Objective assessment of microcirculatory response in venous disease to therapy

Venous stasis is associated with leucocyte & endothelial activation as well as local growth factor response in chronic venous distasease (CVD). There is no good data on the response of this increased activation to treatment. The theme of this thesis was to show changes in leucocyte/endothelial activation as well as microcirculatory stasis in response to medical, surgical and compression therapy. Thus these may act as objective measures of response to treatment. Vascular endothelial growth factor (VEGF) is being investigated extensively in various arterial scenarios I demonstrated high plasma levels of among patients with CVD for the first time. Levels in patients were about 60% higher (82pg Vs 52 pg in controls). This may represent an (reparative!) angiogenic response existing along with the leucocyte inflammatory response. I used a model of medical treatment (60 days oral flavonoid therapy) and demonstrated significant change in plasma VEGF (50% reduction i.e. 98 pg to 57 pg/dl), ICAM (32%), VCAM (29%) & lactoferrin (36%) levels in patients. Thus I showed that endothelial cell activation (ECA) as well as VEGF might be used as an objective surrogate marker in CVD. I propose that amelioration of endothelial activation may be a mechanism of action for these compounds. I studied the response of these parameters to surgical treatment of varicose veins in 20 patients. I showed that there is an increased plasma lactoferrin at 4 weeks that goes below starting base line levels at 6 months (865 Vs 870 Vs 519). VEGF levels continued to increase (65 Vs 83 Vs 134 pg/dl) in these patients and this may represent vascular remodelling. Although not all of them are easily explainable, the microcirculatory parameters were shown to have a definable response to therapy. I used a new apparatus (Laser capillary anemometer) to assess the response of the velocity of blood in the microvasculature of patients with venous, arterial or mixed disease. I demonstrated that compression increases velocity of blood in the sub-papillary plexus & lower levels of compression (20 mm Hg) are more effective in increasing velocity in patients with mixed disease. This may explain the basis for using compression therapy in these patients. Thus I have shown that various parameters of microcirculation may be used to assess the response to therapy in CVD. Future uses of these findings may include design of new and novel therapeutic approaches and to prognosticate for the development of skin changes and ulceration of the leg in CVD

Preventing Cardiovascular Disease. Complementary precision medicine.

AbstractBackground: Non-communicable diseases are the number one killer worldwide and the leading one,cardiovascular disease (CVD), is responsible for more than 30% of all deaths. CVD is a progressive disease whichalso makes it economical, easy and effective to prevent. There are many stages of CVD that ultimately can lead tocoronary atherosclerosis, measurable as coronary artery calcification (CAC) score by cardiac computed tomography(CT). Before coronary atherosclerosis develops there are many stages of the process: inflammation, reducedendothelial function, hypertension and impaired microcirculation. Precision medicine is a popular novelty inmedicine that combines well-established results and medical history with computer science and novel biomedicalinformation.Aims: The aims of the study were: (I) to evaluate whether aged garlic extract (AGE) can influence CAC and topredict the individual effect of AGE; (II) to assess the effect of long-term treatment with AGE on cutaneous tissueperfusion; (III) to evaluate whether a daily supplement of AGE could reduce inflammation in females with low risk ofcardiovascular disease; (IV) to assess the effect of long-term treatment with AGE on peripheral tissue perfusion inpatients with confirmed atherosclerosis; and (V) to validate a prediction model to explore whether an individualpatient will have a positive effect of AGE on their CAC score and blood pressure.Methods: Studies I-IV were single-centre parallel randomised controlled studies. Patients were randomised, in adouble-blind manner, through a computer-generated randomisation chart to an intake of placebo or AGE (2400 mgdaily) for 12 months. In Study I a prediction model was developed using a cross-industry standard process for datamining and in Study V this method for developing prediction models was validated in a new cohort.The cohort usedwas pooled from previously published studies in the USA.Results: There was a significant change in CAC progression (OR: 2.95 [1.05–8.27]), in favour of the AGE group.The developed algorithm could predict with 79% precision which patient would have a more favourable effect ofAGE on CAC score. Cutaneous microcirculation was measured at 0 and 12 months and the mean post-occlusivereactive hyperaemia (PORH) differed significantly between time points. The mean percent was 102, 64 (174, 15)%change for AGE and 78, 62 (107, 92)% change for the placebo group (F[1, 120] = 5. 95, p < 0.016). Femalestreated with AGE showed lower levels of inflammatory biomarker interleukin-6 (IL-6) after 12 months of AGEtreatment. After 12 months of AGE, an increase of 21.6% (95% CI 3.2%-40.0%, p < 0.05) was seen in the relativechange of PORH. The same response was seen for CVC and acetylcholine with an increase of 21.4% (95% CI3.4%-39.4%, p < 0.05) in the AGE group. Study V demonstrated that it is possible to develop predictive models.Theconstructed algorithm was able to predict with 64% precision which patient would have a significant reduction ofCAC.Conclusion: AGE inhibits CAC progression, lowers IL-6, glucose levels and blood pressure and increases themicrocirculation in patients at increased risk of cardiovascular events. It is also possible to predict which patient willhave a more favourable effect of AGE. AGE lowers IL-6 in females with a low risk of CVD. AGE regeneratedperipheral tissue perfusion and increased microcirculation in patients with arteriosclerosis.For many patients it is essential to know if they will have an effect of a treatment before changing their daily lives.The developed algorithm shows that it is feasible to develop predictive models for answering this question

Basic and Clinical Understanding of Microcirculation

Microcirculation is key to providing enough nutrition and oxygen from head to toe. This is possible only through an extensive network of blood vessels spread around the body. Effect of microcirculation abnormalities stretch beyond one’s comprehension. The effects could be felt at any age, from the foetal life to the adulthood. The chapters present in this book describe how these abnormalities could lead to diseases such as atherosclerosis, thrombosis, diabetes, hypertension. Disorders of microcirculation could be related to the structural and/or functional damage to the inner lining of the blood vessels. Early identification of these disorders could benefit many ailments including cardiovascular and cerebrovascular diseases such as heart attack and stroke

Why Venous Leg Ulcers Have Difficulty Healing: Overview on Pathophysiology, Clinical Consequences, and Treatment

none5sìVenous leg ulcers (VLUs) are one of the most common ulcers of the lower extremity. VLU affects many individuals worldwide, could pose a significant socioeconomic burden to the healthcare system, and has major psychological and physical impacts on the affected individual. VLU often occurs in association with post-thrombotic syndrome, advanced chronic venous disease, varicose veins, and venous hypertension. Several demographic, genetic, and environmental factors could trigger chronic venous disease with venous dilation, incompetent valves, venous reflux, and venous hypertension. Endothelial cell injury and changes in the glycocalyx, venous shear-stress, and adhesion molecules could be initiating events in VLU. Increased endothelial cell permeability and leukocyte infiltration, and increases in inflammatory cytokines, matrix metalloproteinases (MMPs), reactive oxygen and nitrogen species, iron deposition, and tissue metabolites also contribute to the pathogenesis of VLU. Treatment of VLU includes compression therapy and endovenous ablation to occlude the axial reflux. Other interventional approaches such as subfascial endoscopic perforator surgery and iliac venous stent have shown mixed results. With good wound care and compression therapy, VLU usually heals within 6 months. VLU healing involves orchestrated processes including hemostasis, inflammation, proliferation, and remodeling and the contribution of different cells including leukocytes, platelets, fibroblasts, vascular smooth muscle cells, endothelial cells, and keratinocytes as well as the release of various biomolecules including transforming growth factor-β, cytokines, chemokines, MMPs, tissue inhibitors of MMPs (TIMPs), elastase, urokinase plasminogen activator, fibrin, collagen, and albumin. Alterations in any of these physiological wound closure processes could delay VLU healing. Also, these histological and soluble biomarkers can be used for VLU diagnosis and assessment of its progression, responsiveness to healing, and prognosis. If not treated adequately, VLU could progress to non-healed or granulating VLU, causing physical immobility, reduced quality of life, cellulitis, severe infections, osteomyelitis, and neoplastic transformation. Recalcitrant VLU shows prolonged healing time with advanced age, obesity, nutritional deficiencies, colder temperature, preexisting venous disease, deep venous thrombosis, and larger wound area. VLU also has a high, 50-70% recurrence rate, likely due to noncompliance with compression therapy, failure of surgical procedures, incorrect ulcer diagnosis, progression of venous disease, and poorly understood pathophysiology. Understanding the molecular pathways underlying VLU has led to new lines of therapy with significant promise including biologics such as bilayer living skin construct, fibroblast derivatives, and extracellular matrices and non-biologic products such as poly-N-acetyl glucosamine, human placental membranes amnion/chorion allografts, ACT1 peptide inhibitor of connexin 43, sulodexide, growth factors, silver dressings, MMP inhibitors, and modulators of reactive oxygen and nitrogen species, the immune response and tissue metabolites. Preventive measures including compression therapy and venotonics could also reduce the risk of progression to chronic venous insufficiency and VLU in susceptible individuals.openRaffetto, Joseph D; Ligi, Daniela; Maniscalco, Rosanna; Khalil, Raouf A; Mannello, FerdinandoRaffetto, Joseph D; Ligi, Daniela; Maniscalco, Rosanna; Khalil, Raouf A; Mannello, Ferdinand

Wyciąg z ruszczyka kolczastego w leczeniu przewlekłej choroby żylnej

Leczenie przewlekłej choroby żylnej łączy postępowanie zachowawcze, które obejmuje terapię uciskową i stosowanie leków flebotropowych, oraz procedury zabiegowe. Leki flebotropowe są zalecane we wszystkich stadiach przewlekłej choroby żylnej. Jednym z najczęściej stosowanych leków flebotropowych są wyciągi z ruszczyka kolczastego. Zawarte w nich saponiny sterolowe: ruskogenina i neoruskogenina, zmniejszają przepuszczalność naczyń, wykazują działanie przeciwzapalne, naczyniozwężające, a także przeciwkrzepliwe oraz hamują aktywność elastazy uszkadzającej włókna elastynowe. Preparaty zawierające wyciąg z ruszczyka stosowane przewlekle zmniejszają zarówno nasilenie bólu, skurczów, uczucia ciężkości nóg i parestezji, jak i objętość krwi żylnej zalegającej w kończynach dolnych (o 0,7 ml/100 ml), prowadząc do zmniejszenia obwodu łydki (o 7,3 mm) i w kostce (o 11,7 mm) oraz redukcji obrzęków u pacjentów z przewlekłą chorobą żylną. Ostatnio w badaniu obserwacyjnym wykazano również porównywalny wpływ preparatów zawierających diosminę i wyciąg z ruszczyka kolczastego na proces gojenia się owrzodzeń żylnych. Skuteczność preparatów zawierających wyciągi z ruszczyka kolczastego w łagodzeniu objawów przewlekłej choroby żylnej została potwierdzona w badaniach randomizowanych z zastosowaniem placebo

Vascular Diseases of the Gastrointestinal Tract

Chronic gastrointestinal ischemia (CGI) results from insufficient blood supply to the stomach, small intestine and colon. In most cases this is caused by stenosis of the supplying arteries with lack of sufficient collateral circulation. Most often the stenosis is due to atherosclerosis [1], but other non-occlusive causes are also known [2, 3]. Three direct branches of the abdominal aorta are responsible for the arterial blood supply of the gastrointestinal tract: the celiac artery (CA), the superior mesenteric artery (SMA) and the inferior mesenteric artery (IMA). CGI is a diagnostic challenge. Currently, there is no single test with high sensitivity and specificity to diagnose or exclude this condition. The aim of this thesis is to explore various aspects and diagnostic methods for the detection of CGI, by means of functional testing using VLS, a prediction model for CGI, and hypoxia-inducible factor-1α (HIF-1α) as a marker for CGI. This is followed by studies of CGI due to portal vein thrombosis and CGI induced liver injury. Furthermore, treatment of other vascular diseases of the gastrointestinal tract such as variceal bleeding, are discussed

The influence of exercise on ulcer healing in patients with chronic venous insufficiency

Venous leg ulcer (VLU) is a common chronic clinical problem and it is the most serious complication of chronic venous insufficiency. Although venous ulcer has a huge burden on individuals and states, the standard type of treatment for this debilitating condition, compression therapy, has not changed in the last 2000 years. There is growing evidence that exercise could help in venous ulcer management. This study investigated the effect of exercise on 80 VLU patients. These patients were randomised into four groups; a control group, a compression therapy only group, an exercise only group and a compression and exercise group. Non-invasive measurements were performed at the beginning of the 3 month period of regular exercise, and again at the end of the exercise period. This was necessary in order to evaluate the effect of exercise on VLU healing parameters, which include; tcPO2 level, laser Doppler measurements, resting skin flux (RF), range of ankle joint movement (ROM) and ulcer size. The exercise composed of 10 dorsiflexions each hour, while the participant was awake over a period of 3 months. Findings included, an increase in the tcPO2 level and range of ankle joint movement in individuals who had performed the exercise compared to those who did not (p < 0.001). Moreover tcPO2 measurements were higher in the exercise and compression group than those seen in the exercise only group. Ulcer size and RF measurements decreased in patients who had performed exercise compared to those who did not, groups 3 and 4 showed a significant decrease in ulcer size with p values = 0.001 and < 0.001 respectively. With RF measurements, only groups 3 and 4 showed significant decrease, p < 0.001. The findings indicated that there were changes in the VLU parameters in response to the 3 months period of regular exercise. Regular unsupervised exercise may be included as an integral part of the leg ulcer management.Open Acces

Novel diagnostic approaches and management of coronary microvascular dysfunction

\ua9 2024 The Authors. The mechanism underlying ischaemic heart disease (IHD) has been primarily attributed to obstructive coronary artery disease (CAD). However, non-obstructive coronary arteries are identified in &gt;50% of patients undergoing elective coronary angiography, recently leading to growing interest in the investigation and management of angina/ischaemia with non-obstructive coronary arteries (ANOCA/INOCA). INOCA is an umbrella term encompassing a multiple spectrum of possible pathogenetic entities, including coronary vasomotor disorders which consist of two major endotypes: coronary microvascular dysfunction (CMD) and vasospastic angina. Both conditions can coexist and be associated with concomitant obstructive CAD. Particularly, CMD refers to myocardial ischaemia due to reduced vasodilatory capacity of coronary microcirculation secondary to structural remodelling or impaired resting microvascular tone (functional) or a combination of both. CMD is not a benign condition and is more prevalent in women presenting with chronic coronary syndrome compared to men. In this setting, an impaired coronary flow reserve has been associated with increased risk of major adverse cardiovascular events. ANOCA/INOCA patients also experience impaired quality of life and associated increased healthcare costs. Therefore, research in this scenario has led to better definition, classification, and prognostic stratification based on the underlying pathophysiological mechanisms. The development and validation of non-invasive imaging modalities, invasive coronary vasomotor function testing and angiography-derived indices provide a comprehensive characterisation of CMD. The present narrative review aims to summarise current data relating to the diagnostic approach to CMD and provides details on the sequence that therapeutic management should follow