Mechanisms of Vascular Inflammation and Potential Therapeutic Targets: A Position Paper From the ESH Working Group on Small Arteries.

Inflammatory responses in small vessels play an important role in the development of cardiovascular diseases, including hypertension, stroke, and small vessel disease. This involves various complex molecular processes including oxidative stress, inflammasome activation, immune-mediated responses, and protein misfolding, which together contribute to microvascular damage. In addition, epigenetic factors, including DNA methylation, histone modifications, and microRNAs influence vascular inflammation and injury. These phenomena may be acquired during the aging process or due to environmental factors. Activation of proinflammatory signaling pathways and molecular events induce low-grade and chronic inflammation with consequent cardiovascular damage. Identifying mechanism-specific targets might provide opportunities in the development of novel therapeutic approaches. Monoclonal antibodies targeting inflammatory cytokines and epigenetic drugs, show promise in reducing microvascular inflammation and associated cardiovascular diseases. In this article, we provide a comprehensive discussion of the complex mechanisms underlying microvascular inflammation and offer insights into innovative therapeutic strategies that may ameliorate vascular injury in cardiovascular disease.

The importance of microvascular inflammation in ageing and age-related diseases: a position paper from the ESH working group on small arteries, section of microvascular inflammation.

Microcirculation is pervasive and orchestrates a profound regulatory cross-talk with the surrounding tissue and organs. Similarly, it is one of the earliest biological systems targeted by environmental stressors and consequently involved in the development and progression of ageing and age-related disease. Microvascular dysfunction, if not targeted, leads to a steady derangement of the phenotype, which cumulates comorbidities and eventually results in a nonrescuable, very high-cardiovascular risk. Along the broad spectrum of pathologies, both shared and distinct molecular pathways and pathophysiological alteration are involved in the disruption of microvascular homeostasis, all pointing to microvascular inflammation as the putative primary culprit. This position paper explores the presence and the detrimental contribution of microvascular inflammation across the whole spectrum of chronic age-related diseases, which characterise the 21st-century healthcare landscape. The manuscript aims to strongly affirm the centrality of microvascular inflammation by recapitulating the current evidence and providing a clear synoptic view of the whole cardiometabolic derangement. Indeed, there is an urgent need for further mechanistic exploration to identify clear, very early or disease-specific molecular targets to provide an effective therapeutic strategy against the otherwise unstoppable rising prevalence of age-related diseases.

Impact of type 1 diabetes and its duration on wall-to-lumen ratio and blood flow in retinal arterioles.

BACKGROUND: Subclinical damage to both the small and large vessels may contribute to the development and progression of cardiovascular disease. Scanning laser Doppler flowmetry (SLDF), an established method used to measure retinal microcirculation, has been successfully applied in hypertensive and post-stroke patients. METHODS: Retinal microcirculation was assessed in 158 patients with type 1 diabetes and 38 age-matched healthy controls. The diabetics were divided into 3 groups: group A with diabetes duration <12 months, group B with diabetes with 1-10 years, and group C >10 years of diabetes. Retinal capillary structure and perfusion were evaluated using a Heidelberg retina flowmeter and automatically analyzed with full-field perfusion imaging. RESULTS: Age and BMI were comparable in all the diabetic patients and the controls (mean age 24.8 ± 4.7 years, mean BMI 22.9 ± 4.1). In the univariate analyses, RCF (retinal capillary flow) was significantly higher in group A (297 ± 121 arbitrary units [AU]) vs group B (236 ± 52 AU; p = 0.007) and group C (236 ± 70 AU; p = 0.008) and comparable to that of the controls (p = 0.46). Additionally, the WLR (Wall-to-Lumen Ratio) was highest in group C compared to the other diabetic subgroups and controls (p = 0.001). Multivariate regression analyses including age, BMI, sex, HbA1c, smoking, systolic blood pressure, and diabetes duration as covariates, showed, that only diabetes duration was significantly associated with WLR variations, whereas HbA1c was significantly linked to retinal capillary flow levels. CONCLUSIONS: New-onset diabetes is associated with an increase in RCF, which then gradually decreased with the duration of the disease. Structural changes of the retinal arterioles estimated via WLR are evident later in the course of diabetes, especially when the disease duration exceeded 10 years.

Vascular Aging and Damage in Patients with Iron Metabolism Disorders.

Vascular aging is a physiological, multifactorial process that involves every type of vessel, from large arteries to microcirculation. This manifests itself as impaired vasomotor function, altered secretory phenotype, deteriorated intercellular transport function, structural remodeling, and aggravated barrier function between the blood and the vascular smooth muscle layer. Iron disorders, particularly iron overload, may lead to oxidative stress and, among other effects, vascular aging. The elevated transferrin saturation and serum iron levels observed in iron overload lead to the formation of a non-transferrin-bound iron (NTBI) fraction with high pro-oxidant activity. NTBI can induce the production of reactive oxygen species (ROS), which induce lipid peroxidation and mediate iron-related damage as the elements of oxidative stress in many tissues, including heart and vessels' mitochondria. However, the available data make it difficult to precisely determine the impact of iron metabolism disorders on vascular aging; therefore, the relationship requires further investigation. Our study aims to present the current state of knowledge on vascular aging in patients with deteriorated iron metabolism.

COVID-19 vaccination reduces mortality in patients on maintenance hemodialysis.

Patients with chronic kidney disease on maintenance hemodialysis (HD) have a very high risk of death in the course of COVID-19. The aim of the study was to assess the effectiveness of COVID-19 vaccination to reduce the incidence of COVID-19 and the fatality rate in HD patients. A retrospective registry-based cohort study was performed in all HD adult patients in the Pomeranian Voivodeship. Vaccinations were carried out from January to April 2021 with mRNA vaccines, either BNT162b2 or mRNA-1273 with two-dose schedule. In the first analysis (2nd pandemic wave), 1,160 unvaccinated patients were included (59.7% males, 25.7% diabetic). In the second analysis (4th pandemic wave), 1,131 (59.4% male, 30.7% diabetic) individuals were included, 1,042 (92.13%) were fully vaccinated. Three hundred and fifteen HD patients (27.2%) were COVID-19 positive during the 2nd wave, and 6.9% (78/1,131) during the 4th wave. Within the fully vaccinated patients of the 4th wave, 60 were COVID-19 positive, 5.8 vs. 20.2% of unvaccinated COVID-19 positive patients in 2nd wave, respectively. COVID-19 incidence rate ratio (IRR) was 0.21 (4th wave-vaccinated vs. 2nd wave-unvaccinated) indicating a 79% reduction. The IRR between vaccinated and unvaccinated patients of the 4th wave was 0.28 in favor of vaccinated patients with 72% reduction. In the 2nd wave, 93 patients died as a result of COVID-19 (fatality rate: 29.5%). The fatality rate of fully vaccinated patients during the 4th wave was 6.7% (p = 0.004), while the fatality rate in the 4th wave within unvaccinated patients accounted for 11.1%. Significant clinical effectiveness of COVID-19 vaccination was demonstrated in a multicenter study in HD patients.

Predictors of Mortality in Hemodialyzed Patients after SARS-CoV-2 Infection.

INTRODUCTION: The determinants of COVID-19 mortality are well-characterized in the general population. Less numerous and inconsistent data are among the maintenance hemodialysis (HD) patients, who are the population most at risk of an unfavorable prognosis. METHODS: In this retrospective cohort study we included all adult HD patients from the Pomeranian Voivodeship, Poland, with laboratory-confirmed SARS-CoV-2 infection hospitalized between 6 October 2020 and 28 February 2021, both those who survived, and also those who died. Demographic, clinical, treatment, and laboratory data on admission, were extracted from the electronic medical records of the dedicated hospital and patients' dialysis unit, and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with 3-month all-cause mortality. RESULTS: The 133 patients (53.38% males) aged 73.0 (67-79) years, with a median duration of hemodialysis of 42.0 (17-86) months, were included in this study. At diagnosis, the majority were considered to have a mild course (34 of 133 patients were asymptomatic, another 63 subjects presented mild symptoms), while 36 (27.07%) patients had low blood oxygen saturation and required oxygen supplementation. Three-month mortality was 39.08% including an in-hospital case fatality rate of 33.08%. Multivariable logistic regression showed that the frailty clinical index of 4 or greater (OR 8.36, 95%CI 1.81-38.6; p < 0.01), D-Dimer of 1500 ng/mL or greater (6.00, 1.94-18.53; p < 0.01), and CRP of >118 mg/L at admission (3.77 1.09-13.01; p = 0.04) were found to be predictive of mortality. CONCLUSION: Very high 3-month all-cause mortality in hospitalized HD patients was determined mainly by frailty. High CRP and D-dimer levels upon admission further confer mortality risk.

The use of single-pill combinations as first-line treatment for hypertension: translating guidelines into clinical practice.

: The 2008 European Society of Cardiology/European Society of Hypertension guidelines recommend the first-line prescription of two antihypertensive drugs in single-pill combinations (SPCs), also known as fixed-dose combinations, for the treatment of most patients with hypertension. This recommendation is based on a large amount of data, which shows that first-line treatment with SPCs supports reaching blood pressure targets rapidly and reducing cardiovascular outcome risk while keeping the therapeutic strategies as simple as possible and fostering adherence and persistence. As this approach constitutes a big shift from the stepped-care approaches that have been dominant for many years, practicing physicians have expressed concerns about using SPCs as first-line agents. In this review, we will discuss the barriers to the uptake of this recommendation. We will also offer suggestions to reduce the impact of these barriers and address specific concerns that have been raised.

Subclinical macroangiopathic target organ damage in type 1 diabetes mellitus patients.

PURPOSE: We have summarized key studies regarding the assessment of subclinical macroangiopathic target organ damage (TOD) in type 1 diabetes mellitus (T1DM). RESULTS: Although chronic complications resulting from hyperglycemia, in particular macroangiopathies, are still the first cause of death in T1DM, there has been growing recognition of the role of hypoglycemia in cardiovascular morbidity and mortality. Subclinical TOD diagnosis ensures early implementation of the complex management aiming at either partial reversal of these complications or at least its downturn. To better identify patients with early TODs, several non-invasive diagnostic techniques are employed, including the ultrasonographic assessment of the intima-media thickness (IMT), computed tomography (CT) for coronary artery calcium (CAC) scores, and pulse wave velocity (PWV) measurement for arterial stiffness evaluation. Various studies reported that T1DM patients present an increased IMT. An increasing IMT fairly correlates with the cardiovascular (CV) events risk even after the adjustment to age, diabetes duration, quality of glucose control as well as the presence of hypertension, and chronic complications. Another, well established marker of the organ damage - CAC score is recommended by ACC/AHA guidelines to assess the overall CV risk in T1DM. Also, the arterial stiffness evaluation with PWV may further improve CV risk prediction, which has been reported in multiple studies including the Framingham Heart Study. CONCLUSIONS: There is shortage of data from prospective studies which could confirm the benefits of early treatment initiation based on the presence of the subclinical organ damage in T1DM. Most evidence comes from T2DM trials, where effective preventive measures were identified i.e.: smoking cessation, reasonable blood glucose control, efficacious hypertension treatment, and dyslipidemia management, as well as renoprotection. There is still a field for further research to see if routine assessment of asymptomatic vascular damage and early implementation of aggressive treatment would reduce mortality excess from CVD in T1DM.

Update of the position paper on arterial hypertension and erectile dysfunction.

: Sexual health is an integral part of overall health, and an active and healthy sexual life is an essential aspect of a good life quality. Cardiovascular disease and sexual health share common risk factors (arterial hypertension, diabetes mellitus, dyslipidemia, obesity, and smoking) and common mediating mechanisms (endothelial dysfunction, subclinical inflammation, and atherosclerosis). This generated a shift of thinking about the pathophysiology and subsequently the management of sexual dysfunction. The introduction of phosphodiesterase type 5 inhibitors revolutionized the management of sexual dysfunction in men. This article will focus on erectile dysfunction and its association with arterial hypertension. This update of the position paper was created by the Working Group on Sexual Dysfunction and Arterial Hypertension of the European Society of Hypertension. This working group has been very active during the last years in promoting the familiarization of hypertension specialists and related physicians with erectile dysfunction, through numerous lectures in national and international meetings, a position paper, newsletters, guidelines, and a book specifically addressing erectile dysfunction in hypertensive patients. It was noted that erectile dysfunction precedes the development of coronary artery disease. The artery size hypothesis has been proposed as a potential explanation for this observation. This hypothesis seeks to explain the differing manifestation of the same vascular condition, based on the size of the vessels. Clinical presentations of the atherosclerotic and/or endothelium disease in the penile arteries might precede the corresponding manifestations from larger arteries. Treated hypertensive patients are more likely to have sexual dysfunction compared with untreated ones, suggesting a detrimental role of antihypertensive treatment on erectile function. The occurrence of erectile dysfunction seems to be related to undesirable effects of antihypertensive drugs on the penile tissue. Available information points toward divergent effects of antihypertensive drugs on erectile function, with diuretics and beta-blockers possessing the worst profile and angiotensin receptor blockers and nebivolol the best profile.

Facing the Challenge of Lowering Blood Pressure and Cholesterol in the Same Patient: Report of a Symposium at the European Society of Hypertension.

A symposium held at the 29th European Meeting on Hypertension and Cardiovascular Protection in Milan, Italy, discussed the potential impact and long-term benefits of early active management of cardiovascular disease (CVD) risk in patients with hypertension, and potential barriers to this strategy. Hypertension often aggregates with other cardiovascular risk factors, exponentially increasing morbidity and mortality. While effective therapies to treat hypertension exist, a substantial number of patients still experience major cardiovascular events. Two major issues account for these disappointing results: interventions initiated too late in the disease trajectory and lack of effective translation of the research findings into daily clinical practice. Results from genetic studies suggest that lifetime exposure to lower blood pressure (BP) and cholesterol levels due to protective gene mutations, can provide greater cardiovascular benefits than middle-/late-age interventions. Clinical guidelines suggest adding statins to BP-lowering therapies for further cardiovascular benefits in most hypertensive patients; however, real-world data show that physicians' compliance with these recommendations and patients' adherence to BP- and lipid-lowering treatments remain poor, resulting in poor risk factor control and an increased risk of adverse outcomes. The use of single-pill combinations (SPC) can partially mitigate these issues, as they are associated with increased patient adherence and improved BP control. Treatment with SPC has been recommended in the European Hypertension Guidelines, but optimization of the total CVD risk may need adoption of more ambitious treatment strategies aimed to deliver single pills that control multiple CVD risk factors. Amlodipine, perindopril and atorvastatin have been shown to improve BP and lipid levels to a great extent when given separately, and this combination has also been shown to improve cardiovascular outcomes. Overall, early intervention in patients with hypertension with use of an effective, high-intensity cardiovascular risk reduction regimen and attention to medication adherence through reducing pill burden are likely to result in optimal outcomes.

Aortic stiffness is not only associated with structural but also functional parameters of retinal microcirculation.

OBJECTIVE: The aim of the study was to test the hypothesis that alterations in large arteries are associated with microvascular remodelling and decreased retinal capillary blood flow. METHODS: The study group comprised of 88 patients with essential hypertension and 32 healthy controls. Retinal microcirculation was evaluated by scanning laser Doppler flowmetry. Macrovascular changes were assessed on the basis of arterial stiffness measurement (carotid-femoral pulse wave velocity), its hemodynamic consequences (central pulse pressure, augmentation pressure, augmentation index) and intima media thickness of common carotid artery. RESULTS: Pulse wave velocity was inversely correlated to mean retinal capillary blood flow in hypertensive patients (R = -0.32, p < 0.01). This relationship remained significant in multivariate regression analysis after adjustment for age, sex, central systolic blood pressure (BP) and body mass index (ß = -31.27, p < 0.001). Lumen diameter (LD) of retinal arterioles was significantly smaller in hypertensive then normotensive subjects (79.4 vs. 83.8, p = 0.03). Central and brachial systolic, diastolic and mean BPs were significantly correlated with LD and outer diameter of retinal arterioles. The relationship between LD and central BPs remained significant in multivariate analysis (ß = -0.15, p = 0.03 for cSBP; ß = -0.22, p = 0.04 for cDBP; ß = -0.21, p = 0.03 for cMBP). Moreover, in a subgroup with cardiac damage central and brachial pulse pressure were positively associated with retinal wall thickness, wall cross sectional area, and wall to lumen ratio. CONCLUSION: In conclusion, the study provides a strong evidence that microcirculation is coupled with macrocirculation not only in terms of structural but also functional parameters.

Current understanding of the effects of inspiratory resistance on the interactions between systemic blood pressure, cerebral perfusion, intracranial pressure, and cerebrospinal fluid dynamics.

Negative intrathoracic pressure (nITP) is generated by the respiratory muscles during inspiration to overcome inspiratory resistance, thus enabling lung ventilation. Recently developed noninvasive techniques have made it possible to assess the effects of nITP in real time in several physiological aspects such as systemic blood pressure (BP), intracranial pressure (ICP), and cerebral blood flow (CBF). It has been shown that nITP from 0 to -20 cmH2O elevates BP and diminishes ICP, which facilitates brain perfusion. The effects of nITP from -20 to -40 cmH2O on BP, ICP, and CBF remain largely unrecognized, yet even nITP at -40 cmH2O may facilitate CBF by diminishing ICP. Importantly, nITP from -20 to -40 cmH2O has been documented in adults in commonly encountered obstructive sleep apnea, which justifies research in this area. Recent revelations about interactions between ICP and BP have opened up new fields of research in physiological regulation and the pathophysiology of common diseases, such as hypertension, brain injury, and respiratory disorders. A better understanding of these interactions may translate directly into new therapies in various fields of clinical medicine.

Impact of slow breathing on the blood pressure and subarachnoid space width oscillations in humans.

The aim of the study was to assess cardiac and respiratory blood pressure (BP) and subarachnoid space (SAS) width oscillations during the resting state for slow and fast breathing and breathing against inspiratory resistance. Experiments were performed on a group of 20 healthy volunteers (8 males and 12 females; age 25.3 ± 7.9 years; BMI = 22.1 ± 3.2 kg/m2). BP and heart rate (HR) were measured using continuous finger-pulse photoplethysmography. SAS signals were recorded using an SAS monitor. Oxyhaemoglobin saturation (SaO2) and end-tidal CO2 (EtCO2) were measured using a medical monitoring system. Procedure 1 consisted of breathing spontaneously and at controlled rates of 6 breaths/minute and 6 breaths/minute with inspiratory resistance for 10 minutes. Procedure 2 consisted of breathing spontaneously and at controlled rates of 6, 12 and 18 breaths/minute for 5 minutes. Wavelet analysis with the Morlet mother wavelet was applied for delineation of BP and SAS signals cardiac and respiratory components. Slow breathing diminishes amplitude of cardiac BP and SAS oscillations. The overall increase in BP and SAS oscillations during slow breathing is driven by the respiratory component. Drop in cardiac component of BP amplitude evoked by slow-breathing may be perceived as a cardiovascular protective mechanism to avoid target organ damage. Further studies are warranted to assess long-term effects of slow breathing.

Cognitive Dysfunction in Type 1 Diabetes Mellitus.

CONTEXT: We have summarized key studies assessing the epidemiology, mechanisms, and consequences of cognitive dysfunction (CD) in type 1 diabetes. EVIDENCE SYNTHESIS: In a number of studies, the severity of CD in type 1 diabetes was affected by the age of onset and duration, and the presence of proliferative retinopathy and autonomic neuropathy. Diabetes-related CD has been observed, not only in adults, but also in children and adolescents. Most neuroimaging studies of patients with type 1 diabetes did not show any differences in whole brain volumes; however, they did reveal selective deficits in gray matter volume or density within the frontal, posterior, and temporal cortex and subcortical gray matter. Studies of middle-age adults with long-standing type 1 diabetes using diffusion tensor imaging have demonstrated partial lesions in the white matter and decreased fractional anisotropy in posterior brain regions. The mechanisms underlying diabetes-related CD are very complex and include factors related to diabetes per se and to diabetes-related cardiovascular disease and microvascular dysfunction, including chronic hyperglycemia, hypoglycemia, macro- and microvascular disease, and increased inflammatory cytokine expression. These mechanisms might contribute to the development and progression of both vascular dementia and Alzheimer disease. CONCLUSIONS: Higher rates of CD and faster progression in type 1 diabetes can be explained by both the direct effects of altered glucose metabolism on the brain and diabetes-related cardiovascular disease. Because the presence and progression of CD significantly worsens the quality of life of patients with diabetes, further multidisciplinary studies incorporating the recent progress in both neuroimaging and type 1 diabetes management are warranted to investigate this problem.

Impact of orthostatic hypotension and antihypertensive drug treatment on total and cardiovascular mortality in a very elderly community-dwelling population.

OBJECTIVE: The aim of this study was to examine the relationship between orthostatic hypotension, cardiovascular drug intake and mortality in a very elderly community-dwelling population (>80 years of age). METHODS: In 2013-2014, 224 (71 M, 31.7%) 80-year-old individuals from one primary care practice were invited to participate. Basic clinical information was gathered and blood pressure (BP) measurements were performed while sitting and after 1 and 3 min in the standing position on 209 patients. The individuals were followed till December 2016. RESULTS: Orthostatic hypotension was present, depending on applied definition, in 34.5% of the individuals at 1 min, 38.3% at 3 min; 44.9% on either 1 or 3 min, and 27.8% individuals in both measurements. Sixty-nine (30.8%) individuals died during the follow-up. Presence of orthostatic hypotension, irrespective of definition, did not have any significant association with the mortality risk in all groups. Intensive hypertension treatment (more than two drugs versus none) was associated with longer survival. In a multivariate logistic regression analysis, only age and presence of coronary heart disease/congestive heart failure had a negative predictive value on mortality. In both treated and untreated individuals, presence of orthostatic hypotension was not linked to mortality. CONCLUSION: Although orthostatic hypotension is very common among the very elderly, its presence is not related to increased risk of death (all-cause/cardiovascular). Intensively treated elderly patients had significantly longer survival time than untreated individuals.

Lumen narrowing and increased wall to lumen ratio of retinal microcirculation are valuable biomarkers of hypertension-mediated cardiac damage.

Purpose: In the course of hypertension, left ventricular hypertrophy and diastolic dysfunction develop very often and may progress toward heart failure. The aim of the study was to analyze the relationship between abnormalities of retinal microcirculation and cardiac damage defined as left ventricular hypertrophy and/or diastolic dysfunction.Materials and methods: The study comprised 88 patients with essential hypertension. The group was divided into two subgroups: hypertensives without cardiac damage (n = 55) and with cardiac damage (n = 33). Control group comprised 32 normotensive subjects. Scanning laser Doppler flowmetry was used to evaluate retinal microcirculation. Echocardiography was used to assess cardiac damage.Results: Lumen diameter of retinal arterioles was significantly smaller in patients with cardiac damage vs. controls (77 vs. 84 µm, p = 0.02). Additionally, there was an evident trend with respect to lumen diameter (LD) across all three studied subgroups; i.e.: the smallest dimeters were present in cardiac damage patients, moderate size in hypertensives' without cardiac damage, and the largest diameters in healthy controls (pfor trend < 0.01). Lumen diameter was inversely correlated with cardiac intraventricular septum diameter (R = -0.25, p = 0.02), left ventricular mass (R = -0.24, p = 0.02), and left atrial volume (R = -0.22, p = 0.04). Wall to lumen ratio was associated with intraventricular septum diameter (R = 0.21, p = 0.044) and left atrial volume (R = 0.21, p = 0.045). In multivariable regression analysis, lumen diameter was independently associated with intraventricular septum diameter (ß = -0.05, p = 0.03), left ventricular mass (ß = -1.15, p = 0.04), and left atrial volume (ß = -0.42, p = 0.047); wall to lumen ratio was independently associated with intraventricular septum diameter (ß = 3.67, p = 0.02) and left atrial volume (ß = 30.0, p = 0.04).Conclusions: In conclusion, retinal arterioles lumen diameter and wall to lumen ratio were independent biomarkers of cardiac damage. Retinal examination performed by means of scanning laser Doppler flowmetry might be a valuable tool to improve cardiovascular risk stratification of hypertensive patients.