular dysfunction, predefined by an index of microcirculatory resistance >20, was observed in 46% of patients at 1 year. A history of acute rejection and undersized donor hearts were associated with microvascular dysfunction at 1 year, with odds ratio of 4.0 (1.3-12.8) and 3.6 (1.2-11.1), respectively. Patients with microvascular dysfunction had lower cardiac index (3.1±0.7 versus 3.5±0.7 L/min per m(2); P=0.02) and mild graft dysfunction measured by echocardiography-derived left and right myocardial performance indices ([0.54±0.09 versus 0.43±0.09; P<0.01] and [0.47±0.14 versus 0.32±0.05; P<0.01], respectively). Microvascular dysfunction was also associated with a higher likelihood of death, graft failure, or allograft vasculopathy at 5 years after transplant (hazard ratio, 2.52 [95% CI, 1.04-5.91]). A history of acute rejection during the first year and smaller donor hearts were identified as risk factors for early microvascular dysfunction. Microvascular dysfunction assessed using index of microcirculatory resistances at 1 year was also associated with worse graft function and possibly worse clinical outcomes.