Macrovascular Changes Research Articles

The effects of resistance training on cardiovascular factors and anti-inflammation in diabetic rats

Diabetes induces a range of macrovascular and microvascular changes, which lead to significant clinical complications. Although many studies have tried to solve the diabetic problem using drugs, it remains unclear. In this study, we investigated whether resistance exercise affects cardiovascular factors and inflammatory markers in diabetes. The study subjected Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which have genetically induced diabetes mellitus, to a resistance exercise program for 12 weeks and assessed the levels of cardiovascular factors and inflammatory markers using western blotting analysis, ELISA, and immunohistochemistry. During the training period, OLETF + exercise (EX) group exhibited lower body weight and reduced glucose levels when compared with OLETF group. Western blotting analysis, ELISA, and immunohistochemistry revealed that the levels of PAI-1, VACM-1, ICAM-1, E-selectin, TGF-β, CRP, IL-6, and TNF-α were decreased in OLETF + EX group when compared with the OLETF group. Moreover, the anti-inflammatory markers, IL-4 and IL-10, were highly expressed after exercise. Therefore, these results indicate that exercise may influence the regulation of cardiovascular factors and inflammatory markers, as well as help patients with metabolic syndromes regulate inflammation and cardiovascular function.

Influence of metabolic profile on macro- and microvascular damage in patients with moderate, high and very high cardiovascular risk

Aim. To evaluate the association of the triglyceride-glucose index (TGI) with micro- and macrovascular changes in patients with moderate, high and very high cardiovascular risk (CVR).Material and methods. The study included 134 men and 129 women aged 40 to 65 years with a SCORE2 ten-year risk of adverse cardiovascular events of 2,5% or more. Based on a detailed survey, a comprehensive physical and paraclinical examination, the relationship between TGI and CVR factors was assessed using Pearson correlation analysis, followed by a linear correlation strength assessment using the Chaddock scale. Modeling of the TGI association with macro- and microvascular damage in patients with moderate CVD was performed using multivariate logistic regression.Results. According to regression analysis, increased TGI was associated with an increased risk of both macrovascular and microvascular changes. Similar results were obtained using multivariate logistic regression with model adjustment for age, sex, body mass index, waist circumference, smoking, hypertension, family history of premature cardiovascular disease, lipid-lowering therapy, and glucose-lowering therapy. An increased level of TGI was associated with an increase in the odds ratio (OR) of carotid atherosclerosis (OR 1,73, 95% confidence interval 1,27-2,36, P for trend <0,001), an increase in the urine albumin-creatinine ratio (OR 1,61, 95% CI 1,22-2,13, P for trend <0,001) and a decrease in estimated glomerular filtration rate (OR 1,67, 95% CI 1,10-1,50, P for trend =0,02).Conclusion. TGI is an important and accessible additional risk factor for both micro- and macrovascular damage in everyday clinical practice, regardless of whether the patient has diabetes. For personalized CVR stratification and determination of further management tactics for patients with moderate, high and very high CR, the maximum available factors should be assessed, each of which can influence the disease course, while the summation of the main and additional factors significantly worsens the prognosis.

Predictive value of cerebrovascular time constant for delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage

Time constant of the cerebral arterial bed (τ) is a transcranial Doppler (TCD) based metric that is expected to quantify the transit time of red blood cells from the insonation point to the arteriole-capillary boundary during a cardiac cycle. This study aims to assess the potential of τ as an early predictor of delayed cerebral ischemia (DCI). Consecutive patients (56 ± 15 years) treated for aneurysmal subarachnoid haemorrhage were included in the study. τ was assessed through a modelling approach that involved simultaneous recordings of arterial blood pressure and cerebral blood flow velocity (CBFV) from TCD's first recordings. 71 patients were included. 17 patients experienced DCI. τ was significantly shorter in patients who later developed DCI: 187 ± 64 ms vs. 249 ± 184 ms; p = 0.040 with moderate effect size (rG = 0.24). Logistic regression showed that there was a significant association between increased CBFV, shortened τ, and the development of DCI (χ2 = 11.54; p = 0.003) with AUC for the model 0.75. Patients who had both shortened τ and increased CBFV were 20 times more likely to develop DCI (OR = 20.4 (2.2–187.7)). Our results suggest that early alterations in τ are associated with DCI after aSAH. The highest performance of the model including both CBFV and τ may suggest the importance of both macrovascular and microvascular changes assessment.

The impact of duration and control of type 1 diabetes mellitus on microvascular function is strongly modified by the gene for connexin 37

Abstract Introduction Type 1 diabetes mellitus (T1DM) is almost inevitably accompanied by microvascular dysfunction. This could be responsible for cardiovascular events and is supposed to be caused mainly by long-term exposure to hyperglycemia. Nevertheless, relationship between duration and control of T1DM with microvascular complications can be modified by genetic factors; one of frequently discussed candidate genes is connexin37 (cx37), namely its rs1764391 (C1019>T (Pro319>Ser) polymorphism. We already observed sex specific association between cx37 polymorphism with macrovascular changes but also with retinopathy, neuropathy and diabetic foot. In the recent study, we analyzed if the impact of duration and control of T1DM on directly measured microvascular function is modified by cx37 gene polymorphism. Methods In 235 men and 227 women with T1DM (mean age 43.6 ± 13.6 years; mean duration of diabetes 22.1 ± 11.3 years) wide spectrum of clinical, laboratory and hemodynamic parameters was measured. Establishment of microvascular function measured by photoplethysmography (detection of blood volume changes in the microvasculature in lower extremities) and calculated as Oliva/Roztocil index (ORI), was analyzed. Cx37 gene polymorphism was measured by PCR-RFLP. The correlation (Pearson’s correlation coefficient) between duration of T1DM and ORI was calculated including analysis of potential modification by control of diabetes (HbA1c) and by cx37 gene polymorphism and standardized for potential confounders (sex, age, smoking, presence of hypertension, central obesity …) by multiple regression. The analysis was conducted separately for duration of T1DM below (n=256) and above (n=206) 20 years as the linear relationship between ORI and T1DM duration tends to change accordingly. Results In patients with T1DM, distribution of Cx37 genotypes did not differ from the already described populations (TT/CT/CC: 9.7/44.4/45.9%). In patients with satisfactory control of diabetes (HbA1c<53 mmol/mol; n=105) we detected worsening (increase) of ORI with duration of diabetes only in TT homozygotes and CT heterozygotes for duration of at least 20 years (r=0.6, p=0.006), while in patients with unsatisfactory control (HbA1c>60 mmol/mol;n=270), we detected worsening of ORI with duration of diabetes only in CC homozygotes, both for duration 0-20 years (r=0.35, p=0.03) and for duration of at least 20 years (r=0.47, p=0.03). Conclusion Microvascular function in satisfactory controlled T1DM was worsening with diabetes duration only in T allele carriers of Cx37 gene, the worsening was detected only for patients with duration longer than 20 years. However, if T1DM control was insufficient, microcirculation was worsening only in CC homozygotes.

Investigating Diabetic Foot Pathophysiology and Amputation Prevention Strategies through Behavioral Modification

Diabetic foot complications stem from intricate interactions between macrovascular and microvascular changes, neuropathy, inflammation, immune responses, hyperglycemia, oxidative stress, and infection susceptibility. Macrovascular factors like atherosclerosis lead to tissue ischemia, while microvascular dysfunction worsens perfusion deficits. Neuropathy contributes significantly to such complications, causing sensory loss, motor problems, and autonomic dysfunction. This results in unnoticed injuries, muscle atrophy, deformities, and dry skin, elevating the risk of non-healing wounds and infections. Inflammation and immune responses amplify tissue damage and hinder healing. Chronic hyperglycemia generates advanced glycation end products, stiffening tissues, while oxidative stress exacerbates damage. Mitochondrial dysfunction further compromises cellular energy production, worsening tissue repair challenges. These multifaceted factors collectively contribute to diabetic foot complications. The impact of modifiable behavior factors such as smoking, heavy alcohol consumption, and exercise on the risk of lower extremity amputation (LEA) in diabetic patients is also not to be ignored. Substantial data had identified increased LEA risk from smoking and heavy alcohol intake and reduced risk from regular exercise. The cumulative impact of these behaviors underscores the significance of behavior modification in preventing LEA and enhancing the well-being of diabetic patients. Understanding these mechanisms is vital for developing effective preventive strategies, diagnostics, and treatments, addressing the impact of diabetic foot complications on individuals and healthcare systems.

Impact of youth onset type 2 diabetes during pregnancy on microvascular and cardiac outcomes

AimsTo examine the impact of pregnancy on microvascular and cardiovascular measures in women with youth-onset T2D. MethodsMicrovascular and cardiovascular measures were compared in in a cohort of 116 women who experienced a pregnancy of ≥ 20 weeks gestation and 291 women who did not among women in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. ResultsCox regression models adjusted for participant characteristics at baseline including age, race/ethnicity, household income, diabetes duration, HbA1c (>6%), and BMI, demonstrated those who experienced pregnancy had 2.76 (1.38–5.49; p = 0.004) fold increased risk of hyperfiltration (eGFR ≥ 135 ml/min/1.73 m2), compared to those without a pregnancy. No differences were observed in rates of retinopathy (48.9% vs. 41.1%) or neuropathy (23.3% vs. 16.3%) in women who experienced pregnancy vs. women who did not, respectively. In fully adjusted models, pregnancy did not impact changes in echocardiographic or arterial stiffness compared to changes in women who were never pregnant. ConclusionsThese results indicate that pregnancy increases the risk of hyperfiltration in women with youth-onset T2D, but not other micro or macrovascular complications. The rates of vascular complications are very high in youth-onset T2D potentially obscuring micro- and macrovascular changes attributable to pregnancy.Clinical Trial Information: ClinicalTrials.gov numbers,NCT01364350andNCT02310724.

Evaluation of outcome of acoustic reflex tests in patients with type 2 diabetes mellitus: a cross-sectional study

PurposeType 2 diabetes mellitus (T2DM) may induce micro-vascular and macro-vascular changes that can lead to neuropathic changes which may affect the auditory pathway resulting in hearing loss. The study aims to evaluate the outcome of ipsilateral and contralateral acoustic reflex (AR) parameters and reflex decay tests (RDT) in patients with T2DM, and the relationship between average AR parameters, and duration and control of T2DM.MethodsAn analytical cross-sectional study was conducted in a tertiary care setup in 126 subjects which included 42 subjects with T2DM between 30 and 60 years of age, age-matched with 84 non-diabetic subjects. The subjects were evaluated for pure tone average (PTA), speech identification score (SIS), AR parameters [acoustic reflex threshold (ART), acoustic reflex amplitude (ARA), acoustic reflex latency (ARL)] and RDT.ResultsThe subjects with T2DM showed increased PTA in both ears when compared to the subjects with no disease. No significant difference was found in the SIS between both groups. There was no significant difference in the ART and ARL between the two groups. There was a significant difference in the ipsilateral and contralateral ARA at 500 Hz, 1000 Hz and broadband noise (BBN) when compared between the diabetic and non-diabetic groups. No significant difference was found between average AR parameters and duration and control of T2DM.ConclusionT2DM increases hearing thresholds and reduces ipsilateral and contralateral AR at lower frequencies and BBN. Duration and control of T2DM do not affect the AR parameters.

Obstructive Sleep Apnea and Right Ventricular Remodeling: Do We Have All the Answers?

Obstructive sleep apnea (OSA) syndrome is a very important sleep-related breathing disorder related to increased cardiovascular and overall morbidity and mortality. It is associated with multisystemic target organ damage due to micro- and macrovascular changes, resulting in carotid and coronary atherosclerosis, increased arterial stiffness, retinal damage, microalbuminuria, and cardiac remodeling. The latter consists of left ventricular (LV) hypertrophy, as well as diastolic and systolic dysfunction. The increasing burden of evidence shows that OSA also induces right ventricular (RV) remodeling that is more difficult to diagnose, but may also contribute to cardiovascular morbidity and mortality in these patients. Conventional echocardiographic parameters for assessment of RV systolic and diastolic functions are often not sensitive enough to detect subclinical and subtle changes in the RV function. Data published over last decade showed that the RV function, particularly systolic, is impaired in OSA patients and related with its severity. However, the introduction of speckle tracking echocardiography and the particularly longitudinal strain enabled the earlier detection of functional and mechanical changes even when conventional echocardiographic parameters of RV systolic function remained unchanged. The 3D echocardiography provided the possibility to evaluate the entire RV, with its unique shape, and determine 3D RV ejection fraction, which is comparable with results obtained by cardiac magnetic resonance. The use of this modality also provided a new insight into RV systolic (dys)function in OSA patients. In addition to weight loss, which has been proven very helpful in OSA patients, the only approved therapeutic approach is continuous positive airway pressure (CPAP) therapy. It is very important to assess if this therapy induces any improvement in cardiac structure and function. Limited data on this topic show that RV longitudinal strain is a more sensitive parameter rather than other conventional RV indexes in the detection of improvement in RV systolic function and mechanics. The aim of this review article is to summarize the current understanding of RV structural, functional, and mechanical changes in patients with OSA. Furthermore, we sought to provide the current knowledge regarding the effect of CPAP therapy on RV reverse remodeling in OSA patients.

Pecan-enriched diet improves cholesterol profiles and enhances postprandial microvascular reactivity in older adults

Pecan-enriched diets have been linked to improved lipid metabolism; however, the impact of pecans on vascular health has yet to be examined. We hypothesized that 4 weeks of a pecan-enriched diet would improve fasting and postprandial blood lipids and vascular function compared with a nut-free diet. In this randomized control study, 44 older adults (59 ± 6 years) consumed 68 g of pecans/d (pecan; n = 21) or avoided all nuts (control; n = 23) for 4 weeks. At pre- and post-diet visits, fasting and postprandial blood lipids, macrovascular (by flow-mediated dilation), and microvascular (tissue saturation index reactive hyperemia [RH] kinetics by continuous-wave near-infrared spectroscopy) function were assessed. From the pre- to post-diet visit, there were greater reductions in fasting total cholesterol (pecan: –14 ± 4.0 vs control: –0.2 ± 5.4 mg/dL; P = .04), low-density lipoprotein (LDL) cholesterol (pecan: –15 ± 3.7 vs control: +1.9 ± 4.4 mg/dL; P = .01), non–high-density lipoprotein cholesterol (pecan: –15 ± 3.6 vs control: –0.5 ± 4.8 mg/dL; P = .02), LDL particle number (pecan: –126 ± 51 vs control: +43 ± 42 nmol/L; P = .01), and LDL medium (pecan: –34 ± 13 vs control: +16 ± 11 nmol/L; P < .01), for pecan vs control. Further, postprandial triglyceride was suppressed for pecan (P = .01) compared with control (P = .78). Postprandial RH slope (P = .04) and RH time to half (P = .004) was different by group, driven by improvements in pecan vs control. However, fasting macro- and microvascular function was unaffected. Daily pecan consumption for 4 weeks improved fasting and postprandial blood lipids and microvascular reactivity in older adults. Because changes in microvascular function typically precipitate macrovascular changes, long-term pecan consumption may improve vascular health and reduce risk for cardiovascular events. This trial was registered at clinicaltrials.gov (NCT04385537).

Capillary microarchitectural changes are independent of disease activity in acromegaly.

Although atherosclerosis-related macrovascular complications are well known in acromegaly, studies on endothelial function and arteriolar level are contradictory. In order to test the hypothesis, microvascular changes associated with macrovascular changes in acromegaly, we aimed to evaluate microvascular changes in nailfold capillaries and carotid intima-media thickness (CIMT) in patients with acromegaly. In this cross-sectional observation study, of total 70 patients with acromegaly [ten (14.3%) were active acromegaly (AA), 60 (85.7%) were controlled acromegaly (CA)] and 74 healthy controls were enrolled. Microvascular structure was evaluated using the nailfold video capillaroscopy, and CIMT was measured using ultrasonography. The median number of capillaries was less [10 no./mm (min-max: 5-16) vs. 11 no./mm (min-max: 9-15); p=0.001] in the acromegaly group than in the controls. Capillaries below 6-8 per/mm was more common in the acromegaly patients [six (8.6%) vs. one (1.4%); p=0.046]. All capillaroscopic parameters were similar among the patients with CA or AA. CIMT levels were higher in the acromegaly group than in the control group [0.60mm (0.43-0.86) vs. 0.38mm (0.27-0.59); p<0.001], and AA patients had higher CIMT than CA patients (p=0.037). None of the clinical or laboratory parameters including growth hormone and IGF-1 were related to capillaroscopic parameters or CIMT. Decreased capillary number was the major capillaroscopic finding in acromegaly and there was no significant difference between active and controlled cases, but CIMT was found to be higher in the active group. Increased CIMT levels in acromegaly were not associated with capillary changes. Large-scale, prospective studies are needed to make a definite conclusion about the effect of the disease activity on nailfold capillaries and its association with macrovascular changes.

PS-BPC03-8: MORNING BLOOD PRESSURE SURGE AND THE VASCULATURE: A COMPARISON BETWEEN YOUNG DIPPERS AND NON-DIPPERS FROM THE AFRICAN-PREDICT STUDY

Background and aim: Adverse changes in large arteries and retinal microvascular calibres are predictors for hypertension and stroke. These adverse changes were reported in response to the suppressed night-time dipping as well as in hypertensive individuals with exaggerated morning surge. However, it is unknown whether young healthy individuals with normal morning surge, but with non-dipping night-time blood pressure profile, will already present with early onset of micro and macrovascular changes. We investigated the relationship of morning surge with retinal vessel calibres and large artery stiffness in healthy young dippers and non-dippers. Methods: We included black and white participants (N = 323), aged 20–30 years, determined sleep-trough surge. We determined central retinal artery and vein equivalents from fundus images, as well as carotid-femoral pulse wave velocity. Results: Dippers had a greater morning surge (within normal range) (p &lt; 0.001) and a greater proportion of individuals with exaggerated morning surge (p &lt; 0.001). In dippers only, we found a positive relationship between central retinal artery equivalent and morning surge (p = 0.040). In sensitivity analysis, the association between central retinal artery equivalent and morning surge in dippers lost significance (p = 0.09) when 24-hour diastolic blood pressure was replaced with night-time diastolic blood pressure. However, an independent negative association between central retinal artery equivalent and night-time diastolic blood pressure (p &lt; 0.001) emerged. Normal morning surge of dippers was positively associated with central retinal artery equivalent (dependent on night-time dipping). Conclusion: Normal night-time dipping may therefore be involved in preserving retinal arteriolar diameter of dippers, which may reflect a lower vascular resistance.

Remember Diabetes Mellitus When Assessing Renal Blood Flow in Hypertensive Patients: A Renal Frame Count Study.

Diabetes mellitus (DM) progresses with dynamic changes in renal blood flow and glomerular filtration. Renal frame count (RFC) is a cineangiographical parameter that is capable of presenting microvascular and macrovascular changes in the renal blood flow. We aimed to show the changes, which may be caused by DM in the perfusion, by using RFC. Totally 110 hypertensive subjects consisting of 55 DM patients and 55 non-DM patients as a control group who underwent renal angiography were retrospectively enrolled in the study. The RFC values of all subjects were calculated and compared to each other. There were no significant differences between the two groups in terms of basal demographic characteristics and antihypertensive medications. The RFC value measured from the left renal artery was significantly lower in the DM group compared to the control group. (11.33±2.55, 13.49±3.24, respectively; p<0.001). The RFC value measured the right renal artery was detected to be significantly lower in the DM group than the control group (11.07±2.43, 13.33±3.07, respectively; p<0.001). The mean RFC value was also significantly lower in the DM group compared to the control group (11.20±2.18, 13.41±2.84, respectively;p<0.001). In the multivariable linear regression analysis conducted to determine the variables which may affect mean RFC, it was determined that only the HbA1C level had a relation with the mean RFC value. To the best of our knowledge, this is the first study to show the influence of DM on RFC. RFC seems to decrease in DM subjects.

Establishment of an in vivo Streptozotocin-Induced Type 1 Diabetes Model Recapitulating Early Brain and Retinal Fibrosis

INTRODUCTION: Diabetes has risen to one of the top American public health concerns. The hyperglycemic state of chronic diabetes leads to microvascular and macrovascular changes that predispose patients to delayed wound healing and organ fibrosis. The validation of models to specifically detect early, quantifiable fibrotic changes seen in the diabetic state is of fundamental importance for understanding the diabetic pathophysiology and exploring earlier management options. Here, we investigated if we could detect early signs of internal fibrosis in a streptozotocin (STZ) diabetic mouse model by quantifying α-SMA expression in various organs using flow cytometry. METHODS: We used a low-dose STZ-induced T1DM model. T1DM was confirmed via sustained hyperglycemia (&gt;250mg/dl) over 8-10 weeks. Delayed healing of full thickness wounds was confirmed by tracking wound healing progression over two weeks. Wounded and unwounded skin samples were analyzed histologically to quantify collagen deposition as a sign of fibrosis. Organ fibrosis was assessed in a semi-high-throughput manner using flow cytometry to quantify the percentage of alpha-Smooth Muscle Actin (α-SMA) positive cells in diabetic versus normoglycemic controls. RESULTS: Combining STZ with post-injection glucose treatment yielded highly efficient 100% pathogenesis with 100% survival. Diabetic mice showed signs of hyperglycemia, polyuria, and delayed wound healing. Histological analysis indicated a greater increase in epidermal height and lower levels of collagen deposition in diabetic wounds. After 10-12 weeks of hyperglycemia, we observed elevated α-SMA in brain and retinal tissues. DISCUSSION: The STZ model has previously presented cumbersome, costly, and time-intensive limitations for the study of diabetic complications. Here we tested a quantitative method for detecting early signs of fibrosis using flow cytometry. The higher percentage of α-SMA positive cells in retinal and brain tissue of diabetic mice suggests fibrosis of these tissues. We argue that this is a suitable method to study early diabetic complications. Keywords: diabetes, hyperglycemia, fibrosis, murine

The clinical effect of radiotherapy on pulpal microvasculature: a systematic review.

Introduction/objectives Radiotherapy (RT) has a detrimental effect on the histomorphology of oral tissues. Patients undergoing RT are at risk of developing macrovascular and microvascular changes, which can lead to significant clinical consequences. Despite advances in RT delivery systems, radiation injury remains a modern-day clinical problem. The aim of this systematic review is to investigate the available evidence regarding the impact of RT to the dental pulp and the clinical manifestations of these effects.Data and sources A multi-database search (PubMed, Medline, Embase and CINAHL) was performed to identify related papers published from inception until November 2021. An additional manual search was performed to identify further articles. The data extracted from relevant papers were analysed according to the outcomes selected in this review.Study selection The search generated seven articles eligible for analysis with a total of 2,709 teeth included. RT dose exposure ranged from 30-71.2 Gray with a common finding that RT decreases the number of teeth responding to pulp sensibility testing.Conclusions Knowledge related to the impact of RT on dental pulp is limited and based on weak evidence and a low-level quality of studies. Future studies should incorporate exact RT doses to the teeth and use replicable pulpal testing methods. Understanding the pulpal status post-RT remains an important consideration as dental extractions should be avoided in this cohort due to the risk of osteoradionecrosis.

Evaluation of Circulating Platelet Extracellular Vesicles and Hypertension Mediated Organ Damage.

Elevated circulating platelet-derived extracellular vesicles (pEVs) have been associated with arterial hypertension. The role of hypertension-mediated organ damage (HMOD) to induce EV release is still unknown. We studied the micro- and macro-vascular changes (retinal vascular density and pulse wave velocity), endothelial function (flow-mediated vasodilation of brachial artery and finger plethysmography), and assessed the psychosocial status (anxiety and depression) in hypertensive patients to determine their relationship with EV release. Pulse wave velocity showed a significant positive correlation with pEVs (r = 0.33; p = 0.01). Systolic blood pressure (SBP) negatively correlated with retinal vascularity. The superficial retinal vascular plexus density in the whole image showed a significant negative correlation with 24 h SBP (r = −0.38, p < 0.01), day-SBP (r = −0.35, p = 0.01), and night-SBP (r = −0.27, p = 0.04). pEVs did not show significant associations with microvascular damage (retinal vascular density), endothelial function (flow-mediated vasodilation of brachial artery and finger plethysmography), or psychosocial status (anxiety and depression). Our results indicate that the pEV levels were associated with macrovascular damage measured by PWV, whereas no significant association between pEVs and microvascular damage, endothelial function, or emotional status could be detected. The potential utility of pEV in clinical practice in the context of HMOD may be limited to macrovascular changes.

Plasma Biomarkers of Amyloid and Neurodegeneration predictive of Neuropathologic Scales of Cerebrovascular Disease

AbstractBackgroundBlood‐based biomarkers of amyloid and neurodegeneration are increasingly used in clinical trials and entering clinical use. Differentially mapping the plasma markers to post‐mortem neuropathology in a community‐based sample is critical for interpretation.MethodWe identified 64 Mayo Clinic Study of Aging (MCSA) participants with antemortem plasma markers (Aβ42, Aβ40, NfL, T‐tau, Aβ42/40 ratio) measured on the Quanterix Simoa HD‐1 analyzer and with postmortem neuropathologic assessments of Alzheimer’s pathology (Braak tangle stage, Thal phase, neuritic plaque burden) and cerebrovascular pathology (Strozyk scale focused on macrovascular brain changes and Kalaria scale focused on detailed micro‐ and macro‐ vascular brain changes). Weighted linear regression models with adjustment for time between plasma markers and death were conducted with exact permutation tests to evaluate the relationships between antemortem plasma and postmortem neuropathology markers.ResultHigher plasma NfL levels and Aβ42/40 ratio were associated with both cerebrovascular neuropathologic scales (p&lt;0.05) but were not associated with Braak neurofibrillary tangle stage, neuritic plaque score, or Thal stage (p&gt;0.5). Plasma T‐tau was not associated with any pathological assessment. Plasma Aβ42/40 and NfL explained up to 18% of the variability in cerebrovascular neuropathologic scales.ConclusionIn this community sample of participants predominantly without dementia, plasma markers for amyloid (Aβ42/40) and neurodegeneration (NfL) were associated with cerebrovascular neuropathology at autopsy. NfL is a non‐specific marker of brain injury, therefore, its association with cerebrovascular neuropathology was in the expected direction. The association between greater cerebrovascular neuropathology and elevated Aβ42/40 requires further investigation. These findings provide evidence that cerebrovascular disease may significantly influence levels of plasma biomarkers proposed for Alzheimer’s disease. This information will be important to consider for accurate clinical interpretation of the proposed biomarkers.

Erectile Function, Sexual Satisfaction, and Cognitive Decline in Men From Midlife to Older Adulthood.

Vascular theories of cognitive aging have focused on macrovascular changes and cognitive decline. However, according to the artery-size hypothesis, microvascular changes, such as those that underlie changes in erectile function, may also play an important role in contributing to cognitive decline. Thus, we examined associations between erectile function, sexual satisfaction, and cognition starting in middle age because this represents a transition period where declines in these areas emerge. We examined 818 men from the Vietnam Era Twin Study of Aging across three waves at mean ages 56, 61, and 68. Erectile function and sexual satisfaction were measured using the International Index of Erectile Function. Cognitive performance was measured using factor scores for episodic memory, executive function, and processing speed. We tested multilevel models hierarchically, adjusting for demographics, frequency of sexual activity, and physical and mental health confounders to examine how changes in erectile function and sexual satisfaction related to changes in cognitive performance. Lower erectile function at baseline was related to poorer performance in all cognitive domains at baseline and faster declines in processing speed over time. However, baseline sexual satisfaction was unrelated to cognitive performance. Decreases in erectile function and sexual satisfaction were both associated with memory decline. Decreasing sexual health may signal an increased risk for cognitive decline. We discuss potential mechanisms, including microvascular changes and psychological distress. Discussing and tracking sexual health in middle-aged men may help to identify those likely to face memory decline.

Macrovascular and microvacular changes in diabetes mellitus type 1 are modified by the gene for connexin 37 in men but not in women

Abstract Introduction Diabetes mellitus type 1 (DMT1) is a strong risk factor for macrovascular and microvascular disease. These vascular pathologies can be strongly modified by genetic factors. One of intensively investigated candidate genes is the gene for connexin37 (Cx37) (C1019&amp;gt;T (Pro319&amp;gt;Ser). The role of this gene in cardiovascular disease and diabetes mellitus had been already described in several different populations, but not in patients with DMT1. Purpose To determine whether the presence of macrovascular and microvascular changes is modified by Cx37 gene polymorphism in middle aged men and women diagnosed with DMT1 of similar age and with similar duration of DMT1. Methods In 253 men (mean age 43.0±14.5 years; mean duration of diabetes 22.6±14.0 years) and 245 women (mean age 43.9±12.9 years; mean duration of diabetes 21.3±10.5 years) macrovascular disease was measured by duplex B-Mode ultrasound and classified as Belcaro score (1–4) in carotid and femoral arteries. Microvascular disease was assessed by the presence of retinopathy, nephropathy, neuropathy and diabetic foot. Cx37 gene polymorphism was established by PCR. Results In men, in CC homozygotes we observed more advanced macrovascular changes in carotid arteries (Belcaro score more than 2) than in CT heterozygotes/TT homozygotes (7.5 vs. 15.2%; p=0.031). No significant differences were found in changes of carotid arteries in women and in changes of femoral arteries both in men and women. Regarding microvascular changes, in men, in CC homozygotes, the diabetic foot was diagnosed more frequently than in CT heterozygotes/TT homozygotes (7.4 vs. 16.1%; p=0.046). No significant differences were found in women and in other types of microvascular disease both in men and women. Conclusion These results indicate that macrovascular and microvascular changes in DMT1 can be modified by Cx37 gene polymorphism in men, but not in women. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by the Ministry of Health of the Czech Republic, grant No. NU20-01-00083 and by Ministry of Health of the Czech Republic under its conceptual development of the research organization program (Institute for Clinical and Experimental Medicine–IKEM, IN 00023001. All rights reserved.

Erectile dysfunction, generalized vascular disease and the long term effects of smoking exposure on arterial properties: time is of the essence

Abstract Introduction Erectile dysfunction (ED) is considered an early manifestation of generalized vascular disease and may precede clinically overt cardiovascular disease (CVD) by 2 to 5 years. We examined macrovascular changes according to time of ED onset and the impact of smoking on the severity of penile vascular damage and large artery wall changes. Methods We measured carotid-femoral pulse wave velocity (PWV), carotid intima media thickness (cIMT), augmentation index (AIx) and brachial flow-mediated dilation (FMD) in 378 males with ED (age: 54±7 years). All participants had no clinical manifestations or a history of atherosclerotic disease. They were assessed using the Sexual Health in Men (SHIM)-5 score for ED severity and the penile colour Doppler ultrasonography after intracavernous injection of prostaglandin E1 for measurement of peak systolic velocity (PSV). Low PSV values indicate impaired penile blood inflow and severe vasculogenic ED. ED duration was defined as the time interval between age at diagnosis and study entry. Results The study population was divided into three groups according to duration of ED. Group 1: &amp;lt;2 years, Group 2: 2–5 years and Group 3: &amp;gt;5 years. Comparison of various parameters among the three groups using one-way ANOVA or the Kruskal–Wallis test did not demonstrate statistically significant differences in age, prevalence of hypertension, diabetes, smoking, peripheral blood pressure (BP) and metabolic parameters (fasting blood glucose, lipid profile, testosterone levels). Total tobacco cigarette exposure was greater in males with ED duration &amp;gt;5 years (Group 3), compared to Group 2 and 1 patients (23.8 vs 22.5 vs 20.7 pack-years, P&amp;lt;0.01). PWV, AIx and cIMT increased and FMD decreased across the three groups (Figure 1). The three groups had comparable PSV value. We then divided the study population into four subgroups according to tobacco exposure (never smokers; light smokers&amp;lt;20 pack-years, moderate smokers 20–40 pack-years and heavy smokers &amp;gt;40 pack-years). The subgroups have similar age and BP. The three smoking subgroups had significantly higher PWV (P&amp;lt;0.001), AIx (P&amp;lt;0.01), cIMT (P&amp;lt;0.01) and lower FMD (P&amp;lt;0.05) and PSV (P&amp;lt;0.05) compared to never smokers. Post hoc analysis revealed higher PWV, AIx and cIMT and lower FMD in heavy smokers compared to moderate and light smokers (all p&amp;lt;0.05). PSV was similar across the three smoking subgroups. Conclusions The study shows that longer ED duration is associated with a more pronounced vascular dysfunction and subclinical vascular wall changes and that heavy tobacco cigarette exposure significantly deteriorates macrovascular parameters. Furthermore there was a significant impairment of penile vasculature even in light smokers. These findings may partly explain why the same process that contribute to CVD may cause earlier ED symptoms and imply that smoking cessation should be a premising non pharmacological intervention in men with ED. Funding Acknowledgement Type of funding sources: None.

Protective effect of the curcumin-baicalein combination against macrovascular changes in diabetic angiopathy.

Endothelial dysfunction is an early pathological event in diabetic angiopathy which is the most common complication of diabetes. This study aims to investigate individual and combined actions of Curcumin (Cur) and Baicalein (Bai) in protecting vascular function. The cellular protective effects of Cur, Bai and Cur+Bai (1:1, w/w) were tested in H2O2 (2.5 mM) impaired EA. hy926 cells. Wistar rats were treated with vehicle control as the control group, Goto-Kakizaki rats (n=5 each group) were treated with vehicle control (model group), Cur (150 mg/kg), Bai (150 mg/kg), or Cur+Bai (75 mg/kg Cur + 75 mg/kg Bai, OG) for 4 weeks after a four-week high-fat diet to investigate the changes on blood vessel against diabetic angiopathy. Our results showed that Cur+Bai synergistically restored the endothelial cell survival and exhibited greater effects on lowering the fasting blood glucose and blood lipids in rats comparing to individual compounds. Cur+Bai repaired the blood vessel structure in the aortic arch and mid thoracic aorta. The network pharmacology analysis showed that Nrf2 and MAPK/JNK kinase were highly relevant to the multi-targeted action of Cur+Bai which has been confirmed in the in vitro and in vivo studies. In conclusion, Cur+Bai demonstrated an enhanced activity in attenuating endothelial dysfunction against oxidative damage and effectively protected vascular function in diabetic angiopathy rats.