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Aging-induced pathological alterations of the circulatory system play a critical role in morbidity and mortality of older adults. While the importance of cellular and molecular mechanisms of arterial aging for increased cardiovascular risk in older adults is increasingly appreciated, aging processes of veins are much less studied and understood than those of arteries. In this review, age-related cellular and morphological alterations in the venous system are presented. Similarities and dissimilarities between arterial and venous aging are highlighted, and shared molecular mechanisms of arterial and venous aging are considered. The pathogenesis of venous diseases affecting older adults, including varicose veins, chronic venous insufficiency, and deep vein thrombosis, is discussed, and the potential contribution of venous pathologies to the onset of vascular cognitive impairment and neurodegenerative diseases is emphasized. It is our hope that a greater appreciation of the cellular and molecular processes of vascular aging will stimulate further investigation into strategies aimed at preventing or retarding age-related venous pathologies.

Összefoglaló. A HUNgarian COronaVirus disease-19 Epidemiological Research (H-UNCOVER) vizsgálat egy országos szintű reprezentatív felmérés volt, melyet az Innovációs és Technológiai Minisztérium (ITM) támogatásával végzett el a négy orvostudományi képzést folytató magyar egyetem a Központi Statisztikai Hivatallal (KSH) együttműködve. A vizsgálat célja az volt, hogy egy reprezentatív mintán keresztül felmérje a magyar lakosság SARS-CoV-2 átfertőzöttségét, és támaszul szolgáljon a koronavírus első hulláma kapcsán meghozott restriktív intézkedések utáni lazításra. A világszinten is jelentős méretű vizsgálat alacsony átfertőzöttségi arányt mutatott, így nemcsak a restriktív intézkedések hatékonyságát mutatta meg, de egy biztos járványügyi támaszt jelentett a gazdaság újranyitásának tervezéséhez. Summary. Close to the end of the first wave of the COVID-19 pandemic in Europe, many countries started to consider the possibility of reopening their economy, and lifting some of the containment measures introduced in the previous weeks. Such a decision is utterly complicated, as reopening might easily lead to an increase in active SARS-CoV-2 cases, but a delay puts an almost unbearable burden on the country’s economy. The objective of the HUNgarian COronaVirus disease-19 Epidemiological Research (H-UNCOVER) study was to conduct a cross-sectional survey among the Hungarian population to estimate the total number of infectious cases and the prevalence of prior SARS-CoV-2 exposure, and by using these data help to plan an exit strategy. The H-UNCOVER study was performed by the 4 medical universities in Hungary (Semmelweis University, University of Pécs, University of Debrecen and University of Szeged) with the help of the Central Statistical Office, Hungarian National Ambulance Service, Governmental offices and General Practitioners. The study was initiated 50 days after the Hungarian restrictions and performed between 1-16 May. With the help of the Central Statistical Office, 17,787 people were selected to represent the Hungarian population of 14 years or older living in private households (n=8,283,810). SARS-CoV-2 PCR and blood tests were performed to assess the prevalence of active infection and seropositivity. These tests were accompanied by a questionnaire about symptoms, comorbidities, and COVID-19 contacts. More specifically, questions included topics about home office, going abroad after the 1st of March, or possible contacts with COVID-19 positive, or quarantined individuals, as well as symptoms which might be due to COVID-19 infection. Altogether 67.7% of the selected individuals participated in some form in the study, which is an exceptionally high number compared to such studies. 10,502 individuals had SARS-CoV-2 PCR testing and 10,501 people had a blood test to assess SARS-CoV-2 IgG levels. Of the tested individuals, three had positive PCR and 69 had positive serological tests. Population estimates of the number of SARS-CoV-2 infections and seropositivity were 2,421 and 56,439, respectively, thus the active infection rate (2.9/10,000, 95% confidence interval: 0-6.7/10,000) and the prevalence of prior SARS-CoV-2 exposure (68/10,000, 95% confidence interval: 50-86/10,000) were low. A total of 10,474 individuals completed the questionnaire. Self-reported loss of smell or taste and body aches were significantly more frequent among those with SARS-CoV-2. Our study suggested that the early containment measures initiated by the Government of Hungary were effective in preventing the escalation of the first wave of COVID-19 in Hungary. We also found that the highest prevalence of the disease was in Budapest, and those who attended their workplace on a regular basis, travelled abroad after the 1st of March, or contacted with a COVID-19 positive or quarantined individual had a higher tendency to become infected. In conclusion, the H-UNCOVER study supported the exit strategy after the first wave of COVID-19 in Hungary.

Uvod: Vysoký pocet připadů onemocněni COVID-19 klade vysoke naroky na zdravotnicke systemy. V zemich těžce postižených pandemii uvaději lekaři meně pacientů přivažených do nemocnic s akutnimi koronarnimi syndromy (AKS). Znepokojujici je skutecnost, že u pacientů s život ohrožujicim onemocněnim může dochazet k vice komplikacim, připadně mohou zemřit na infarkt myokardu. Informaci o peci o jedince s AKS v zemich meně postižených pandemii je malo. Vzhledem k tomu, že do teto skupiny zemi patři Maďarsko, bylo nasim cilem posoudit změny v peci o jedince s infarktem myokardu na největsim pracovisti v zemi, ktere provadi perkutanni koronarni intervence. Metody: Byly analyzovany výsledky cekem 512 po sobě nasledujicich pacientů; z tohoto poctu jich 396 bylo osetřeno v letech 2018 a 2019 ve srovnani se 116 jedinci s AKS v roce 2020 během pandemie. V nasi studii jsme porovnali demograficke a klinicke charakteristiky pacientů i pocty umrti mimo nemocnici v době před vypuknutim pandemie a v jejim průběhu. Výsledky: Během pandemie doslo k 41% (116/298) poklesu poctu vsech AKS a k 29% sniženi poctu pacientů s infarktem myokardu s elevacemi useku ST (STEMI) (61/87) i 51% sniženi poctu pacientů s infarktem myokardu bez elevaci useku ST (NSTEMI) (54/111). Podil pozdě přijatých pacientů se STEMI přitom vzrostl (17,49 %, 18/105 vs. 34,48 %, 10/29). Zaznamenali jsme i pokles v poctu těžkých připadů, intervenci na kmeni leve věncite tepny i pacientů s vysoce rizikovým NSTEMI. Umrtnost mimo nemocnici vzrostla o 17 %. Zavěr: I když v prvni vlně byl maďarský zdravotnický system pandemii meně zasažen, pozorovali jsme významný pokles v poctu připadů AKS. Opožděne poskytnuti pece nebo jeji naprosta absence mohou mit zavažne důsledky pro prognozu pacienta. Vzhledem ke zvysujicim se poctům připadů onemocněni COVID-19 ve druhe vlně nabýva na významu nutnost zvýsit povědomi pacientů i zdravotnických pracovniků o nezbytnosti casneho poskytnuti pece jedincům s AKS. © 2021, CKS.

After months of restrictive containment efforts to fight the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) epidemic, European countries are planning to reopen. To support the process, we conducted a cross-sectional survey among the Hungarian population to estimate the prevalence of infectious cases and prior SARS-CoV-2 exposure. A representative sample (n = 17,787) for the Hungarian population of 14 years or older living in private households (n = 8,283,810) was selected. The study was performed within 16 days after 50 days of restrictions, when the number of confirmed cases was stable low. Naso- and oropharyngeal smears and blood samples were collected for PCR and antibody testing. The testing was accompanied by a questionnaire about symptoms, comorbidities, and contacts. Design-based prevalence estimates were calculated. In total, 10,474 individuals (67.7% taken into account a sample frame error of 2315) of the selected sample participated in the survey. Of the tested individuals, 3 had positive PCR and 69 had positive serological test. Population estimate of the number of SARS-CoV-2 infection and seropositivity were 2421 and 56,439, respectively, thus active infection rate (2.9/10,000) and the prevalence of prior SARS-CoV-2 exposure (68/10,000) was low. Self-reported loss of smell or taste and body aches were significantly more frequent among those with SARS-CoV-2. In this representative, cross-sectional survey of the Hungarian population with a high participation rate, the overall active infection rate was low in sync with the prevalence of prior SARS-CoV-2 exposure. We demonstrated a potential success of containment efforts, supporting an exit strategy. NCT04370067, 30.04.2020.

Cerebral microhemorrhages (CMHs; microbleeds), which are small focal intracerebral hemorrhages, importantly contribute to the pathogenesis of cognitive decline and dementia in older adults. Although recently it has been increasingly recognized that the venous side of the cerebral circulation likely plays a fundamental role in the pathogenesis of a wide spectrum of cerebrovascular and brain disorders, its role in the pathogenesis of CMHs has never been studied. The present study was designed to experimentally test the hypothesis that venous congestion can exacerbate the genesis of CMHs. Increased cerebral venous pressure was induced by internal and external jugular vein ligation (JVL) in C57BL/6 mice in which systemic hypertension was induced by treatment with angiotensin II plus L-NAME. Histological analysis (diaminobenzidine staining) showed that mice with JVL developed multiple CMHs. CMHs in mice with JVL were often localized adjacent to veins and venules and their morphology was consistent with venous origin of the bleeds. In brains of mice with JVL, a higher total count of CMHs was observed compared to control mice. CMHs were distributed widely in the brain of mice with JVL, including the cortical gray matter, brain stem, the basal ganglia, subcortical white matter, cerebellum, and the hippocampi. In mice with JVL, there were more CMHs predominantly in cerebral cortex, brain stem, and cerebellum than in control mice. CMH burden, defined as total CMH volume, also significantly increased in mice with JVL. Thus, cerebral venous congestion can exacerbate CMHs. These observations have relevance to the pathogenesis of cognitive impairment associated with right heart failure as well as elevated cerebral venous pressure due to jugular venous reflux in older adults.

The 72-year-old male patient came to the oral surgical department of Kaposi Mor Educational Hospital in May 2018 complaining about a 15-centimetre big cornu cutaneum on the right side of the lower lip, which had been growing there for decades. In addition ulcerated mucous membrane lesions were recognisable on the left side of his lip.After examining and diagnosing the patient’s mucous membrane lesions (CT, PET-CT-screening, scaling, radix removal) we deeply resected them from the intact part with linear excision. The results of the biopsy were Grade 1–2 squamous cell cc. of the lower (in the left third of the lip) as well as cornu cutaneum (in the right third of the lip). Thus according to the decision of the oncological team, the patient is under tight control (medical check-up every 3–6–9–12 month). Currently the patient is symptom and complaint-free, and his regular follow-up indicates unchanged status.

Adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling (NVC) plays an important role in the maintenance of healthy cognitive function. Strong evidence demonstrates that age-related cerebromicrovascular endothelial dysfunction and consequential impairment of NVC responses contribute importantly to cognitive decline. Recent studies demonstrate that NAD(+) availability decreases with age in the vasculature and that supplemental NAD(+) precursors can ameliorate cerebrovascular dysfunction, rescuing NVC responses and improving cognitive performance in aged mice. The mechanisms underlying the age-related decline in [NAD(+)] in cells of the neurovascular unit are likely multifaceted and may include increased utilization of NAD(+) by activated poly (ADP-ribose) polymerase (PARP-1). The present study was designed to test the hypothesis that inhibition of PARP-1 activity may confer protective effects on neurovascular function in aging, similar to the recently demonstrated protective effects of treatment with the NAD+ precursor nicotinamide mononucleotide (NMN). To test this hypothesis, 24-month-old C57BL/6 mice were treated with PJ-34, a potent PARP inhibitor, for 2 weeks. NVC was assessed by measuring CBF responses (laser speckle contrast imaging) in the somatosensory whisker barrel cortex evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. Treatment with PJ-34 improved NVC responses by increasing endothelial NO-mediated vasodilation, which was associated with significantly improved spatial working memory. PJ-34 treatment also improved endothelium-dependent acetylcholine-induced relaxation of aorta rings. Thus, PARP-1 activation, likely by decreasing NAD(+) availability, contributes to age-related endothelial dysfunction and neurovascular uncoupling, exacerbating cognitive decline. The cerebromicrovascular protective effects of pharmacological inhibition of PARP-1 highlight the preventive and therapeutic potential of treatments that restore NAD+ homeostasis as effective interventions in patients at risk for vascular cognitive impairment (VCI).

There has been an increasing appreciation of the role of vascular contributions to cognitive impairment and dementia (VCID) associated with old age. Strong preclinical and translational evidence links age-related dysfunction and structural alterations of the cerebral arteries, arterioles, and capillaries to the pathogenesis of many types of dementia in the elderly, including Alzheimer’s disease. The low-pressure, low-velocity, and large-volume venous circulation of the brain also plays critical roles in the maintenance of homeostasis in the central nervous system. Despite its physiological importance, the role of age-related alterations of the brain venous circulation in the pathogenesis of vascular cognitive impairment and dementia is much less understood. This overview discusses the role of cerebral veins in the pathogenesis of VCID. Pathophysiological consequences of age-related dysregulation of the cerebral venous circulation are explored, including blood-brain barrier disruption, neuroinflammation, exacerbation of neurodegeneration, development of cerebral microhemorrhages of venous origin, altered production of cerebrospinal fluid, impaired function of the glymphatics system, dysregulation of cerebral blood flow, and ischemic neuronal dysfunction and damage. Understanding the age-related functional and phenotypic alterations of the cerebral venous circulation is critical for developing new preventive, diagnostic, and therapeutic approaches to preserve brain health in older individuals.

Preclinical studies demonstrate that generalized endothelial cell dysfunction and microvascular impairment are potentially reversible causes of age-related vascular cognitive impairment and dementia (VCID). The present study was designed to test the hypothesis that severity of age-related macro- and microvascular dysfunction measured in the peripheral circulation is an independent predictor of cognitive performance in older adults. In this study, we enrolled 63 healthy individuals into young ( 65 years old) groups. We used principal component analysis (PCA) to construct a comprehensive peripheral vascular health index (VHI) encompassing peripheral microvascular reactivity, arterial endothelial function, and vascular stiffness, as a marker of aging-induced generalized vascular dysfunction. Peripheral macrovascular and microvascular endothelial function were assessed using flow-mediated dilation (FMD) and laser speckle contrast imaging tests. Pulse waveform analysis was used to evaluate the augmentation index (AIx), a measure of arterial stiffness. Cognitive function was measured using a panel of CANTAB cognitive tests, and PCA was then applied to generate a cognitive impairment index (CII) for each participant. Aged subjects exhibited significantly impaired macrovascular endothelial function (FMD, 5.6 ± 0.7% vs. 8.3 ± 0.6% in young, p = 0.0061), increased arterial stiffness (AIx 29.3 ± 1.8% vs 4.5 ± 2.6% in young, p

Introduction to SPIE Defense and Commercial Sensing conference 11741: Infrared Technology and Applications XLVII

Early ventricular fibrillation (EVF) predicts mortality in ST-segment elevation myocardial infarction (STEMI) patients. Data are lacking about prognosis and management of non-ST-segment elevation myocardial infarction (NSTEMI) EMI with EVF, especially at higher age. In the daily clinical practice, there is no clear prognosis of patients surviving EVF. The present study aimed to investigate the risk factors and factors influencing the prognosis of NSTEMI patients surviving EVF, especially at higher age. Clinical data, including 30-day and 1-year mortality of 6179 NSTEMI patients, were examined; 2.44% (n=151) survived EVF and were further analyzed using chi-square test and uni- and multivariate analyses. Patients were divided into two age groups below and above the age of 70 years. Survival time was compared with Kaplan-Meier analysis. EVF was an independent risk factor for mortality in NSTEMI patients below (HR: 2.4) and above the age of 70 (HR: 2.1). Mortality rates between the two age groups of NSTEMI patients with EVF did not differ significantly: 30-day mortality was 24% vs 40% (p=0.2709) and 1-year mortality was 39% vs 55% (p=0.2085). Additional mortality after 30 days to 1 year was 15% vs 14.6% (p=0.9728). Clinical characteristics of patients with EVF differed significantly from those without in both age groups. EVF after revascularization—within 48 h—had 11.2 OR for 30-day mortality above the age of 70. EVF in NSTEMI was an independent risk factor for mortality in both age groups. Invasive management and revascularization of NSTEMI patients with EVF is highly recommended. Closer follow-up and selection of patients (independent of age) for ICD implantation in the critical first month is essential.

Serum chitotriosidase (CTO) activity was proposed as a biomarker in sarcoidosis being potentially useful in diagnostics. Nevertheless, a common duplication polymorphism (c.1049_1072dup24, Dup24) of the CTO gene influences CTO activity and thereby compromises its use in sarcoidosis. Here we aimed to substitute CTO activity with CTO concentration to prevent the confounding effect of Dup24. CTO activity, concentration and genetic backgrounds were determined in 80 histopathology proven sarcoidosis patients and 133 healthy individuals. CTO activities were lower in healthy individuals and sarcoidosis patients heterozygous for Dup24 mutation (472 ± 367 mU/L, n = 49; 2300 ± 2105 mU/L, n = 29) than in homozygous wild types (838 ± 856 mU/L, n = 81; 5125 ± 4802 mU/L, n = 48; p

Background Autonomic dysregulation in heart failure with reduced ejection fraction plays a major role in endothelial dysfunction. Low-level tragus stimulation (LLTS) is a novel, noninvasive method of autonomic modulation. Methods and Results We enrolled 50 patients with heart failure with reduced ejection fraction (left ventricular ejection fraction of ≤40%) in a randomized, double-blinded, crossover study. On day 1, patients underwent 60 minutes of LLTS with a transcutaneous stimulator (20 Hz, 200 μs pulse width) or sham (ear lobule) stimulation. Macrovascular function was assessed using flow-mediated dilatation in the brachial artery and cutaneous microcirculation with laser speckle contrast imaging in the hand and nail bed. On day 2, patients were crossed over to the other study arm and underwent sham or LLTS; vascular tests were repeated before and after stimulation. Compared with the sham, LLTS improved flow-mediated dilatation by increasing the percent change in the brachial artery diameter (from 5.0 to 7.5, LLTS on day 1, P = .02; and from 4.9 to 7.1, LLTS on day 2, P = .003), compared with no significant change in the sham group (from 4.6 to 4.7, P = .84 on day 1; and from 5.6 to 5.9 on day 2, P = .65). Cutaneous microcirculation in the hand showed no improvement and perfusion of the nail bed showed a trend toward improvement. Conclusions Our study demonstrated the beneficial effects of acute neuromodulation on macrovascular function. Larger studies to validate these findings and understand mechanistic links are warranted.

Age-related gait dysfunction and balance disorders are a major cause of falls and injury in the elderly population. Epidemiological studies have shown that disturbances in gait coordination which manifest with age are associated with increased morbidity and mortality, impaired cognitive capacity, as well as reduced level of function and loss of independence. In geroscience, mice are the most frequently used model system to test efficiency of antiaging interventions. Despite the clinical importance of age-related gait abnormalities in older adults, the impact of aging on mouse gait coordination is not well documented in the literature. To characterize the effect of aging on mouse gait, we assessed gait function in young (3-month-old) and aged (24-month-old) freely moving C57BL/6 mice using the semiautomated, highly sensitive CatWalk XT system for quantitative assessment of footfall and motor performance. We found that aged mice exhibited significantly decreased cadence and increased stride time variability. Aging also tended to alter footfall patterns. In aged mice, speed, swing speed, stride length, duty cycle, base of support, terminal dual stance, the regularity index, and the gait symmetry index were unaltered. Thus, aging is associated with characteristic alterations in gait function in C57BL/6 mice, which could potentially be assessed as clinically relevant endpoints in geroscience studies testing the effects of antiaging interventions.

Obesity is one of the major risk factors for cardiovascular diseases and its prevalence is increasing in all age groups, with the biggest impact observed in middle-aged and older adults. A critical mechanism by which obesity promotes vascular pathologies in these patients involves impairment of endothelial function. While endothelial dysfunction in large vessels promotes atherogenesis, obesity-induced microvascular endothelial dysfunction impairs organ perfusion and thereby is causally related to the pathogenesis of ischemic heart disease, chronic kidney disease, intermittent claudication, exercise intolerance, and exacerbates cognitive decline in aging. Reduction of weight via calorie-based diet and exercise in animal models of obesity results in significant improvement of endothelial function both in large vessels and in the microcirculation, primarily due to attenuation of oxidative stress and inflammation. Clinical data on the protective effects of weight loss on endothelial function is limited to studies of flow-mediated dilation assessed in brachial arteries. Currently, there is no guideline on testing the effects of different weight management strategies on microvascular endothelial function in obese patients. Here, we provide proof-of-concept that weight loss-induced improvement of microvascular endothelial function can be reliably assessed in the setting of a geriatric outpatient clinic using a fast, reproducible, non-invasive method: laser speckle contrast imaging-based measurement of endothelium-dependent microvascular responses during post-occlusive reactive hyperemia tests. Our study also provides initial evidence that short-term weight loss induced by consumption of a low-carbohydrate low-calorie diet can reverse microvascular endothelial dysfunction associated with obesity.

Connective tissue growth factor (CTGF, also known as CCN2) is a matricellular protein expressed in the vascular wall, which regulates diverse cellular functions including cell adhesion, matrix production, structural remodeling, angiogenesis, and cell proliferation and differentiation. CTGF is principally regulated at the level of transcription and is induced by mechanical stresses and a number of cytokines and growth factors, including TGFβ. In this mini-review, the role of age-related dysregulation of CTGF signaling and its role in a range of macro- and microvascular pathologies, including pathogenesis of aorta aneurysms, atherogenesis, and diabetic retinopathy, are discussed. A potential role of CTGF and TGFβ in regulation and non-cell autonomous propagation of cellular senescence is also discussed.

Strong epidemiological and experimental evidence indicates that hypertension has detrimental effects on the cerebral microcirculation and thereby promotes accelerated brain aging. Hypertension is an independent risk factor for both vascular cognitive impairment (VCI) and Alzheimer’s disease (AD). However, the pathophysiological link between hypertension-induced cerebromicrovascular injury (e.g., blood–brain barrier disruption, increased microvascular oxidative stress, and inflammation) and cognitive decline remains elusive. The present study was designed to characterize neuronal functional and morphological alterations induced by chronic hypertension and compare them to those induced by aging. To achieve that goal, we induced hypertension in young C57BL/6 mice by chronic (4 weeks) infusion of angiotensin II. We found that long-term potentiation (LTP) of performant path synapses following high-frequency stimulation of afferent fibers was decreased in hippocampal slices obtained from hypertensive mice, mimicking the aging phenotype. Hypertension and advanced age were associated with comparable decline in synaptic density in the stratum radiatum of the mouse hippocampus. Hypertension, similar to aging, was associated with changes in mRNA expression of several genes involved in regulation of neuronal function, including down-regulation of Bdnf, Homer1, and Dlg4, which may have a role in impaired synaptic plasticity. Collectively, hypertension impairs synaptic plasticity, reduces synaptic density, and promotes dysregulation of genes involved in synaptic function in the mouse hippocampus mimicking the aging phenotype. These hypertension-induced neuronal alterations may impair establishment of memories in the hippocampus and contribute to the pathogenesis and clinical manifestation of both vascular cognitive impairment (VCI) and Alzheimer’s disease (AD).

Increasing evidence from epidemiological, clinical, and experimental studies indicates that cerebromicrovascular dysfunction and microcirculatory damage play critical roles in the pathogenesis of many types of dementia in the elderly, including both vascular cognitive impairment (VCI) and Alzheimer's disease. Vascular contributions to cognitive impairment and dementia (VCID) include impairment of neurovascular coupling responses/functional hyperemia ("neurovascular uncoupling"). Due to the growing interest in understanding and pharmacologically targeting pathophysiological mechanisms of VCID, there is an increasing need for sensitive, easy-to-establish methods to assess neurovascular coupling responses. Laser speckle contrast imaging (LSCI) is a technique that allows rapid and minimally invasive visualization of changes in regional cerebromicrovascular blood perfusion. This type of imaging technique combines high resolution and speed to provide great spatiotemporal accuracy to measure moment-to-moment changes in cerebral blood flow induced by neuronal activation. Here, we provide detailed protocols for the successful measurement in neurovascular coupling responses in anesthetized mice equipped with a thinned-skull cranial window using LSCI. This method can be used to evaluate the effects of anti-aging or anti-AD treatments on cerebromicrovascular health.

Alpha–melanocyte-stimulating hormone (α-MSH) is a protein with known capacity for protection against cardiovascular ischemia–reperfusion (I/R) injury. This investigation evaluates the capacity of α-MSH to mitigate I/R effects in an isolated working rat heart model and determine the dependency of these alterations on the activity of heme oxygenase-1 (HO-1, hsp-32), a heat shock protein that functions as a major antioxidant defense molecule. Healthy male Sprague Dawley rats were used for all experiments. After treatment with selected doses of α-MSH, echocardiographic examinations were performed on live, anesthetized animals. Hearts were harvested from anesthetized rats pretreated with α-MSH and/or the HO-1 inhibitor SnPP, followed by cardiac function assessment on isolated working hearts, which were prepared using the Langendorff protocol. Induction of global ischemia was performed, followed by during reperfusion assessment of cardiac functions. Determination of incidence of cardiac arrhythmias was made by electrocardiogram. Major outcomes include echocardiographic data, suggesting that α-MSH has mild effects on systolic parameters, along with potent antiarrhythmic effects. Of particular significance was the specificity of dilatative effects on coronary vasculature, and similar outcomes of aortic ring experiments, which potentially allow different doses of the compound to be used to selectively target various portions of the vasculature for dilation.

Summary Clinical and experimental studies show that aging exacerbates hypertension‐induced cerebral microhemorrhages (CMHs), which progressively impair neuronal function. There is growing evidence that aging promotes insulin‐like growth factor 1 (IGF‐1) deficiency, which compromises multiple aspects of cerebromicrovascular and brain health. To determine the role of IGF‐1 deficiency in the pathogenesis of CMHs, we induced hypertension in mice with liver‐specific knockdown of IGF‐1 (Igf1 f/f + TBG‐Cre‐AAV8) and control mice by angiotensin II plus l‐NAME treatment. In IGF‐1‐deficient mice, the same level of hypertension led to significantly earlier onset and increased incidence and neurological consequences of CMHs, as compared to control mice, as shown by neurological examination, gait analysis, and histological assessment of CMHs in serial brain sections. Previous studies showed that in aging, increased oxidative stress‐mediated matrix metalloprotease (MMP) activation importantly contributes to the pathogenesis of CMHs. Thus, it is significant that hypertension‐induced cerebrovascular oxidative stress and MMP activation were increased in IGF‐1‐deficient mice. We found that IGF‐1 deficiency impaired hypertension‐induced adaptive media hypertrophy and extracellular matrix remodeling, which together with the increased MMP activation likely also contributes to increased fragility of intracerebral arterioles. Collectively, IGF‐1 deficiency promotes the pathogenesis of CMHs, mimicking the aging phenotype, which likely contribute to its deleterious effect on cognitive function. Therapeutic strategies that upregulate IGF‐1 signaling in the cerebral vessels and/or reduce microvascular oxidative stress, and MMP activation may be useful for the prevention of CMHs, protecting cognitive function in high‐risk elderly patients.

Whole brain irradiation (WBI) is a mainstream therapy for patients with both identifiable brain metastases and prophylaxis for microscopic malignancies. However, it also promotes accelerated senescence in healthy tissues and leads to progressive cognitive dysfunction in up to 50% of tumor patients surviving long term after treatment, due to γ-irradiation-induced cerebromicrovascular injury. Moment-to-moment adjustment of cerebral blood flow (CBF) via neuronal activity-dependent cerebromicrovascular dilation (functional hyperemia) has a critical role in maintenance of healthy cognitive function. To determine whether cognitive decline induced by WBI associates with impaired cerebromicrovascular function, C56BL/6 mice (3 months) subjected to a clinically relevant protocol of fractionated WBI (5 Gy twice weekly for 4 weeks) and control mice were compared. Mice were tested for spatial memory performance (radial arm water maze), sensorimotor coordination (computerized gait analysis, CatWalk), and cerebromicrovascular function (whisker-stimulation-induced increases in CBF, measured by laser Doppler flowmetry) at 3 to 6 months post-irradiation. We found that mice with WBI exhibited impaired cerebromicrovascular function at 3 months post-irradiation, which was associated with impaired performance in the radial arm water maze. At 6 months, post-irradiation progressive impairment in gait coordination (including changes in the regularity index and phase dispersion) was also evident. Collectively, our findings provide evidence for early and persisting neurovascular impairment after a clinically relevant protocol of fractionated WBI, which predict early manifestations of cognitive impairment.

Whole brain irradiation (WBI, also known as whole brain radiation therapy or WBRT) is a mainstream therapy for patients with identifiable brain metastases and as a prophylaxis for microscopic malignancies. WBI accelerates brain aging, causing progressive cognitive dysfunction in ~ 50% of surviving patients, thus compromising quality of life. The mechanisms responsible for this WBI side effect remain obscure, and there are no effective treatments or prevention strategies. Here, we test the hypothesis that WBI induces astrocyte senescence, which contributes to impaired astrocytic neurovascular coupling (NVC) responses and the genesis of cognitive decline. To achieve this goal, we used transgenic p16-3MR mice, which allows the detection and selective elimination of senescent cells. We subjected these mice to a clinically relevant protocol of fractionated WBI (5 Gy twice weekly for 4 weeks). WBI-treated and control mice were tested for spatial memory performance (radial arm water maze), astrocyte-dependent NVC responses (whisker-stimulation-induced increases in cerebral blood flow, assessed by laser speckle contrast imaging), NVC-related gene expression, astrocytic release of eicosanoid gliotransmitters and the presence of senescent astrocytes (by flow cytometry, immunohistochemistry and gene expression profiling) at 6 months post-irradiation. WBI induced senescence in astrocytes, which associated with NVC dysfunction and impaired performance on cognitive tasks. To establish a causal relationship between WBI-induced senescence and NVC dysfunction, senescent cells were depleted from WBI-treated animals (at 3 months post-WBI) by genetic (ganciclovir treatment) or pharmacological (treatment with the BCL-2/BCL-xL inhibitor ABT263/Navitoclax, a known senolytic drug) means. In WBI-treated mice, both treatments effectively eliminated senescent astrocytes, rescued NVC responses, and improved cognitive performance. Our findings suggest that the use of senolytic drugs can be a promising strategy for preventing the cognitive impairment associated with WBI.

Cognitive impairment is one of the most common co-occurring chronic conditions among elderly heart failure patients (incidence: up to ~ 80%); however, the underlying mechanisms are not completely understood. It is hypothesized that in addition to decreased cardiac output, increases in central-and consequentially, cerebral-venous pressure (backward failure) also contribute significantly to the genesis of cognitive impairment. To test this hypothesis and elucidate the specific pathogenic role of venous congestion in the brain, we have established a novel model of increased cerebral venous pressure: mice with jugular vein ligation (JVL). To test the hypothesis that increased venous pressure in the brain contributes to the development of cognitive deficits by causing blood-brain barrier disruption, dysregulation of blood flow, and/or promoting neuroinflammation, in C57BL/6 mice, the internal and external jugular veins were ligated. Cognitive function (radial arm water maze), gait function (CatWalk), and motor coordination (rotarod) were tested post-JVL. Neurovascular coupling responses were assessed by measuring changes in cerebral blood flow in the whisker barrel cortex in response to contralateral whisker stimulation by laser speckle contrast imaging through a closed cranial window. Blood-brain barrier integrity (IgG extravasation) and microglia activation (Iba1 staining) were assessed in brain slices by immunohistochemistry. Neuroinflammation-related gene expression profile was assessed by a targeted qPCR array. After jugular vein ligation, mice exhibited impaired spatial learning and memory, altered motor coordination, and impaired gait function, mimicking important aspects of altered brain function observed in human heart failure patients. JVL did not alter neurovascular coupling responses. In the brains of mice with JVL, significant extravasation of IgG was detected, indicating blood-brain barrier disruption, which was associated with histological markers of neuroinflammation (increased presence of activated microglia) and a pro-inflammatory shift in gene expression profile. Thus, cerebral venous congestion per se can cause blood-brain barrier disruption and neuroinflammation, which likely contribute to the genesis of cognitive impairment. These findings have relevance to the pathogenesis of cognitive decline associated with heart failure as well as increased cerebal venous pressure due to increased jugular venous reflux in elderly human patients.

Adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling (NVC) plays an important role in the maintenance of healthy cognitive function. Strong evidence demonstrates that age-related cerebromicrovascular endothelial dysfunction and consequential impairment of NVC responses contribute importantly to cognitive decline. Recent studies demonstrate that NAD+ availability decreases with age in the vasculature and that supplemental NAD+ precursors can ameliorate cerebrovascular dysfunction, rescuing NVC responses and improving cognitive performance in aged mice. The mechanisms underlying the age-related decline in [NAD+] in cells of the neurovascular unit are likely multifaceted and may include increased utilization of NAD+ by activated poly (ADP-ribose) polymerase (PARP-1). The present study was designed to test the hypothesis that inhibition of PARP-1 activity may confer protective effects on neurovascular function in aging, similar to the recently demonstrated protective effects of treatment with the NAD+ precursor nicotinamide mononucleotide (NMN). To test this hypothesis, 24-month-old C57BL/6 mice were treated with PJ-34, a potent PARP inhibitor, for 2 weeks. NVC was assessed by measuring CBF responses (laser speckle contrast imaging) in the somatosensory whisker barrel cortex evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. Treatment with PJ-34 improved NVC responses by increasing endothelial NO-mediated vasodilation, which was associated with significantly improved spatial working memory. PJ-34 treatment also improved endothelium-dependent acetylcholine-induced relaxation of aorta rings. Thus, PARP-1 activation, likely by decreasing NAD+ availability, contributes to age-related endothelial dysfunction and neurovascular uncoupling, exacerbating cognitive decline. The cerebromicrovascular protective effects of pharmacological inhibition of PARP-1 highlight the preventive and therapeutic potential of treatments that restore NAD+ homeostasis as effective interventions in patients at risk for vascular cognitive impairment (VCI).

Clinical and experimental studies show that age-related decline in circulating insulin-like growth factor-1 (IGF-1) levels promotes the pathogenesis of intracerebral hemorrhages, which critically contribute to the development of vascular cognitive impairment and disability in older adults. Yet, the mechanisms by which IGF-1 deficiency compromises structural integrity of the cerebral vasculature are not completely understood. To determine the role of IGF-1 deficiency in pathological remodeling of middle cerebral arteries (MCAs), we compared alterations in vascular mechanics, morphology, and remodeling-related gene expression profile in mice with liver-specific knockdown of IGF-1 (Igf1(f/f) + TBG-Cre-AAV8) and control mice with or without hypertension induced by angiotensin-II treatment. We found that IGF-1 deficiency resulted in thinning of the media and decreased wall-to-lumen ratio in MCAs. MCAs of control mice exhibited structural adaptation to hypertension, manifested as a significant increase in wall thickness, vascular smooth muscle cell (VSMC) hypertrophy, decreased internal diameter and up-regulation of extracellular matrix (ECM)-related genes. IGF-1 deficiency impaired hypertension-induced adaptive media hypertrophy and dysregulated ECM remodeling, decreasing elastin content and attenuating adaptive changes in ECM-related gene expression. Thus, circulating IGF-1 plays a critical role in maintenance of the structural integrity of cerebral arteries. Alterations of VSMC phenotype and pathological remodeling of the arterial wall associated with age-related IGF-1 deficiency have important translational relevance for the pathogenesis of intracerebral hemorrhages and vascular cognitive impairment in elderly hypertensive patients.

Background and Purpose Omecamtiv mecarbil (OM) is a novel cardiac myosin activator drug for inotropic support in systolic heart failure. Here we have assessed the concentration-dependent mechanical effects of OM in permeabilized cardiomyocyte-sized preparations and single skeletal muscle fibres of Wistar-Kyoto rats under isometric conditions.

Aging-induced pro-inflammatory phenotypic alterations of the cerebral vasculature critically contribute to the pathogenesis of vascular cognitive impairment. Cellular senescence is a fundamental aging process that promotes inflammation; however, its role in cerebrovascular aging remains unexplored. The present study was undertaken to test the hypothesis that advanced aging promotes cellular senescence in the cerebral vasculature. We found that in cerebral arteries of 24-month-old mice, expression of molecular markers of senescence (p16INK4a, p21) is upregulated as compared to that in young controls. Induction of senescence programs in cerebral arteries is associated by an upregulation of a wide range of inflammatory cytokines and chemokines, which are known to contribute to the senescence-associated secretory phenotype (SASP) in vascular cells. Age-related cerebrovascular senescence and inflammation are associated with neuroinflammation, as shown by the molecular footprint of microglia activation in the hippocampus. Genetic depletion of the pro-survival/anti-aging transcriptional regulator Nrf2 exacerbated age-related induction of senescence markers and inflammatory SASP factors and resulted in a heightened inflammatory status of the hippocampus. In conclusion, our studies provide evidence that aging and Nrf2 dysfunction promote cellular senescence in cerebral vessels, which may potentially cause or exacerbate age-related pathology.

Summary Moment‐to‐moment adjustment of cerebral blood flow (CBF) via neurovascular coupling has an essential role in maintenance of healthy cognitive function. In advanced age, increased oxidative stress and cerebromicrovascular endothelial dysfunction impair neurovascular coupling, likely contributing to age‐related decline of higher cortical functions. There is increasing evidence showing that mitochondrial oxidative stress plays a critical role in a range of age‐related cellular impairments, but its role in neurovascular uncoupling remains unexplored. This study was designed to test the hypothesis that attenuation of mitochondrial oxidative stress may exert beneficial effects on neurovascular coupling responses in aging. To test this hypothesis, 24‐month‐old C57BL/6 mice were treated with a cell‐permeable, mitochondria‐targeted antioxidant peptide (SS‐31; 10 mg kg−1 day−1, i.p.) or vehicle for 2 weeks. Neurovascular coupling was assessed by measuring CBF responses (laser speckle contrast imaging) evoked by contralateral whisker stimulation. We found that neurovascular coupling responses were significantly impaired in aged mice. Treatment with SS–31 significantly improved neurovascular coupling responses by increasing NO‐mediated cerebromicrovascular dilation, which was associated with significantly improved spatial working memory, motor skill learning, and gait coordination. These findings are paralleled by the protective effects of SS–31 on mitochondrial production of reactive oxygen species and mitochondrial respiration in cultured cerebromicrovascular endothelial cells derived from aged animals. Thus, mitochondrial oxidative stress contributes to age‐related cerebromicrovascular dysfunction, exacerbating cognitive decline. We propose that mitochondria‐targeted antioxidants may be considered for pharmacological microvascular protection for the prevention/treatment of age‐related vascular cognitive impairment (VCI).

There is correlative evidence that impaired cerebral blood flow (CBF) regulation, in addition to promoting cognitive impairment, is also associated with alterations in gait and development of falls in elderly people. CBF is adjusted to neuronal activity via neurovascular coupling (NVC) and this mechanism becomes progressively impaired with age. To establish a direct cause-and-effect relationship between impaired NVC and gait abnormalities, we induced neurovascular uncoupling pharmacologically in young C57BL/6 mice by inhibiting the synthesis of vasodilator mediators involved in NVC. Treatment of mice with the epoxygenase inhibitor MSPPOH, the NO synthase inhibitor L-NAME, and the COX inhibitor indomethacin significantly decreased NVC mimicking the aging phenotype. Pharmacologically induced neurovascular uncoupling significantly decreased the dynamic gait parameter duty cycle, altered footfall patterns, and significantly increased phase dispersion, indicating impaired interlimb coordination. Impaired NVC also tended to increase gait variability. Thus, selective experimental disruption of NVC causes subclinical gait abnormalities, supporting the importance of CBF in both cognitive function and gait regulation.

The present investigation evaluates the cardiovascular effects of the anorexigenic mediator alpha-melanocyte stimulating hormone (MSH), in a rat model of type 2 diabetes. Osmotic mini pumps delivering MSH or vehicle, for 6 weeks, were surgically implanted in Zucker Diabetic Fatty (ZDF) rats. Serum parameters, blood pressure, and weight gain were monitored along with oral glucose tolerance (OGTT). Echocardiography was conducted and, following sacrifice, the effects of treatment on ischemia/reperfusion cardiac injury were assessed using the isolated working heart method. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity was measured to evaluate levels of oxidative stress, and force measurements were performed on isolated cardiomyocytes to determine calcium sensitivity, active tension and myofilament co-operation. Vascular status was also evaluated on isolated arterioles using a contractile force measurement setup. The echocardiographic parameters ejection fraction (EF), fractional shortening (FS), isovolumetric relaxation time (IVRT), mitral annular plane systolic excursion (MAPSE), and Tei-index were significantly better in the MSH-treated group compared to ZDF controls. Isolated working heart aortic and coronary flow was increased in treated rats, and higher Hill coefficient indicated better myofilament co-operation in the MSH-treated group. We conclude that MSH improves global heart functions in ZDF rats, but these effects are not related to the vascular status.

Pulmonary hypertension (PH) is a progressive disease characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance. According to latest estimations, a PH incidence accounts for 1% of total global population (up to 5 million people) and the median survival rate for patients diagnosed with PH is predicted at 2.8 years. Emerging evidence suggests an important role for cytochrome P450 in the development and progression of PH, as a newer member of cytochrome family Cyp2c44 has been recently implicated in mediating hypoxia-induced pulmonary artery remodeling. Recent studies show that Cyp2c44 effects on the pathophysiology of PH are driven by its ability to produce 15-hydroxyeicosatetraenoic acid (15-HETE). In this article, we discuss new mechanisms by which Cyp2c44 and 15-HETE contribute to the progression of PH.

Hypertension in the elderly substantially increases both the risk of vascular cognitive impairment (VCI) and Alzheimer’s disease (AD); however, the underlying mechanisms are not completely understood. This review discusses the effects of hypertension on structural and functional integrity of cerebral microcirculation, including hypertension-induced alterations in neurovascular coupling responses, cellular and molecular mechanisms involved in microvascular damage (capillary rarefaction, blood-brain barrier disruption), and the genesis of cerebral microhemorrhages and their potential role in exacerbation of cognitive decline associated with AD. Understanding and targeting the hypertension-induced cerebromicrovascular alterations that are involved in the onset and progression of AD and contribute to cognitive impairment are expected to have a major role in preserving brain health in high-risk older individuals.