The aim of the research is to analyse the influence of polymorphisms of endothelin-1 gene and endothelin-1 receptor type A gene on the clinical condition of patients with primary open angle glaucoma. Methods. 285 Polish patients took part in the research . DNA was isolated by standard methods and genotype distributions of four polymorphisms in genes encoding endothelin-1 (K198N) and endothelin-1 receptor type A polymorphisms  were determined. Genotype distributions were compared between NTG and HTG groups. The clinical condition of participants was examined for association with polymorphisms. Results. A similar frequency of occurrence of the polymorphic varieties of the studied genes was observed in patients with NTG and HTG. There is no relation between NTG risk factors and examined polymorphisms. NTG patients with TT genotype of K198N polymorphism presented with the lowest intraocular pressure in comparison to GG + GT genotype (p = 0.03). In NTG patients with CC genotype of C1222T polymorphism (p = 0.028) and GG of C70G polymorphism (p = 0.03) the lowest values of mean blood pressure were observed. Conclusions. The studied polymorphic varieties  do have an influence on intraocular pressure as well as arterial blood pressure in NTG patients. The term “glaucoma” describes a group of diseases that result in progressive and irreparable optic nerve damage characterised by typical advancing changes in the optic disc and ensuing visual field defects. Normal-tension glaucoma (NTG) is a particular kind of glaucoma with a characteristic glaucomatous cupping of the optic disc, visual field defects, open anterior chamber angle, and intraocular pressure classified as normal.Elevated intraocular pressure is one of the most important risk factors in glaucoma development. However, its reduction in patients with normal-tension glaucoma does not entirely prevent the disease from advancing. Research done by the Collaborative Normal-Tension Glaucoma Study Group (CNTGSG) suggests other factors that play a role in the pathogenesis of glaucomatous optic neuropathy. Special attention is paid to primary vascular dysregulation since its symptoms, such as low arterial blood pressure, cold extremities, Raynaud's syndrome, and migraines, often are present in persons with normal-tension glaucoma .So far, scientific research has resulted in a few theories explaining the pathomechanism of glaucomatous optic neuropathy.Mechanical theory assumes that elevated intraocular pressure (IOP), the main risk factor in glaucomatous optic neuropathy, plays an important role in the optic nerve damage. In 1957 Von Graefe noticed that there exists a relation between elevated intraocular pressure and deformation of the lamina cribrosa . NumerouAccording to the vascular theory, glaucomatous optic neuropathy is triggered by a variety of systemic and local vascular factors leading to low ophthalmic perfusion and ischemia. Among systemic factors we can list the following: hypertension and hypotension, cardiovascular diseases, diabetes, and cerebral circulation disorders . TopicalExcitotoxicity theory posits that there are many processes which contribute to the development of glaucomatous optic neuropathy, for example, the toxic influence of cell mediators, neurotrophin deficiency, ischemia, or apoptosis. Ischemia, caused by autoregulation mechanism disorders and endothelium dysfunction, stimulates the release of ET-1, norepinephrine, and nitric oxide (NO), which in turn influence the blood flow in the optic disc. Subsequent reperfusion results in a considerable rise in free oxygen radicals and nitrogen compound concentration. NMDA receptor is then activated which fuels NO synthesis and radicals production. Toxic peroxynitrates, produced in the process, lead to retinal ganglion cell apoptosis.AR and ETBR, which have the opposite effect. Numerous in vitro research has demonstrated that ET-1 can be found in the corneal epithelium, endothelium cells, pigmented part of ciliary body, iris, trabecular meshwork, lens, choroid, retinal pigment epithelium, retinal ganglion cells, and astrocytes [A receptors have been identified in the retinal and choroidal vessels as well as in the iris, whereas ETB receptors have been found in the retinal neurons, glia, and ciliary body. Both kinds of receptors can be found in the lamina cribrosa, which suggests that ET-1 plays an important role in local extracellular matrix remodelling and vascular wall stress regulation [Endothelin-1 (ET-1), discovered by Yanagisawa et al. in 1988 , the strtrocytes . ETA recgulation . Therefo285 Polish Caucasian patients treated at the Department of Diagnostics and Microsurgery of Glaucoma in Lublin (Poland) between 2009 and 2013 took part in the study. To demonstrate the differences between the two types of primary open-angle glaucoma patients were divided into two groups: those diagnosed with normal-tension glaucoma  and those presenting with high-tension glaucoma (HTG) and intraocular pressure above 21 mmHg . Patients were accepted for the study only if they had been previously informed about the aim and scope of the research, expressed their consent for participating in the study, and met the following criteria. The investigation was conducted in compliance with the tenets of the Declaration of Helsinki.Criteria for diagnosing high-tension glaucoma (with high intraocular pressure) are as follows: diagnosed glaucomatous optic neuropathy based on changes in the optic disc and visual field defects, open anterior chamber angle in gonioscopy, and intraocular pressure above 21 mmHg at the time of diagnosis evaluated on the basis of a 24-hour intraocular pressure monitoring. In the case of NTG intraocular pressure at the time of diagnosis was below 21 mmHg.A comprehensive ophthalmic examination was performed in both groups. Visual acuity was tested using Snellen charts. Intraocular pressure was measured by means of an applanation tonometer. An ultrasound pachymeter was used to measure the thickness of cornea. All patients were also given a biomicroscopic examination with a slit lamp. To assess anterior chamber angle a gonioscopy was performed using a Zeiss gonioscope. Schaffer classification was applied in evaluating the width of the angle. Examination of the fundus of the eye made it possible to assess the optic disc structure, presence of peripapillary atrophy, notching of the neuroretinal rim, and optic disc haemorrhages. Moreover, patients with best corrected visual acuity equal to or better than 0.1 had their visual field analysed using Humphrey perimeter and 30-2 SITA-Fast strategy. Results were considered credible if the sum of falsely positive and falsely negative answers was lower than 15%. When assessing the results of visual field analysis, the mean deviation (MD) at the time of diagnosis  was taken into account. Prior to clinical examination patients were asked whether they had been diagnosed with hypertension, hypotension, diabetes mellitus, or any cardiovascular disorders .DNA was isolated from peripheral blood leukocytes by means of QIAamp DNA Blood Midi Kit . DNA concentration was measured using NanoDrop 2000/2000c Spectrophotometer V1.0 (Thermo Fisher Scientific). TaqMan SNP probe (Applied Biosystems) and CFX96 Real-Time PCR Detection System thermal cycler (Bio-Rad) were used to assay 4 polymorphisms of the single nucleotide of the endothelin-1 gene (K198N) and endothelin-1 receptor type A . DNA amplification was obtained by means of a Real-Time Polymerase Chain Reaction .K198N polymorphism of the endothelin-1 gene (rs 5370) leads to transversion of purine guanine (G) into pyrimidine thymine (T) in nucleotide 5665 in exon 5 (Lys/Asn change in codon 198). C1222T polymorphism of the endothelin-1 receptor type A gene (rs 5343), involving transition of pyrimidine cytosine (C) into thymine (T), concerns nucleotide 1363 in exon 8 in 3′ untranslated region (3′UTR). C70G polymorphism of the endothelin-1 receptor type A gene (rs 5335) is a transversion of pyrimidine cytosine (C) into purine guanine (G) and is located in 3′ untranslated region (3′UTR). This polymorphism concerns nucleotide 211 in exon 8. Point mutation changes the chemical structure of DNA; however, its function still remains unknown. Polymorphism of the EDN RIn order to assess patients' arterial blood pressure rhythm a 24-hour ambulatory blood pressure monitoring was conducted using an ABPM device.p < 0,05 was considered statistically significant.Statistical analysis of the obtained results was conducted by means of the IBM SPSS Statistica 19 and Statistica 10 software. The value of Differences in age and sex in both study groups were not demonstrated. More demographics data are presented in χ2 test, p < 0.05). GT genotype was more frequent in men with NTG rather than with HTG (40% versus 28.9%). The difference was statistically significant .When analysing C1222T polymorphism it was observed that in both groups homozygous wild type CC genotype appeared in 100 patients (35.2%), homozygous mutant TT genotype in 41 patients (14.4%), and heterozygous CT genotype in 143 patients (50.4%). TT genotype was more frequent in men with NTG rather than with HTG (22% versus 13.2%).χ2 test, p > 0.05).There was no statistically significant difference in the frequency of occurrence of particular genotypes of C70G and G231A polymorphisms in both study groups  .When comparing both groups in terms of the frequency of occurrence of particular genotypes of the researched polymorphisms, no statistically significant differences were found ((i) Intraocular Pressure. Intraocular pressure differed statistically significantly between the two groups . When analysing K198N polymorphism the lowest intraocular pressure, 13.7 mmHg, was observed in the group of patients with NTG with TT genotype and the highest pressure, 17.6 mmHg, in patients with GG genotype . There were no statistically significant differences between intraocular pressure and the occurrence of particular genotypes of C1222T, C70G, and G231A polymorphisms in the study groups . Interestingly, the highest intraocular pressure was observed in patients with HTG with AA genotype of G231A polymorphism, whereas in patients with NTG and with the same genotype intraocular pressure was one of the lowest (14.8 mmHg), however, without statistical significance  ( > 0.05) . (ii) Visual Field. Average value of the mean deviation (MD) at the time of diagnosis was −8.58 dB in the group of patients with normal-tension glaucoma and −13.83 dB in the group of patients with high-tension glaucoma. Average value of MD at the time of glaucoma diagnosis was statistically significant in both study groups . There was no relation between the stage of glaucoma and the occurrence of particular genotypes of the studied polymorphisms (orphisms .(iii) Influence of Gene Polymorphisms on Vascular Risk Factors Tables  and 9. Optic disk haemorrhages were present in 27 patients (18.7%) from the NTG group and 4 patients (4.3%) from the HTG group .Notching of the neuroretinal rim was observed in 50.7% of patients (70 persons) with normal-tension glaucoma and 16.3% of patients (14 persons) with high-tension glaucoma . Moreover, in the group of patients with NTG, notching was statistically significantly more frequent in women than in men .Peripapillary atrophy was present in 21.7% of patients with normal-tension glaucoma and 13.4% of patients with high-tension glaucoma. No statistically significant changes were demonstrated in peripapillary atrophy occurrence in both study groups .χ2, p > 0.05).In the group of patients with NTG there was no relation between the occurrence of polymorphic variations of the studied genes and the occurrence of risk factors such as optic disc haemorrhages, notching, or peripapillary atrophy  than with HTG (28.6%), . What is more, in both study groups these symptoms were more common in women  rather than in men .Low arterial blood pressure presented much more often in the group of patients with NTG (69.7%) than in the group of patients with HTG (16.7%). The frequency of occurrence of low blood pressure in both study groups was statistically significantly different . Additionally, in the group of patients with NTG low blood pressure was much more common in women (77.8%) than in men (33.3%), χ2 test with Yates's correction for continuity, p = 0.02. migraines, and they were predominantly women .In both study groups only NTG patients complained ofχ2 test, p > 0.05).No statistically significant relation was observed between symptoms such as cold extremities, low blood pressure and migraines, and the occurrence of particular genotypes of the studied polymorphisms in both groups  and lowest in persons with homozygous wild type CC genotype (123 ± 14.7 mmHg). The difference was statistically significant, ANOVA test, p = 0.028. An interesting observation is that average diastolic pressure at night was highest in patients with homozygous mutant TT genotype (72.4 ± 15.2 mmHg) and the lowest in patients with homozygous wild type CC genotype (61.3 ± 6 mmHg). The difference was close to being statistically significant, ANOVA test, p = 0.055.Maximum systolic pressure during the day was observed in patients with CT genotype (176.8 ± 33.1 mmHg) and the lowest in patients with homozygous CC genotype (152.3 ± 21.2 mmHg). The difference is statistically significant, ANOVA test, p = 0.088. The lowest average systolic pressure at night was observed in patients with homozygous GG genotype (103.8 ± 9.91 mmHg) and the highest in patients with heterozygous CG genotype (116.45 ± 15.62 mmHg), ANOVA test, p = 0.081.The highest average systolic pressure during the day was observed in persons with heterozygous CG genotype (135.8 ± 10.36 mmHg) and the lowest in patients with homozygous mutant GG genotype (124 ± 25.73 mmHg), ANOVA test, When comparing G231A polymorphism genotypes of the endothelin-1 receptor type A gene and ambulatory blood pressure monitoring results, no statistically significant differences were shown.Polymorphisms of the endothelin-1 gene are in the centre of attention of many scientists from different fields of medicine. Unfortunately, among all studies available in international literature there are only few concerning their relation to the development and occurrence of glaucoma.Many reports confirm that endothelin-1 has its part in the pathogenesis of glaucoma by influencing local blood flow in the eyeball, as well as regulating intraocular pressure and retinal ganglion cell apoptosis. Hence, it seems justified to search for a relation between ET-1 gene and ET-1 receptor type A polymorphisms and the development and occurrence of glaucomatous optic neuropathy, especially normal-tension glaucoma, whose risk factors are related to vasoconstriction.In our research, when comparing the frequency of occurrence of particular genotypes of K198N polymorphism of the endothelin-1 gene, C1222T, C70G, and G231A of endothelin-1 gene receptor type A, no statistically significant differences were demonstrated between the study groups , also taking into account the patients' gender. So far, not many publications referring to the above-mentioned issue have been released.p = 0.022)) [p < 0.05). In addition, homozygous wild type genotype was more common in women (76.7% in POAG versus 72.7% in NTG) rather than in men (66% POAG versus 54% NTG) (p > 0.05). The above results might suggest a possible relation between K198N polymorphism of the endothelin-1 gene and glaucoma occurrence. Further research including healthy patients should be conducted to confirm this hypothesis.Ishikawa et al. compared the frequency of occurrence of the polymorphisms of the endothelin-1 gene and its receptors among Japanese population. 426 patients with open-angle glaucoma  and 225 healthy persons participated in the research. They were able to show statistically significant differences in the frequency of occurrence of KK genotype of K198N polymorphism in the study groups ) . Interesp = 0.036) [Furthermore, Ishikawa et al. demonstrated that CC genotype of C1222T polymorphism of the endothelin-1 receptor type A gene was much more common among healthy patients . In our research we obtained a similar pattern of genotypes: CC genotype was present in 35% of patients with NTG (56 persons), CT genotype in 49.4% (79 persons), and TT genotype in 15.6% (25 persons). Later, the researchers compared the frequency of occurrence of C70G and G231A polymorphisms. They were unable to obtain statistically significant results. To sum up, on the basis of the findings the authors of the study were able to confirm a relation between C1222T polymorphism of the endothelin-1 receptor type A and the development of NTG in Korean population [Genetic background of glaucoma development was the subject of a research by Kim et al., who studied polymorphisms of the endothelin-1 gene and its receptors in Korean population. Their study group were 67 patients with normal-tension glaucoma and 100 healthy persons (not treated for glaucoma). The following pattern of C1222T polymorphism genotypes was obtained: CC genotype was observed in 46.3% of patients with NTG (31 persons) and 49% from the control group (49 persons), CT genotype was present in 38.8% of patients with NTG (26 persons) and in 46% of healthy persons (46 persons), and mutant TT genotype was observed in 14.9% of patients with NTG (10 persons) and in 5% from the control group (5 persons) .However, the lowest intraocular pressure at the time of diagnosis was observed in patients with normal-tension glaucoma and homozygous mutant TT genotype of K198N polymorphism (13.7 ± 2.6 mmHg) in comparison to other genotypes (GG genotype 16.8 ± 3.7 mmHg and GT genotype 16.1 ± 3.8 mmHg) (p = 0.047) [p = 0.241). According to above data the presence of homozygous mutant AA genotype of G231A polymorphism might be a good prognostic factor for patient with NTG. The function of this polymorphism is still unknown; then further research is needed to explain it.When analysing the relation between polymorphisms of the endothelin-1 gene and its receptors, Kim et al. noticed a statistically significant difference in the level of the intraocular pressure at the time of diagnosis of NTG between persons with AA genotype of G231A polymorphism (14.0 ± 2.8 mmHg) and GG + GA genotypes (16.2 ± 2.3 mmHg) (p = 0.28).When comparing the occurrence of C70G polymorphism genotypes in patients with normal-tension glaucoma, Ishikawa et al. did not notice any differences in intraocular pressure between particular genotypes  . Similarp < 0.0001). Häntzschel et al., while analysing visual field defects and loss of retinal nerve fibres, observed smaller visual field defect in patients with normal-tension glaucoma than in patients with primary open-angle glaucoma  [p = 0.015).In our study glaucoma, at the time of diagnosis, was less advanced according to MD in the group of patients with normal-tension glaucoma (−8.58 ± 6.26 dB) than in patients with high-tension glaucoma (−13.83 ± 7.01 dB) ( 0.0001) . Our resThe pathogenesis of optic disc haemorrhages is not yet known. It is not clear which vessels they originate from: arterioles, venules, or capillaries. One of theories claims that sudden changes of pressure in stiff scleral vessels lead to their mechanical tear. Others point to the role of primary vascular dysregulation. Elevated level of ET-1 and MMP-9 might spread from the choroid to the optic disk causing vasoconstriction, ischemia, and blood-brain barrier disruption. Such sequence of events might explain optic disk haemorrhages in patients with normal-tension glaucoma . What isFor many years the influence of blood pressure on the development of glaucomatous optic neuropathy, especially normal-tension glaucoma, has been extensively studied. It has been pointed out in many works that hemodynamic parameters such as reduced ocular blood flow and fluctuations in ocular perfusion pressure, nocturnal fall of blood pressure, autoregulation dysfunctions, and migraines, might be the reason for ischemia and optic nerve damage . AmbulatOcular perfusion pressure, understood as a difference between average arterial blood pressure and intraocular pressure, is a crucial parameter for supplying optic nerve in necessary elements. A research conducted by Ramli et al. showed that patients with normal-tension glaucoma had much lower parameters of nocturnal blood pressure and ocular perfusion pressure than healthy persons, which only supports the great importance of ischemia theory in the pathogenesis of normal-tension glaucoma , 20.On the basis of a research by Barbados Eye Study and Framingham Eye Study, diastolic perfusion pressure was acknowledged to be the most permanent vascular risk factor in the development of glaucomatous optic neuropathy , whereasp = 0.039). Taking into account the low pressure as a risk factor for normal-tension glaucoma pathogenesis, it seemed advisable to determine the relationship between systemic blood pressure values and presence of studied polymorphisms only in NTG group. We analysed the relation between the occurrence of particular genotypes of the studied K198N polymorphisms of the endothelin-1 gene, C1222T, C70G, and G231A of the endothelin-1 receptor type A, and ambulatory blood pressure monitoring results. In the case of K198N polymorphism a much higher maximum systolic blood pressure and average systolic blood pressure during the day were observed in patients with heterozygous GT genotype rather than those with homozygous wild type genotype. The difference was close to being statistically significant (p = 0.06). In order to confirm the preliminary observations, the study group should be larger.Following Flammer, who found that nocturnal blood pressure dips are the only risk factor in patients with rapidly developing optic nerve damage in NTG, we investigate systemic blood pressure abnormalities in this group. On the basis of the interview obtained from patients and their medical history we noticed that low blood pressure was presented much more often in NTG group (69.7%) than in HTG group (16.7%) (p = 0.041 and p = 0.028). Interestingly, the highest average nocturnal diastolic pressure was observed in patients with homozygous mutant TT genotype (72.4 ± 15.2 mmHg) and the lowest with homozygous wild type CC genotype (61.3 ± 6 mmHg). The difference was close to statistical significance (p = 0.055).In the case of C1222T polymorphism a statistically significantly higher maximum systolic blood pressure during the day and average systolic blood pressure during the day were observed in the group of patients with heterozygous CT genotype (176.8 ± 33.1 mmHg and 137.4 ± 16.6 mmHg) in comparison to homozygous CC genotype (152.3 ± 21.2 mmHg and 123 ± 14.7 mmHg) (Undoubtedly, polymorphisms of the studied genes do have an influence on the level of arterial blood pressure and its regulation. The above observations might point at the existence of autoregulation mechanisms dysfunction, vascular dysregulation, or even the dysfunction of vascular endothelium responsible for endothelin release. The mechanisms by which those polymorphisms affect function remain to be examined and clarified since functional studies are not yet available.In patients with NTG and HTG a similar frequency of occurrence of polymorphic variants of the studied genes was observed. The is no relation between NTG risk factors and K198N, C1222T, C70G, and G231A polymorphisms. The studied polymorphic variants have an influence on the level of intraocular pressure and arterial blood pressure in patients with NTG. Endothelin might play an important role in glaucoma pathogenesis. Giving a better knowledge of risk factors of NTG will give us more effective tools for preventing its development or even minimizing the glaucomatous damage.


The standardized techniques of blood pressure measurement in the clinic are emphasized and the indications for ambulatory and/or home blood pressure monitoring are specified more broadly. The epidemiologic findings specific to Korean population related to blood pressure are reviewed. Cardiovascular risk of hypertensive patients are stratified based upon the data of a Korean population cohort study. Since the publication of the last Korean Hypertension Treatment Guideline in 2004, new studies have been released and new data on antihypertensive drugs introduced. In response to the changes, the Guideline Committee of the Korean Society of Hypertension began to revise its guideline. To perfectly tailor the needs of our clinical practices, the guideline needs to be based on a great deal of studies performed in Korea. Unfortunately, in reality, there is currently a serious shortage of such study results. The Committee therefore decided to establish the guideline in the form of adaptation. The recently released guideline on hypertension from the European Society of Hypertension/the European Society of Cardiology which is designed to encompass the diverse cardiovascular disease risk levels and socioeconomic statuses of the member nations, and which, therefore, has a broad scope of recommendations, was chosen as a model. Accordingly, a large portion of the 2013 Korean guidelines is based on the European recommendations, although some necessary adjustments are made.Hypertension (HTN) is defined as systolic blood pressure (SBP) or diastolic blood pressure (DBP) greater than or equal to 140 or 90 mm Hg, respectively  risk in evaluation of the risk of high BP. In the best-documented domestic study of the risk of high BP, which enrolled approximately 100,000 male civil officers and private school teachers , the hazard ratio for cerebrovascular and coronary artery disease during a 6-year follow-up period was 2.6 for the HTN group relative to the subjects with BP less than 130/85 mm Hg -6. In anIn the Korean National Health and Nutrition Examination Survey (KNHANES), the age-standardized prevalence of HTN, defined as SBP/DBP of 140/90 mm Hg or higher, was approximately 30% among adults over 30 years of age.As shown in Table BP rises with age, and the difference in BP between the sexes diminishes among those aged more than 60 years. The prevalence of HTN is more than 50% in this older population, i.e., 60 or more years Figure . In geneIn KNHANES 2005, the prevalence of HTN among the elderly was 53.7% among those in their 60s and 54.9% among those in their 70s. The prevalence of HTN among those in their 60s was 53.8% in men and 53.6% in women, showing that the sex difference disappeared among those aged 60 or older. As shown in KNHANES 2011, SBP steadily increase with age more than 60 years  in secondary or tertiary referral centers supported by the Korean Society of Hypertension (KorABP registry) , 14.9% o‘Masked HTN’ is defined as the condition in which the office BP is less than 140/90 mm Hg and the daytime ambulatory BP or home BP is 135/85 mm Hg or higher. According to the KorABP registry data, masked HTN was observed in 17.6% of patients who underwent ABPM for the diagnosis of HTN . Masked There has been no study of white coat HTN and masked HTN in a Korean general population. A study in a western population showed that white coat HTN carries a good prognosis over a follow-up period of 5 years but is associated with increased risk for the onset of HTN and occurrence of CV events over the long-term; therefore, patients with white coat HTN should be monitored regularly . In foreAccurate measurement of BP is necessary for the diagnosis, treatment, and prognostication of individuals with high BP. BP varies according to the environment, body part, and clinical setting of measurement. Therefore, the measurement should be repeated and a standard method should be used.In an office or clinic, BP is usually measured by the auscultation method using a stethoscope. The subject is seated on a chair with his or her back supported. The cuff is placed on the upper arm and maintained at the level of the heart. A mercury or calibrated aneroid sphygmomanometer is used. An automatic sphygmomanometer that has been validated may also be used. The use of mercury sphygmomanometers is decreasing because of the risk of environmental mercury pollution. The use of an automatic sphygmomanometer is recommended in some countries. After the patient has rested for five or more minutes, the BP is measured by the auscultation method. The measurement is performed two or more times. A cuff with an appropriately sized bladder should be used. The standard bladder for adults is 13 cm wide and 22 to 24 cm long. The use of a bladder with a width of at least 40% of the circumference of the arm and a length of 80% to 100% of the circumference of the arm is recommended.A cuff of appropriate size as recommended by the manufacturer should be used. A cuff that is too small can produce an artificially high BP reading, whereas a cuff that is too large can produce an artificially low BP reading. If the pulses of the lower extremities are weak, BP is measured in the legs to exclude the possibility of peripheral arterial disease. The upper arm cuff is applied to the ankle and auscultation performed on the dorsalis pedis or posterior tibial artery. A large cuff can be applied to the thigh, using a bladder that is 20% wider than the diameter of the thigh . Auscultation is performed on the posterior tibial artery. Accurate BP measurement is shown in Table www.koreanhypertension.org. Home BP is lower than clinic BP. HTN can be diagnosed when home BP is 135/85 mm Hg or higher. When making a diagnosis of HTN, it is recommended to measure at least five consecutive days in a week and one to three measurements in each session in the morning and evening. In the morning, it is measured after voiding, within 1 h awakening, and before taking antihypertensive drugs. In the evening, it is measured before sleep. When calculating mean BP, the reading on the first day usually are omitted.Automated device validated for the measurement of out-of-office BP is more and more popular. Home BP is known to be more accurate to predict CV outcomes and cost-effective in HTN patients . Home BPAmbulatory BP measurement provides information on the BP during the daytime, nighttime, and specific periods, for example, early morning. Measurement of BP is performed at 15- to 30-min intervals over a 24-h period. Ambulatory BP measurement provides better prognostic information than does BP measurement in the clinic . The meaDiagnosis and examination are aimed at: 1) differentiating primary and secondary HTN, 2) evaluating the severity of HTN, 3) identifying CV risk factors and lifestyle issues, and 4) searching for CVD, concomitant disease, or subclinical target organ damage that could affect the choice of treatment.Patients with HTN most often have no specific symptoms of high BP. High BP is usually found incidentally when hypertensive patients seek health care for other reasons or else is detected in conjunction with symptoms of hypertensive CVD or an underlying secondary cause of HTN. Headache is often considered a symptom of high BP. However, there is no link between high BP and headache except in cases of severe HTN. Headache accompanied by HTN is commonly localized to the back of the head, occurs early in the morning upon awakening, and subsides spontaneously during the day. Some patients with HTN exhibit general, non-specific symptoms of high BP such as dizziness, palpitation, fatigue, and sexual dysfunction. The symptoms of hypertensive CVD are hematuria, blurred vision, dizziness due to transient cerebral ischemia, angina, and shortness of breath due to heart failure. In some rare cases, chest pain due to aortic dissection or aortic aneurysm can occur. Patients with secondary HTN can have specific symptoms and signs suggestive of the underlying cause. For example, patients with sleep apnea syndrome may experience early morning headache, excessive daytime sleepiness, depression, reduced concentration, and nocturnal dyspnea. Patients with primary aldosteronism may have polyuria, polydipsia, and episodes of muscle weakness; those with Cushing’s syndrome, weight gain and emotional instability; and those with pheochromocytoma, episodic headache, palpitation, sweating, and orthostatic hypotension.The medical history includes: 1) personal history of present illness, past history, and family history; 2) symptoms and signs suggestive of secondary causes of HTN; 3) symptoms and signs of target organ damage; 4) CV risk factors; 5) concomitant diseases; 6) lifestyle factors such as diet, smoking, alcohol consumption, physical activity, exercise, sleep, and personality/psychological state; 7) duration and previous level of high BP, previous treatment and its results, and adverse effects of antihypertensive therapy; 8) use of non-steroidal anti-inflammatory drugs, oral contraceptives, herbs, and other drugs; and 9) socioeconomic status.Physical examination of hypertensive patients includes: 1) measurement of BP in both arms at the first visit as well as the pulse rate; 2) measurement of height and weight to calculate the BMI as well as measurement of waist circumference; 3) auscultation for bruits over the carotid arteries, abdomen, and femoral arteries; 4) palpation of the thyroid; 5) examination of the heart and lungs; 6) examination of the abdomen for kidney enlargement, masses, bladder distension, and abnormal aortic pulsation; 7) examination of the lower extremities for edema and palpation of the pulses; and 8) neurological examination. Waist circumference is measured with a tape measure at the level midway between the lowest rib and the iliac crest with the patient in a standing position, at the end of normal expiration, with the abdomen exposed and without compression of the abdominal skin.Laboratory examination is performed to identify additional CV risk factors, secondary causes of HTN, subclinical organ damage, and concomitant diseases. Routine laboratory tests should be performed before antihypertensive treatment. Other recommended and extended tests may be performed if necessary Table .Table 7HTN is typically accompanied by other CV risk factors, so frequently so that reduction of BP alone is insufficient to control the clinical risk for CV events . In someThe risk stratification of HTN in South Korea was based on the KMIC data, which were drawn from patients with the following characteristics: 1) registered in the early 1990s, 2) relatively young age range of 35 to 59 years, and 3) relatively high socio-economic status. Therefore, this stratification may have limitations including a tendency to underestimate the absolute risk of HTN and lack of representativeness of the entire population . The lowIn the risk table derived from the KMIC data shown in the Korean Society of Lipidology and Atherosclerosis guideline for the treatment of dyslipidemia 2009 , patientSecondary HTN can be diagnosed in approximately 5% of all patients with HTN. Additional testing should be performed when the pretest probability is lower than the sensitivity of the screening tests, as in the following cases: 1) secondary HTN suggested by age, medical history, physical examination, basic laboratory examination, and the severity of HTN; 2) poor response to antihypertensive drugs; 3) BP resistant to previously effective treatment for no apparent reason; and 4) sudden onset of HTN. In some cases, secondary HTN can be cured by surgery or drug therapy. Renovascular HTN is a possibility among patients with HTN beginning at an age of <30 or >55 years, worsening of previously well-controlled HTN, an abdominal bruit, resistant HTN, an increase in the creatinine level of >30% over the baseline level following the administration of an angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB), and the presence of atherosclerotic disease in other organs. Screening for renovascular HTN is performed by using the captopril renal scan, Doppler ultrasound, computed tomography, or magnetic resonance angiography. Hyperkalemia with no apparent cause or an incidentally diagnosed adrenal mass are indications for evaluation for hyperaldosteronism. Because paroxysmal and/or refractory HTN accompanied by hyperadrenergic symptoms suggests the possibility of pheochromocytoma, measurement of the catecholamine level in the plasma and/or 24-h urine, CT, magnetic resonance imaging, or radioisotope imaging (I-131 metaiodobenzylguanidine) is indicated Table . In rece


The impacts of blood pressure (BP) load on target-organ damage in patients with chronic kidney disease (CKD) are largely unclear. We examined whether BP load is correlated with target-organ damage (TOD) in Chinese CKD patients independent of BP level.We recruited 1219 CKD patients admitted to our hospital division in this cross-sectional study. The TOD were measured by estimated glomerular filtration rate (eGFR), proteinuria, left ventricular mass index (LVMI) and carotid intima-media thickness (cIMT) in this study. Univariate and multivariate linear analyses were used to evaluate the relationship between systolic blood pressure (SBP) load, diastolic blood pressure (DBP) load and these renal, cardiovascular parameters.2) and correlated with LVMI, proteinuria in non-diabetic CKD patients without hypertension  and LVMI, cIMT, eGFR in non-diabetic CKD patients with hypertension  in multivariable-adjusted model which already including the 24-h BP. BP load did not refine this correlation based on the 24-h BP level in diabetic CKD patients.In multivariable-adjusted models, BP load and ambulatory BP levels both independently correlated with LVMI, eGFR and proteinuria in all groups of CKD patients (p<0.05), 24-h SBP correlated with cIMT only in non-diabetic CKD patients without hypertension (p<0.05), while nighttime SBP load was associated with cIMT only in non-diabetic CKD patients (p<0.05). Furthermore, nighttime SBP load additionally increased coefficient of determination (RNight-time SBP load was correlated with TOD in patients with non-diabetic chronic kidney disease independent of BP level. Chronic kidney disease (CKD) has become an important public-health issue in China. The number of patients with CKD in China is ≈119.5 million based on the fact that the prevalence of CKD in China is 10.8% . LowerinOver the last decade, ambulatory blood pressure monitoring (ABPM) employing a wearable, oscillometric BP device to automatically measure and record BPs at prescribed intervals has emerged as a valuable tool for assessing BP. ABPM provides additional information on the mean BP (systolic and diastolic), BP load (proportion of BP readings above a threshold BP), and non-dipping (<10% decrease in night-time BP relative to daytime BP). There are many trials on ABPM and the dipper pattern , 5, wherThe role of BP load in patients with CKD is not known. We previously found that TOD such as estimated glomerular filtration rate (eGFR), proteinuria, LVMI and carotid intima-media thickness (cIMT) were significantly related to the parameters of AMBP in Chinese CKD patients . We hypoThe study protocol was approved by the ethics committee of the Third Hospital of Sun Yat-Sen University . This cross-sectional study were from May 2010 to October 2014, all study participants provided written informed consent to be included in the study.Inclusion criteria were: 1) consecutive CKD patients who had not undergone any type of antihypertensive treatment within 1 month; 2) pre-dialysis CKD patients with a stable disease state. Exclusion criteria were: 1) undergoing treatment with corticosteroids or hormones; 2) acute changes in the eGFR >30% in the previous three months; pregnancy; 3) history of abuse of drugs or alcohol; night work or shift-work employment; 4) acquired immunodeficiency syndrome; 5) cardiovascular disorders ; 6) intolerance to ABPM; 7) inability to communicate and comply with all of the study requirements; 8) maintenance dialysis. Finally, 1219 CKD patients were enrolled in this study.Patients underwent 24-h ABPM using a TM-2430 Monitor . Cuff size was chosen based on arm circumference and fixed to the non-dominant arm. BP readings were obtained in the morning at three points from 7 am to 10 pm using a mercury sphygmomanometer by a physician who did not have access to ABP values. Then BP was recorded every 15 min from 7 am to 10 pm, and every 30 min from 10 pm to 7 am. Monitoring was done on a working day. Patients were asked to attend to their usual activities but to keep motionless at the time of measurement. Patients had no access to ABP values. Strenuous physical activity was discouraged in all patients during the monitoring period, and their daily activities were comparable. BP series were eliminated from the analyses if: >30% of the measurements were lacking; they had missing data for >3-h spans; they were collected from subjects who were experiencing an irregular rest–activity schedule or a night-time sleep span <6 h or >12 h during monitoring. Night time BP was defined as the average BP from the time of patients went to bedtime until the time they got out of bed, and daytime as the average BPs recorded during the rest of the day.Cardiac structure was assessed by two investigators trained for this purpose before starting the study. Left ventricular mass (LVM) were assessed using two-dimensional echocardiography. Linear measurements of end-diastolic interventricular septal wall thickness (IVSd), end-diastolic left ventricular internal dimension (LVIDd), and end-diastolic posterior wall thickness (PWTd) were obtained from M-mode tracings. LVM was calculated using the formula , and theCarotid intima-media thickness (cIMT) was assessed by two trained investigators before study commencement. A SonoSite MicroMaxx Ultrasound System paired with a 5–10-MHz Multifrequency High-resolution linear transducer  with Sono-Calc IMT software was used for taking automatic measurements of cIMT. This was achieved by averaging three measurements taken on each carotid artery  and measuring the distance between the leading edge of the lumen–intima interface and the leading edge of the collagenous upper layer of the adventitia using high-resolution B-mode ultrasonography.Kidney damage was assessed by measuring the serum concentrations of creatinine, which is measured by the enzymatic method, traceable to the isotope dilution mass spectrometry. The estimated glomerular filtration rate (eGFR) was calculated using a modified version of the Modification of Diet in Renal Disease (MDRD) equation based on data from Chinese CKD patients.We collected urine samples from 7 am to 7 am the next day to detect the extent of proteinuria and sodium levels over 24 h. These patients were asked to void their bladders at 7 am. Proteinuria was measured by immunoturbidimetry. In addition, medical history, including demographic and laboratory data  were obtained at the initial study visit. All these experimental data were measured using a 7180 Biochemistry Auto-analyzer .The diagnosis of hypertension was based on accepted criteria for ABPM : Ambulat2) for ≥3 months according to guidelines set by the Kidney Disease Outcomes Quality Initiative [CKD was defined as the presence of kidney damage or decreased renal function (eGFR of <60 mL/min per 1.73 mitiative .Diabetes mellitus (DM) was defined as the need for anti-diabetic drugs or meeting the diagnostic criteria for DM specified by chinese guidelines for diabetes prevention and treatment t test or non-parametric test. Differences among categorical variables were analyzed using the χ2 test or the two-tailed Fisher’s exact test, as appropriate. The relationship between two continuous variables was assessed by a bivariate correlation method (Pearson’s correlation).Continuous variables are the mean ± standard deviation (SD). Frequency distributions were used for qualitative variables. Non-parametric variables are expressed as median and interquartile ranges. Log transformation for the eGFR was done in view of the skewed distribution of these data. Comparisons for continuous variables between groups were tested by the Student’s Univariate linear regression models (enter method) were used to study the association of TOD  and BP load , DM , triglycerides (TG), low-density lipoprotein-cholesterol (LDL-C), cholesterol, hemoglobin, albumin (ALB), eGFR, calcium, phosphorus, body mass index (BMI), 24-h SBP and 24-h DBP respectively. To further study the association of 24-BP level, BP load and TOD, multivariate linear regression analysis were performed (stepwise method) which adjusted for age, sex , current smoker , alcohol intake  and those variables with a significant association with a dependent variable in the univariate linear regression. In the next step of the analysis, we added BP load (only the BP load which P<0.05 in model 2) to model 3 which already including the 24-h BP (only the BP which P<0.05 in model 2) and other covariables. We tested whether BP load was able to additionally explain the variance of TOD. All values are two-tailed. p<0.05 was considered significant. Data were analyzed using SPSS v18.0 A total of 1219 CKD patients were enrolled in this study. The mean age was 44.0±16.6. The male:female ratio was 723:496, which comprised 432 non-diabetic CKD patients without hypertension, 565 non-diabetic CKD patients with hypertension and 222 diabetic patients (18.2%).Hypertensive non-diabetic CKD patients were older, a higher percentage of smokers and alcohol consumers, higher BMI, higher 24h BP and BP load, higher fasting glucose, cholesterol, LDL-C, calcium, phosphate, creatinine, PTH levels, lower eGFR and hemoglobin, higher LVMI and cIMT compared with non-diabetic CKD patients without hypertension(p<0.05). While diabetic patients were older, a higher percentage of smokers and alcohol consumers, higher BMI, higher 24h BP and BP load, higher fasting glucose, cholesterol, LDL-C, calcium, phosphate, creatinine, PTH levels, lower eGFR and hemoglobin, higher LVMI and cIMT (p<0.05) compared with non-diabetic CKD patients without hypertension(p<0.05). Compared with diabetic CKD patients with hypertension, diabetic patients were older and had: higher BMI, higher BP load and 24h DBP levels, higher fasting glucose, cholesterol, LDL-C, creatinine, PTH levels, lower eGFR and hemoglobin, higher cIMT (p<0.05) compared with non-diabetic CKD patients without hypertension(p<0.05) .Univariate correlation analyses showed that daytime SBP load, night-time BP load and 24h BP levels correlated with LVMI, cIMT and eGFR in non-diabetic CKD patients without hypertension (p<0.05), while only 24h SBP, rather than BP load, was associated with proteinuria in these patients. BP load and 24h BP levels were significantly related to LVMI and eGFR (p<0.05), SBP load and 24h SBP levels correlated with cIMT (p<0.05), while no correlation was found between BP load and proteinuria in non-diabetic CKD patients with hypertension .SBP load and 24h SBP correlated with LVMI (p<0.05), daytime SBP load, nighttime BP load and 24h SBP correlated with eGFR (p<0.05), BP load and 24h BP levels correlated with proteinuria (p<0.05), while no correlation was found between BP load and cIMT in diabetic patients .2 = 0.034, P<0.001 and R2 = 0.012, P = 0.006 respectively)  in model 1 and model 2 inclusion, nighttime SBP load was able to additionally explain the variance of LVMI and proteinuria in these patients (Rctively) .2 = 0.008, P = 0.037, R2 = 0.016, P = 0.011 and R2 = 0.009, P < 0.001 respectively  in model 1 and model 2 inclusion, nighttime SBP load was able to additionally explain the variance of LVMI, cIMT and eGFR in these patients  in model 1 and model 2 inclusion, the inclusion of BP load cannot additionally explain the variance of LVMI, cIMT, proteinuria and eGFR in these patients (P>0.05) .The present study showed both ambulatory blood pressure and BP load were independent associated with TOD in CKD patients, furthermore, nighttime SBP load was able to additionally explain the variance of TOD in non-diabetic CKD patients. In this regard, nighttime BP load correlated with TOD in non-diabetic CKD patients was not fully dependent 24-h BP levels. According to our best knowledge, this is the first study to show the relationship between BP load and cardiac, large vascular, and renal damage in CKD patients. Our study suggested that nighttime SBP load might play a role in non-diabetic CKD patients.One study from 8711 subject showed that BP load did not improve risk stratification based on 24-hour BP level even in patients without hypertension . HoweverCurrent therapy to retard the progression of CKD has yielded disappointing outcomes despite aggressive control of BP. Parameters currently used to assess the adequacy of BP control need to be reassessed . BP is fDiabetes mellitus is an established risk factor for coronary heart disease and ischemic stroke. It confers an approximate two fold increased risk for a wide range of vascular diseases compared with non-diabetic patients . DiabetiIn our current study, the correlation coefficients between level and load were all >0.6, multiple regression analysis which include both level and load to assess the independent effect of a single variable may be misleading because of multicollinearity. To avoid the effect of multicollinearity, 24h-BP and load were included in model 1 and model 2 respectively by multivariable-adjusted analysis. In the next step, to investigate whether the correlations between BP load and TOD were over and beyond the 24-h BP level. We added significantly associated BP load to model 3 which already including the significantly associated 24-h BP and other covariables and computed the R squared change and p value.This study had limitations that should be considered when evaluating our results. Firstly, because of the cross-sectional design of the study, we could not establish a causal relationship between BP load and TOD, but merely observe an association. Secondly, drug would not have affected the result of analyses since patients who received any antihypertensive drug in the previous month were excluded. However, we could not rule out the effect of chinese medicines. Thirdly, all CKD patients were admitted to our hospital division. Actually, these patients had severe proteinuria or severe renal damage, so some CKD patients with non-severe proteinuria or non-severe renal damage might have been omitted, which lead to some difference from general CKD patients. Therefore, further multi-center, larger-sample follow-up studies are necessary to explore the relationship between BP load and TOD.In conclusion, our analyses showed that BP level and load were both independently associated with TOD. However, adding BP load to models already including BP level was able to additionally explain the variance of TOD in non-diabetic CKD patients. Our study provides important information that BP load might be an independent risk factor for cardiac, large vascular and renal damages in non-diabetic CKD patients, and we should undertake comprehensive assessment of BP in the management of non-diabetic CKD patients.


While there was a tendency for higher occurrence of diabetes and smoking, groups did not differ significantly in respect to major vascular disease risk factors. Groups did not differ in main ambulatory blood pressure, total cholesterol, or even CRP. Importantly, flow mediated dilatation (FMD) was significantly lower in DRS than in non-DRS subjects, while nitroglycerin induced vasorelaxation (NMD) or intima-media thickness (IMT) was similar. Interestingly, while triglyceride levels were normal in both groups, they were higher in DRS subjects, although they did not correlate with either FMD or NMD. Conclusions. Denture related stomatitis is associated with endothelial dysfunction in elderly patients with dentures. This is in part related to the fact that diabetes and smoking increase risk of both DRS and cardiovascular disease.Oral inflammation, such as periodontitis, can lead to endothelial dysfunction, accelerated atherosclerosis, and vascular dysfunction. The relationship between vascular dysfunction and other common forms of oral infections such as denture-related stomatitis (DRS) is unknown. Similar risk factors predispose to both conditions including smoking, diabetes, age, and obesity. Accordingly, we aimed to investigate endothelial function and major vascular disease risk factors in 44 consecutive patients with dentures with clinical and microbiological features of DRS ( Oral inflammation is an important element in the pathogenesis of vascular disease. In particular, large body of evidence has accumulated recently that chronic periodontitis is a potential novel risk factor for atherosclerosis and endothelial dysfunction –5. Indee Candida albicans is fungal component of the physiological microflora of the human oral cavity [While numerous studies have focused on the links between periodontitis and endothelial dysfunction, little is known about the links between other forms of oral infection and inflammation in the context of cardiovascular risk. In particular, denture-related stomatitis (DRS) is an inflammatory process of the oral mucosa in contact with a denture and is one of the most common diseases in elderly patients, affecting up to 70% of patients in the course of life , 10. It l cavity , 15; howγ, TNF-alpha, interleukin 6, or 17 [While in periodontitis systemic activation of the immune system is very important in mediating increased cardiovascular risk, the extent of systemic response to DRS is poorly characterized. Systemic inflammation may affect vascular dysfunction in number of ways, which include activation of monocytes and T cells with overproduction of cytokines such as interferon 6, or 17 , subsequ6, or 17 –18 and i6, or 17 –21, as w6, or 17 –26. Thes Candida species presence. Based on clinical and microbiological investigations, patients were divided into DRS (n = 20) group and non-DRS (n = 24) group. Diagnosis was confirmed by an independent observer. Control, non-DRS patients had clinically healthy oral mucosa and negative oral Candida swabs. Clinically healthy oral mucosa was a pale pink, smooth mucosal membrane without redness or swelling and with no pain or discomfort reported by patient. Exclusion criteria included acute inflammatory disorders other than DRS, neoplastic disease relapses or chemotherapy courses less than 5 years before the enrolment, and using antibiotics in less than 4 weeks or anti-inflammatory drugs  in less than 2 months before the enrolment. Patients with history of myocardial infarction, acute coronary incident or vascular inflammation in 5 weeks or less before the enrolment, chronic haematological disorders, and immunodeficiency or major medication changes during less than 5 weeks before or during study were also excluded. The study was approved by local ethics committee of Jagiellonian University. Informed consent was obtained from all patients and all work was conducted in accordance with the Declaration of Helsinki (1964).Using 44 consecutive patients with dental prostheses for at least 6 months were included in this study. Their oral mucosa was examined by the dentist to clinically identify inflammation and DRS. The clinical signs of oral mucosa inflammation in DRS include erythema and swelling of palatal mucosa, sometimes combined with subjective symptoms, such as dysgeusia or burning sensation. These observations were confirmed by routine microbiological laboratory diagnostic tests forSwabs were taken from the hard palate . Samples were collected after an overnight fast and after at least 6 hours of continous denture usage, without the use of adhesives or rinsing the mouth with disinfectants. The material was collected in accordance with the general principles of microbial material collection.Patients' blood pressure  was monitored for 24 hours using ambulatory blood pressure monitoring system . Systolic diastolic and mean arterial pressures were recorded every 20 minutes for 24 hours. Day and night averages were calculated. One patient in control group did not agree to wear the ABPM monitor. Major risk factors for both atherosclerosis and DRS were recorded based on patient medical records and detailed patient history. Clinical risk factors were defined as follows: hyperlipidemia , diabetes , hypertension (blood pressure ≥ 140/90 mmHg or current treatment with antihypertensive agents), and smoking (current or within last 6 months) based on . Blood sFlow-mediated dilatation (FMD) method was used to determine the vascular endothelial function and NMD (nitroglycerine-mediated dilatation) for measuring endothelial-independent vasodilatation. Measurements were conducted using Toshiba Xario Diagnostic Ultrasound System after 1, 2, and 4-5 minutes after manometer cuff deflation or sublingual administration of nitroglycerine and presented as percentage of the diameter of the artery before intervention. Method validation in our laboratory has been described elsewhere . ObserveThe measurements of intima-media thickness were performed in 12 different points , on right and left common carotid artery, measuring the distance between the border between artery lumen and carotid artery intima and second bright line-m (border between media and adventitia) as described previously .Q1), 75th (Q3) percentiles. For those variables nonparametric statistical tests were used, Mann-Whitney U test for continuous variables or, for dichotomous variables, χ2 for the expected frequencies > 5 or χ2 with Yates' correction for the expected frequencies < 5 with confirmation of Fisher's exact test and Spearman correlation. For variables with normal distribution Student's t-test was applied and data are presented as mean with standard deviation (SD). Method of presentation of results is given for each variable in the text. Values of P < 0, 05 were considered statistically significant.Analysis was performed using Statsoft Statistica software. Compliance of the distribution of variables with normal distribution was tested by Shapiro-Wilk test. Most of the variables did not have normal distributions, and therefore the results are presented as medians and 25th  value, and antihypertensive treatment. There were more smokers and patients with diabetes mellitus (DM) in DRS group than in control group, although these differences were not statistically significant. Higher prevalence of DM and smoking in DRS group is consistent with epidemiologic data and is understandable, as both are recognized as a risk factor for developing DRS . The proAmbulatory blood pressure monitoring has shown no significant differences in both mean systolic and mean diastolic blood pressure in DRS and control non-DRS group . MoreoveP = 0,4).Flow-mediated dilatation measurements showed a significantly reduced median percentage of arterial dilation in response to flow in the DRS group in comparison with control patients . At the P = 0, 86.Intima-media thickness evaluation showed no significant differences in either maximal or mean IMT in studied groups. It is important to point out that neither of the groups showed very high values of mean IMT . MoreoveR Spearman = −0,13, P = 0,42) and NMD   .P = 0,0032) and TG levels .As there was a much lower proportion of males in our study population, we performed an additional subgroup analysis in female population. It revealed that all studied vascular phenomena were observed to the same extent as in total studied population, including the difference in endothelium derived vasorelaxations (FMD (mean ± SD): 5,95 ± 3,80% in female DRS patients and 9,72 ± 3,31% in control subjects; The oral health impact on the general health is evident. Oral infections and inflammation have been implicated in many disease entities, such as rheumatoid arthritis , obesity Candida infection.While numerous previous studies have shown increased cardiovascular risk in subjects with oral inflammatory conditions such as periodontitis –5, endodPrevious studies focused on a positive association between periodontitis and vascular endothelial dysfunction. Amar et al. and Blum et al. observed that subjects with advanced periodontal disease exhibit worse endothelial function when compared to the healthy controls , 36. BluThe mechanisms of increased cardiovascular risk in oral inflammatory conditions are multifactorial and range from chronic systemic inflammation (periodontitis) to the effects of risk factors such as diabetes, hyperlipidemia, smoking, and age which predispose to both cardiovascular diseases and oral disorders, such as periodontitis –5, carie C. albicans antigens [ Candida-evoked oral mucosal inflammation is not causing significant activation of systemic inflammatory response. The CRP levels among edentulous were assessed by Ajwani et al. at Helsinki Aging Study involving over 600 patients older than 75 years old [The role of systemic inflammation, very well defined in periodontitis, is not known in DRS. The mechanisms through which DRS could affect endothelial dysfunction are unclear. In periodontitis, bacteria lead to the activation of the local immune response, leading to systemic inflammation. Similarly, immune stimulation of T cells and monocytes has been reported in response to fungalantigens , 40. Howears old . They idears old . In the  Candida infection may impact peripheral blood mononuclear cells state, measured by amount of cytokines produced in vitro in response to Candida antigens [ Candida cells on the vascular system is unlikely, since systemic fungal infections are characterized, in contrast to the DRS, by extremely serious symptoms; moreover, fungal DNA has not been detected in atherosclerotic lesions [De Oliveira et al. and Rodriguez-Archilla et al. have found that oralantigens , 40. Dir lesions .However our results may point us to the potential role of vascular risk factors such as diabetes, smoking, and hypertriglyceridemia in mediating vascular dysfunction. Although no relationship was found between triglyceride levels and endothelial dysfunction in a simple correlation analysis, when multivariate linear regression was introduced including diabetes, smoking, and/or triglyceride levels, the difference in endothelial function was no longer significant (data not shown). One has to however bear in mind that statistical power of such analysis in the studied group was relatively modest.While the finding that classical risk factors may be main mediators of endothelial dysfunction may not sound exceptionally interesting, it is very important to show that this is the case in DRS subjects, and therefore this group of patients should be carefully studied in larger epidemiological trials. This is particularly important in the light of ageing population.Despite the lack of differences in the levels of total, HDL, and LDL cholesterol in the blood of healthy subjects and DRS, we observed significantly higher levels of triglycerides in patients with DRS. Our surprising finding that DRS is associated with selective increase in triglyceride levels is quite intriguing and could be related to the fact that denture wearing can change dietary habits. It could also suggest that increased triglyceride levels could be a risk factor of DRS, although our study was not powered to answer this question. There are no studies looking at lipid parameters in DRS, while conflicting data are available regarding periodontitis. Sandi et al. and Penumarthy et al. observed higher concentrations of total cholesterol and LDL cholesterol in the blood of patients with periodontal disease than in healthy group, but the differences in the levels of triglycerides and HDL cholesterol were shown only by Penumarthy et al., despite the smaller sample sizes , 45. SimWe did not observe the tendency towards elevated blood pressure in patients with DRS as compared to healthy subjects. This shows potential important difference in oral inflammatory conditions as periodontitis is potentially associated with elevated blood pressure, which was frequently observed . The relIn conclusion, our study shows that patients with denture-related stomatitis are characterized by more pronounced systemic endothelial dysfunction than denture subjects without stomatitis. This difference in vascular function is likely linked with increased cardiovascular risk in DRS and indicates that such patients should be carefully monitored for cardiovascular disease. While our study identifies certain very interesting and potentially very important cardiovascular aspects of denture-related stomatitis, a larger study is warranted to finally confirm these observations. This may be very important for clinical practice considering ageing population.


Systemic pharmacological inhibition of nitric oxide (NO) causes a hypertensive response, which has been attributed both to inhibition of peripheral NO-mediated vasodilatation and to inhibition of central nervous NO-production leading to a later onset sympathetic vasoconstriction. In the present study we aimed to test the importance of these two mechanisms by comparing the time-courses of the hypertensive responses in spinal cord injured (SCI) subjects with varying degrees of loss of sympathetic vascular control depending on level of injury as well as able-bodied controls. We hypothesized that high level SCI with no sympathetic vasoconstrictor control would have an abbreviated time-course of the hypertensive response to the NO-inhibitor L-NAME, because they would lack the late onset sympathetic component to the hypertensive response. NO production was blocked in 12 subjects with SCI and 6 controls by intravenous infusion of L-NAME (1.55–2.7 mg/kg). We measured blood pressure, heart rate, and vascular conductance in the carotid, brachial, and femoral arteries before, during, and after 1 h of L-NAME in a 4-h protocol. Peak increases in mean arterial pressure were significantly larger in high level SCI vs. controls: 32 ± 6 vs. 12 ± 2 mmHg (both groups received 1.55 mg/kg). The decreases in vascular conductance in the brachial and femoral vascular beds were also larger in the high level SCI group, whereas decreases in heart rate and carotid conductance were not significantly different between the groups. There were no indications of any abbreviated responses in blood pressure or vascular conductance in the high level SCI compared to control. The mid level and low-level SCI subject had responses similar to controls. These data confirm previous reports that NO inhibition causes a larger increase in blood pressure in high level SCI, and extend these data by providing evidence for differences in vascular conductance in the limbs. The current data do not support an obligatory important role for sympathetic vasoconstriction in maintaining the hypertensive response to L-NAME in humans. Resting blood pressure (BP) is brought about by a combination of cardiac output and peripheral resistance. The primary determinant of peripheral resistance is the internal diameter of the arterioles in the muscle and splanchnic vascular beds, which is controlled on a beat-to-beat basis by reflex vasoconstriction governed by the arterial baroreflex. Flow-mediated dilatation (FMD), which is largely mediated by nitric oxide (NO), is brought about by the shear stress of blood flow through resistance vessels and counteracts this vasoconstriction  patients would shorten the time-course of the hypertensive response to L-NAME.Given that resting BP is often low in SCI, and more so in high-level SCI because of interruption of descending vasoconstrictor drive, one might have expected that NO production would be lower because of reduced perfusion pressure and shear stress through the resistance vessels. However, a recent study revealed that L-NAME caused a higher increase in blood pressure in high-level SCI individuals compared to controls  SCI. One individual with high level SCI did not complete the protocol, due to headache in conjunction with a high blood pressure increase during L-NAME infusion. In this individual the L-NAME-infusion was stopped prior to end-point of the protocol and L-Arginine was given to revert the blood pressure raising effect of NO-inhibition. This individual was subsequently fine, but only a limited dataset from this trial was included in the analysis. We included a full dataset from the remaining 11 individuals with SCI. The SCI patients had suffered their injury 11 months-33 years previously and ranged in age from 22 to 63 years (mean ± SE − 42 ± 3 years). We recruited six healthy controls . All subjects were male with the exception of one SCI and one control subject.We specifically wanted to address whether SCI lesion level  affected the magnitude and the time-course of the changes in BP, heart rate, and blood flow during blockade of NO production. Accordingly, data from groups of four high-level (C5-T2), four mid-level (T4-T6), and four low-level T7-T10) SCI individuals were compared to the control group. These groups of SCI subjects, separated according to level of lesion, and the control subjects are shown in Table 0 SCI indSubjects with a history of cardiovascular disease, diabetes, hypertension, or other co-morbidity were excluded from the study. The SCI subjects continued their normal medication, none of which are known to interfere with the cardiovascular system. All participating subjects gave written  informed consent, and the study received ethical approval from the Human Research Ethics Committees of the University of New South Wales and Prince of Wales Hospital.All subjects were studied in the morning after an overnight fast, resting in a semi-reclined position with the room at a comfortable ambient temperature. The female SCI subject did remain in her motorized wheelchair for testing, but the wheelchair could be reclined so she was in the same position as the other subjects. All subjects emptied their bladder before the procedure, and those SCI subjects with an indwelling catheter were monitored throughout to ensure there were no drainage problems that could interfere with their BP.Blood pressure was monitored non-invasively, using oscillometric arm cuff measurements, and radial artery tonometry . Heart rate (HR) was measured via standard Ag-AgCl ECG surface electrodes on the chest. Each BP and heart rate measurement was averaged over 5 min . In the right common carotid, brachial, and femoral arteries ultrasound 2D-images of vascular diameter  and Doppler-derived mean blood velocities (automated mean blood velocity detection over 3–5 heart beats in steady state) were obtained with a 11 MHz linear-array vascular transducer . Flow was calculated as vascular cross-sectional area times mean blood velocity and conductance as flow divided by mean arterial pressure.A 20 gauge intravenous cannula was inserted into the median cubital vein for infusion of (L-NAME) or L-arginine (a substrate for NO synthesis). After recording baseline measurements of BP, HR, and vascular conductances, L-NAME was administered over 60 min. After the early experience with a high blood pressure response in a patient with high-level SCI, the L-NAME dosing was adjusted such that patients with high-level SCI received 1.55 mg/kg, the remainder of the SCI patients (mid and low) received 2.7 mg/kg. Of the control subjects 4 were matched for gender and age with the high level SCI patients  between the groups . Differences were considered statistically significant at F = 79.39; p < 0.0001]; the largest mean arterial pressure increase in SCI vs. controls: 32 ± 6 vs. 12 ± 2 mmHg ; the largest diastolic blood pressure increase in SCI vs. controls: 24 ± 6 vs. 12 ± 2 mmHg . The differences in blood pressures at baseline, with the high-level SCI group starting much lower than the control group, were completely evened out after L-NAME. Despite the large differences in blood pressure responses, the heart rate changes were not significantly different between the groups: the largest decrease in SCI vs. controls was −19 ± 5 vs. −15 ± 2 bpm . When normalized to the increases in blood pressure, HR decreased by −0.8 and −1.6 bpm/mmHg in the high-level SCI and control groups, respectively; there was no significant difference in these falls in HR.Intravenous infusion of L-NAME 1.55 mg/kg) caused increases in arterial pressures, decreases in heart rate in all SCI and control subjects. Figure .55 mg/kgThe average diameters of the common carotid, brachial, and femoral arteries  before and during L-NAME were not significantly changed in either group. There were some expected differences in absolute diameter between the groups, since the high level SCI group had substantially smaller femoral artery diameter (5.5 ± 0.4 mm) compared to the control group 8.2 ± 1.2 mm), whereas the brachial and carotid diameters were similar between the groups. The actual values before and during L-NAME for all groups  are shown in Table  ± 1.2 mmThe fact that diameter of these conduit arteries do not change during NO blockade means the changes in flow are related to changes in perfusion pressure and degree of downstream vasoconstriction. Vascular conductance measurements accounts for the changes in perfusion pressure in a linear fashion, and Figure F = 3.501; p = 0.0697]. Flow in the brachial artery was higher at baseline in high-level SCI compared to control, and the decrease was large and significant whereas there was no significant change in the control group: −35 ± 8 vs. −4 ± 15%. Brachial vascular conductance also changed markedly in high-level SCI but not significantly in controls: −55 ± 7 vs. −16 ± 12% . In the femoral artery data showed decreases in blood flow: SCI vs. controls: −46 ± 6 vs. −24 ± 6%; and in vascular conductance: SCI vs. controls: −62 ± 7 vs. −34 ± 5% , a clear tendency for larger relative decreases in SCI compared to controls.Flow in the common carotid artery was not significantly changed in either group but carotid vascular conductance was decreased in both groups: change from baseline in SCI vs. controls: −38 ± 6 vs. −32 ± 4% [The effects of intravenous infusion of L-NAME (1.55–2.7 mg/kg) in the three patient groups and the control group were compared by normalizing to the L-NAME dose. Figure Figure As seen in Figures We have confirmed that systemic NO-inhibition in high-level SCI patients causes a significantly higher increase in blood pressure compared to matched control and compared to mid- and low-level SCI patients. Conversely, the bradycardic responses were not significantly different, suggesting the baroreflex-induced vagally-mediated bradycardia is intact in all groups. We have extended this finding by providing data that the relative decreases in vascular conductances in the brachial, and the femoral arteries are large in high level SCI. Although the decrease in femoral conductance in mid-level SCI is similar to high-level SCI, the blood pressure responses were different, suggesting that decreases in vascular conductance in the renal and splanchnic beds must be larger in high level SCI than in any of the other groups.We set out to test the underlying mechanisms for the L-NAME induced increases in blood pressure by studying patients with SCI at different levels. In previous animal and human studies, evidence has been presented for a dominating peripheral mechanism where L-NAME blocks endothelially-derived vasodilatation, and a late-onset smaller effect of central sympathetic activation  high-level SCI has a higher peripheral NO production leading to a higher NO-mediated vasodilation, which when blocked causes a higher increase in total peripheral resistance and hence blood pressure; (2) in subjects with an intact sympathetic nervous system, the L-NAME-induced increase in blood pressure leads to a baroreflex-mediated withdrawal of sympathetic vasoconstriction which buffers the increase in blood pressure, and in high-level SCI, this buffering is absent, because the sympathetic vasoconstrictor drive is absent due to the SCI.We know that following SCI there is vascular remodeling, such that the luminal diameters of the carotid and femoral arteries are reduced  sympathetic innervation of the renal and splanchnic vascular beds. The similar blood pressure responses in mid- and low-level SCI and controls in the present study are consistent with this notion. Previous studies in humans have shown that muscle sympathetic activity is lowered during the initial phase of NO inhibition  was taken off the market around 2006. While we had some L-NAME in stock, we did utilize it during the course of this study, where subjects were enrolled up until 2008. We could have gained important knowledge if we had been able to obtain reliable data for mesenteric and renal vascular conductance, but although we aimed at this, the data quality was only sufficient in about 50%, and given the already small groups we elected not include any unclear data.In conclusion, lack of central sympathetic control in high-level SCI does not cause changes in the time course of the hypertensive response to L-NAME. Furthermore, we confirmed that high-level SCI patients have a significantly more pronounced hypertensive response compared to the mid- and low-level SCI groups as well as controls.DC, MS, and VM designed the study. RB and MS performed the clinical study. RB, MS, and VM performed analysis of the collected data. RB, DC, and VM interpreted the data. RB and VM wrote the manuscript. All authors edited and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Patients with chronic heart failure (CHF) experience progressive deterioration of functional capacity and quality of life (QoL). This prospective, randomized, controlled trial assesses the effect of exercise training (ET) protocol on functional capacity, rehospitalization, and QoL in CHF patients older than 70 years compared with a control group. A total of 343 elderly patients with stable CHF  were randomized to ET  or usual care . The ET protocol involved supervised training sessions for 3 months in the hospital followed by home-telemonitored sessions for 3 months. Assessments, performed at baseline and at 3 and 6 months, included: ECG, resting echocardiography, NT-proBNP, 6-minute walk test (6MWT), Minnesota Living with Heart Failure Questionnaire, and comprehensive geriatric assessment with the InterRAI-HC instrument. As compared to UCG, ET patients at 6 months showed: i) significantly increased 6MWT distance ; ii) increased ADL scores ; iii) 40% reduced risk of rehospitalisation ; and iv) significantly improved perceived QoL . In hospital and home-based telemonitored exercise confer significant benefits on the oldest CHF patients, improving functional capacity and subjective QoL and reducing risk of rehospitalisation. The proportion of elderly patients with CHF is set to rise as a consequence of three main factors: extended average life expectancy, enhanced response rates to treatments, and longer survival after acute cardiovascular events [Congestive heart failure (CHF) is a disabling syndrome affecting 1–2% of the adult western population. Its prevalence increases with age, rising to ≥ 10% among individuals aged ≥ 70 yearsr events .One of the main consequences of CHF is progressively impaired functional capacity, which in the elderly is exacerbated by a significant amount of comorbidities. Even though emerging evidence shows that exercise in adult CHF patients is associated with improvements in symptoms, exercise tolerance, and quality of life (QoL), which ameliorate clinical outcomes , the appA number of clinical trials have confirmed that evidence-based CHF treatments can improve the prognosis of these patients, however very few studies have investigated patients aged > 70 years; in general, HF patients with common comorbidities such as renal failure, liver disease and cognitive impairment were excluded due to their high morbidity and mortality, high rate of hospitalization, and poor QoL . SimilarA recent meta-analysis of seven prospective randomized controlled trials confirmed that exercise training (ET) does not increase mortality/rehospitalisation rates and improves 6 minute-walk test (6MWT) distance in elderly  CHF patients with reduced systolic function and New York Heart Association (NYHA) functional class II or III. The authors conclude that assessment of ET efficacy in old CHF patients requires further investigation using large, rationally designed controlled clinical trials .Recent studies have demonstrated the value of remote telemonitoring in the management of CHF patients -18. HoweThis prospective, controlled trial involved stable CHF patients aged more than 70 years randomized to receive a exercise training program in the hospital for 3 months followed by telemonitored home program for the 3 further months, or usual care.The primary outcome was the effectiveness of CR program in improving functional performance as assessed by the 6MWT; the secondary endpoints were the effectiveness of CR in preventing hospitalization and in improving perceived QoL and multidimensional geriatric assessment.The flow of the enrolled patients is showed in Figure 13 patients (3.8%) died during the study.The baseline characteristics of the study population are reported in Table Men accounted for 56.9% of participants; their mean age was 76.90±5.67 years (43% > 75 years).As regards the cause of CHF, 49% was due to ischemia, 36% to hypertension, and 15% to valve defects. All patients showed significant physical impairment as assessed by the 6MWT (mean 285±121 m at T0) and had mild to moderate left ventricular dysfunction as measured by a mean left ventricular EF (LVEF) of 48.4% (37% with LVEF < 40%).There were no differences between the two groups at baseline. The mortality rate during the study was 3.8% (n=13).Functional capacity as measured by 6MWT distance increased significantly in ET at both T1 and T2 (p < 0.001)  required an hospitalisation (25 ET and 60 UC). The effect of ET on the risk of rehospitalisation was significant (p < 0.001). The HR, 95% CI, and p values for rehospita-lisation for the two groups are reported in Table After adjustment for the covariates, ET was found to reduce the risk of all-cause hospitalizations by 44.2%  Table . ClassifBMI < 26.67 involved an increased risk of rehospitalisation in all CHF patients Figure .The InterRAI-HC data are reported in QoL improved significantly in ET compared with UC subjects (p<0.001) Table . AnalysiNT-proBNP was significantly lower (p<0.001) in ET than in UC patients at both time points. The reduction was stronger at T1; however, even though values then rose at T2 in both groups, they remained lower in ET subjects Table .Overall, 69% of patients attended at least 70% of hospital rehabilitation sessions; the remaining 31% attended at least 50% of sessions.As regards telemonitored home ET, 77% of patientsperformed at least 70% of sessions; the remaining 23% performed at least 50% of sessions.ET was safe and well tolerated, and sustained arrhythmia, pre-lipothymia and syncope, angina, traumatic events, or falls never occurred during sessions.Whereas the benefits of training have widely been documented in large groups of patients with cardiovascular disease, data on CHF patients, especially on elderly patients, are scarce .Our findings provide fresh evidence for the value of ET in elderly subjects with CHF, by demonstrating that also in this subset of CHF patients the benefits of exercise add to those provided by common medications. In our study, functional capacity improved significantly in ET compared with UC patients, with a significantly greater walked distance at both follow-up assessments in the former group. The 95 m distance increase measured at 6 months is much greater than the previously reported minimal important difference (MID) , 22. TheAn interesting and innovative aspect of the present study is the use of telemonitoring for the management of cardiologic rehabilitation in elderly CHF patients. We confirmed our previous results on the effects of home telemonitoring in elderly patients with CHF on rate of hospitalization, compliance with treatment and quality of life, by comparison with a group receiving usual care , 25.In the present study, the walked distance was significantly greater, the QL was improved and NT-proBNP was reduced compared with baseline after in hospital ET phase. Notably, these benefits were maintained also after the further telemonitored home phase ET. These results highlights how even the rehabilitation program for patients with CHF followed by remote monitoring has led to significant results. This is of clinical relevance, since the clinical benefit of physical exercise in CHF management is related to the duration of ET. In this context, the telemonitoring of ET at home could ensure adherence to the rehabilitation program over a long period. In our study to increase compliance at home, a nurse tutor call the patients during the home ET sessions, similar to the hospital sessions, and the quality of each patient's ET was assessed by remote telemonitoring of one lead ECG before and after each session. Taking into account the high prevalence of CHF in elderly people, ET telemonitoring at home could be an efficacy tool to ensure compliance with rehabilitation treatment for CHF patients, especially for the oldest old ones.It was recently reported that the use of telemonitoring in the management of heart failure appears to lead to similar health outcomes as face-to-face or telephone delivery of care . For an ET programs associated with drug treatment can attenuate many of the deleterious systemic and tissue-specific effects of CHF, particularly in the elderly. Since CHF is a severe public health problem, particularly in the West, due to progressive ageing of the population, associating physical training and drug treatment can provide important therapeutic effects and thus should be recommended to elderly subjects.The potential value of “eHealth” applications to support self-management of chronic illness is only beginning to be understood. Conceptually, however, two of the most critical components of self-management, such as self-monitoring and feedback, may both be facilitated by telemonitoring technology. Additionally, eHealth technology offers the potential to provide more ubiquitous and constant support for self-monitoring and feedback than has been previously possible, and therefore represent applications useful into the everyday lives of older adults and elderly patients. One fundamental question, however, is whether older adults, those most likely to have multiple chronic health conditions, such as CHF patients, can be taught to use eHealth applications and, beyond that, whether they will use these devices and applications in ways that improve health. Here we provide some evidence that home telemonitoring could represent a promising tool for the rehabilitation programs of the oldest CHF patients, ensuring that the benefits induced by physical activity remain longer in time.From January 2011 to January 2014, 426 consecutive patients with CHF were screened and recruited at 6 Italian Cardiologic Rehabilitation Centres. Inclusion criteria were: in-patients or out-patients aged > 70 years; CHF from any cause with reduced or preserved ejection fraction (EF); NYHA functional class ≥ II; and a Mini Mental State Examination score > 24.2; severe disabling systemic disease, severe cognitive impairment, and inability to perform ET.Exclusion criteria were a survival prognosis < 6 months: severe uncontrolled diabetes; acute heart de-compensation in the previous 2 months; myocardial infarction in the previous 2 months; severe chronic obstructive pulmonary disease; severe liver failure with a survival prognosis < 12 months; severe chronic kidney disease with a glomerular filtration rate < 15 mL/min/1.73 mThe study was approved by the INRCA Institute Ethics Board and complies with the principles stated in the Declaration of Helsinki. All patients gave their written informed consent to participate.Participants were randomized to a usual care group (UCG) or a training care group (TCG) by a nurse who was not involved in recruitment.Patients were assessed at baseline (T0) and at 3 (T1) and 6 months (T2) by clinical examination, 12-lead ECG, resting echocardiography, serum levels of N-terminal portion of brain-type natriuretic peptide (NT-proBNP), 6MWT, the multidimensional geriatric assessment InterRAI Home Care Assessment System (InterRai-HC)  and the The InterRAI-HC instrument was used to collect data on medical, psychosocial, and functional abilities and limitations, including activities of daily living (ADL) and instrumental ADL (IADL). The MLHFQ was used to assess QoL on a scale from 0 (best) to 105 (worst).Blood for NT-proBNP was drawn in the morning from an antecubital vein after 30 min of bed rest with the patient in supine position. Serum levels were determined by an ElectroChemiLuminescence ImmunoAssay . Il NT-proBNP cut off values were: > 125 pg/ml (< 75 years) and > 450 pg/ml (≥ 75 years).The ET program consisted of two successive 3-month phases involving supervised training at the hospital (out-patient service) and telemonitored home exercise, respectively. Before discharge, all patients across all centres were educated about heart failure, including advice on daily weights, daily self-measurement of blood pressure, rate of carrying out blood examinations, dietary restrictions, including sodium and fluid, and signs and symptoms of a heart failure decompensation.In the first phase, patients attended 3 times weekly, 50-min classes under the supervision of a physiotherapist. Each session consisted of warm-up (10 min), exercise (30 min) and cool-down (10 min); exercise involved riding a cycle ergometer with 5 min warm-up, 20 min of intense exercise at 60 rpm, achieving 60-70% of the maximum predicted heart rate, and 5 min cool-down. ET intensity was based on each participant's functional capacity and was adjusted throughout the study.The rehabilitation program consisted in scheduled telephone call from the nurse-tutor who evaluated the presence of signs and symptoms of decompensation and the need of possible treatment changes, after a consultation with the cardiologists. Before starting the rehabilitation program, the patient recorded a 1-lead ECG signal transmitted to the TMC. One-lead ECG recordings were obtained before and within 5 min of session completion. At the end of the training session, a telemonitoring contact with the nurse-tutor was planned in order to transfer all the 1-lead ECG recordings. Compliance was represented by a heart rate at least 20% higher than that measured before training based on the tele-ECG recorded post-exercise.Patients assigned randomly to UCG were referred to their general practitioner. A structured follow-up with the cardiologist at 12 months in the hospital outpatient department and the appointment with the primary care physician within two weeks from the discharge were planned.Data were analysed using SPSS software, v. 20.0. A p value < 0.05 was considered significant. Continuous data were expressed as mean ± standard deviation (SD) and categorical data as number and percentage. Variables with asymmetric distribution were summarized as medians and interquartile intervals.Differences between the groups during follow-up were tested by ANOVA for repeated measures. A Cox proportional hazard model was applied to analyse the multivariate effects of the risk factors, identified by ANOVA, on rehospitalisation. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were calculated to test the direction and strength of the influence of individual factors on event risk and event-free survival.CHAID (Chi-squared Automatic Interaction Detector) was used to develop a decision-tree analysis to assess the risk of rehospitalisation using all dichotomized variables as predictors. The CHAID algorithm incorporates a sequential merge and split procedure based on chi-square test statistics. The following stopping rules were applied in growing the tree: minimum terminal parental node size, 50 cases, minimum terminal child node size, 25 cases, and α = 0.05 for splitting nodes and merging categories. The convergence criteria for CHAID analysis were Epsilon=0.0010 and 100 maximum iterations before stopping the process.The sample size of 343 patients provides a power of 80% to detect an effect size of 0.10 on variation of 6MWT distance between the groups using ANOVA for repeated measures with a 5% significance level. This level also holds for the other aims of this project.