Reduced level of FEV1  was associated to newly-diagnosed hypertension (p: 0.0002), higher day SBP levels (p: 0.003), higher day DBP levels (p: 0.03), higher 24 h-SBP levels (p: 0.005) and higher 24h-DBP levels (p: 0.03). The regression analysis performed taking into account sex, age, diabetes, fasting glucose, and body mass index confirms the independent role played by asthma: odds ratio (OR): 3.66 (CI: 1.29–11.1). Conclusions: hypertension is highly prevalent in asthma; the use of ABPM has allowed the detection of a considerable number of unrecognized hypertensives.Background: several studies report an increased risk for asthmatic subjects to develop arterial hypertension and the relationship between these two diseases, frequently co-existing, still has some unclear aspects. Methods: The BADA  study is aimed to evaluate the prevalence of the cardiovascular comorbidities of asthma and their impact on the clinical outcome. The main exclusion criteria were the presence of other respiratory diseases, current smoking, any contraindication to ambulatory blood pressure monitoring (ABPM). Results: The overall percentage of asthmatics having also hypertension was 75% (30 patients) vs. 45% (18 patients) of the control group ( Asthma is one of the most common chronic, non-communicable diseases, affecting around 334 million people worldwide . The preThe reasons of the association between asthma and high blood pressure are to large extent unknown. Of note, asthma medications may play a role over development of hypertension: long acting bronchodilators (LABA) have been associated with mortality in asthma populations . SystemiThe BADA  study aimed to evaluate the prevalence of the cardiovascular comorbidities of asthma and their impact on the course of the disease. The main objectives of this pilot study were to evaluate the prevalence of hypertension in asthmatics adding to the cases with already known hypertension those identified by the execution of a 24-h (h) ambulatory blood pressure monitoring (ABPM). This type of approach, which also provides additional information concerning, for example, the circadian rhythm of blood pressure sets the basis for a more in-depth evaluation of the factors influencing the occurrence of arterial hypertension in asthmatic patients, which is the future objective of the BADA Study.In this pilot study forty patients affected by asthma were consecutively recruited among those referring to outpatient clinic of the Division of Respiratory Diseases of the University of Palermo, Italy, in the period between 01/01/2018 and 31/03/2019. All subjects enrolled were Caucasian, were previously informed about the characteristics and the object of the study and a written informed consent was obtained. The study was approved by the ethical committee of our institution (prot 018/2017).-Diagnosis of secondary hypertension-Co-existing chronic obstructive pulmonary disease (COPD)-Co-existing obstructive sleep apnea (OSA)-Current smoking. Current smoking was defined based on a positive response to the question “Do you currently smoke any tobacco products such as cigarettes, cigars, or pipes?”-A medical history of an acute vascular event  in the previous six months.-Finding of supraventricular arrhythmias ;History or clinical evidence of orthostatic hypotension, evaluated comparing sitting and standing Blood Pressure (BP) during the run-in visit;Clinical history of autonomic dysfunction or diabetic neuropathy;Severe obesity; excessive alcohol consumption; history of sleep disturbance; night-workers;Intolerance to the procedure.Every condition contraindicating the reliability and/or the execution of the ABPM:Exclusion criteria:A total of forty consecutive individuals referring to the Division of Internal Medicine and Stroke Care of the University of Palermo for ambulatory examination due to medical reasons different from respiratory diseases served as the control group. All patients in the control group were Caucasian, should not have a history of asthma, should not take steroid therapy for any reason, and should have no evidence of airflow limitation to the spirometry.The initial study procedure included, for all subjects, a comprehensive recording of medical history with specific attention to cardiovascular risk profile, pharmacological anamnesis, complete physical examination, assessment of body mass index (BMI), calculated as the individual’s body weight divided by the square of his or her height, and the following blood biochemical examinations . Subjects were defined as type 2 diabetics if they had known diabetes treated by diet, oral hypoglycemic drugs or insulin. Previous cerebrovascular disease (TIA/ischemic stroke) was assessed by history, specific neurological examination performed by specialists, and hospital or radiological (brain computed tomography or brain magnetic resonance) records of definite previous stroke. Previous coronary heart disease was detected by history, clinical examination, electrocardiogram and echocardiogram. According to the available anamnestic information collected at the time of enrolment there were no significant differences between cases and controls regarding the characteristics of the diet and the level of physical activity .1 (forced expiratory volume in 1 s) expressed in liters and in percent predicted value (FEV1%), FVC  expressed in liters and in percent predicted value (FVC%) and the FEV1/FVC ratio, expressed as absolute values. Reversibility of bronchial obstruction was assessed. Severe asthma was defined as asthma which requires treatment with high dose inhaled corticosteroids (ICS) plus a second controller (and/or systemic corticosteroids) or which remains uncontrolled despite this therapy [1 value (from the highest to the lowest), dividing the sample into quartiles and comparing the top quartile (including patients with the best respiratory function) with the bottom quartile.Asthmatic patients enrolled met the diagnosis of the disease based on Global Initiative for Asthma (GINA) criteria , conside therapy . The sev therapy . In ordeEssential hypertension was defined based on clinical history, hospital records and/or antihypertensive treatments taken daily by the patients. For these subjects, no change of the antihypertensive drugs regularly taken was allowed during the interval of the study. A newly diagnosed hypertension after the ABPM execution was established according to the exceeding of threshold values indicated by the ESC-ESH 2018 Guidelines  for an AMeasurements recorded during the 24h were stored on a personal computer and screened as follows: a 24 h record was rejected for analysis if more than one third of potential day and night measurements were absent or invalid. The ambulatory BP values used for statistical analysis were expressed as 24-h average systolic and diastolic pressures, and 24-h average heart rate. Night/day ratio of BP was calculated as follows: mean nocturnal systolic BP/mean diurnal systolic BP, considering for the analysis the night/day BP ratio as a continuous variable. According to guidelines,  physiolowww.r-project.org)Statistical analysis of quantitative and qualitative data, including descriptive statistics, was performed for all items. Continuous data are expressed as mean ± SD, unless otherwise specified, categorical variables are expressed as percentage. A student T Test for unpaired data was used to compare the continuous variables between the two groups examined. The comparison of the proportions was performed using the Chi square test or the exact Fischer’s test (used when the expected frequency of the event was lower than five times). A multiple logistic regression analysis has been performed taking into account the role played by the main confounding factors  in influencing the relationship we found between the independent variable (IV) asthma and the dependent variable (DV) overall hypertension. We furthermore created a logistic regression model in which the DV was represented by the overall presence of hypertension in our asthmatic sample; the IV was represented by the use of increasing dose of ICS and was represented as a continuous variable. All P-values were two-sided and P-values less than 0.05 were considered statistically significant. Statistical analysis and graphs generation have been performed using R software version 4.0.2 . The proportion of asthmatics also suffering from concomitant arterial hypertension was 75% (30 patients) vs. 45% (18 subjects) in the control group (p: 0.012); of these 12 asthmatics vs. 6 in the control group are newly diagnosed (p: 0.01) A significantly higher prevalence of type 2 diabetes mellitus (T2 DM) was found in asthmatics vs. controls  without significant differences in fasting blood glucose levels . The BMI, an index associated both to T2DM development and to asthma severity, was significantly higher in the asthma group than in the control group .p: 0.05) and a significantly higher morning blood pressure surges than in controls: 21.70 ± 12.8 vs. 12.0 ± 10.6 mmHg (p < 0.0001) for systolic blood pressure (SBP) and 18.0 ± 10.9 vs. 11.2 ± 10.0 mmHg (p < 0.005) for diastolic blood pressure (DBP).1 values are highly significantly associated with high blood pressure levels: 100% vs. 40% (p < 0.0001).1 levels. Reduced FEV1 values are significantly associated with higher 24 h-SBP levels: 142.25 ± 19.25 vs. 122.82 ± 15.50 mmHg (p: 0.005), higher 24h-DBP levels: 81.14 ± 8.36 vs. 73.26 ± 8.14 mmHg (p: 0.03), higher day SBP levels: 148.24 ± 19.51 vs. 128.48 ± 14.28 mmHg (p: 0.003), higher day DBP levels: 85.36 ± 8.99 vs. 77.48 ± 8.84 (p: 0.03).p: 0.01).1 % level and overall hypertension). The regression analysis confirms the independent role played by asthma with an odds ratio (OR) of 3.66 (CI: 1.29–11.1); p: 0.008, severe asthma  and FEV1% .p: 0.7193).p: 0.008, higher than previously reported [The findings of our study strengthen the already well documented association between asthma and arterial hypertension. Our data show a prevalence of hypertension in asthmatics of 75%, up to 80.8% in patients with severe asthma; these values are significantly higher than that reported in other different epidemiological contexts ,10,11 whreported ,10,11. Mreported ,10,11. O1 % predicted and systemic levels of inflammatory markers was demonstrated [Mechanisms underlying the high prevalence of arterial hypertension in asthmatics remain largely unknown. There are several theories trying to explain this epidemiological finding: reduced lung function (FEV1), impairment of smooth muscle tonus regulation, vascular remodeling, adverse effects of therapy, and genetic factors ,21, whicnstrated ,26, and nstrated ,28. Futunstrated ,30,31,321 levels, was the main feature associated to arterial hypertension. The findings of our study confirm previous observations on the association of low FEV1 levels with high BP [1 levels  compared vs. the highest quartile  reaches the statically significance for the association of hypertension . The asthma patients in the lowest quartile for FEV1 also have higher 24-h and diurnal  SBP and DBP levels. To the best of our knowledge, this is the first observation of a peculiar association between reduced FEV1 and maintained physiologic nocturnal fall of BP, whereas preserved FEV1 seems to be featured by an exaggerated nocturnal decrease of BP (extreme dipper profile). This peculiar observation needs to be confirmed in a larger sample because of multiple determinants of the nocturnal BP fall [In our population reduced lung function, assessed by measurement of FEV high BP . In our  BP fall ,34,35. OSeveral authors have hypothesized that steroid therapy may play a role in the development of high BP in asthmatics. High corticosteroid doses has been associated with mineral corticosteroid effects  with retOur study has some limitations, first of all the small number of the enrolled subjects that weakens the statistic power of our analysis, as such, these are preliminary reports of an ongoing study, whose aim is to increase the recruitment to investigate the unanswered questions. It should also be considered that we excluded patient with other concomitant respiratory diseases, such as rhinitis, COPD, OSA and/or bronchiectasis, which are also associated with low-grade systemic inflammation that could to different extent contribute to the risk of develop essential hypertension . MoreoveThese preliminary results of the BADA Study support the idea that arterial hypertension in asthma is more prevalent than how supposed before, emphasizing the need for a deeper cardiovascular screening for asthma patients (mainly for those at higher cardiovascular risk). In particular, our data highlights the need for a more extensive use of ABPM, as recently stated also by other authors ; the 24-1 levels as well as the possible influence of medical therapy on the development of high BP values. The continuation of the BADA Study as well as other studies that may be undertaken in the future are called to clarify the still doubtful aspects of these issues.Our data, although not conclusive, suggest the presence of specific alterations in the nocturnal BP profile associated with low FEV


Cigarette smoking is usually associated with hypertension and may modify vasoconstrictor response.The present study aimed to analyze and compare the interaction of passive cigarette smoking and hypertension on epinephrine and felypressin blood pressure effects after intravascular injection.45-day male Wistar rats had the main left renal artery partially constricted and the right kidney removed (1K1C model). Rats were placed in the chamber for exposition to passive cigarette smoking (10 cigarettes) during 10 min (6 days a week). Hypertensive rats received atenolol (90 mg/kg/day) by gavage for two weeks. Hypotensive and hypertensive response, response duration and heart rate were recorded from direct blood pressure values. The significance level was 5%.Passive cigarette smoking increased maximal hypertensive response to epinephrine in normotensive and 1K1C-atenolol treated rats and to felypressin only in 1K1C-atenolol treated rats; it also reduced epinephrine hypotensive response. Epinephrine increased heart rate in normotensive and hypertensive passive smokers or non-smoker rats. Comparing the two vasoconstrictors, epinephrine showed greater hypertensive response in normotensive smokers, 1K1C-atenolol treated smokers and non-smokers. However, in normotensive-nonsmoker rats, felypressin showed a greater and longer hypertensive effect.Our results suggest that passive cigarette smoking may reduce epinephrine vasodilation and increase hypertensive response when compared to felypressin. Therefore, felypressin may be safe for hypertensive patients to avoid tachycardia and atenolol interaction, but for normotensive and non-smoker patients, epinephrine may be safer than felypressin. Introduction1 Therefore, vasoconstrictors are also used to avoid its absorption and adverse effects: seizures, arrhythmia and cardiac arrest. There are studies indicating vasoconstrictor absorption and systemic effects. Epinephrine can be detected in plasma after infiltration and can increase heart rate in normal subjects.2 There are no clinical data comparing epinephrine and felypressin efficacy or safety, but there is evidence that isolated local anesthetics results in shorter and low quality pain control.3Vasoconstrictor drugs are essential for dental and medical procedures performed under local anesthesia, since the local anesthetic must stay in contact with sensitive nerves. One single local anesthetic cartridge administered via intravascular route can be fatal.4 The WHO estimates that the global prevalence of adults smoking any tobacco product is 36% in adult men and 8% in adult women.5Vasoconstrictor drugs have systemic effects that can be critical in patients with cardiovascular diseases: coronary vasoconstriction, tachycardia, increases in cardiac contraction force, etc. Such effects are related to the most common causes of death in the modern world: heart attack, stroke and thrombosis; and patients usually have multifactorial diseases. Cigarette smoking and hypertension are included in the National Cholesterol Education Program algorithm to predict cardiovascular disease risk, addressing both as modifiable causes of atherosclerosis in prevention efforts.6 Nicotine also affects the autonomous nervous system, having a different effect than cigarette smoking products.7 Catecholamine release and atherosclerotic lipoproteins are increased in the blood levels of smoker patients.8 The vasoactive drugs present, therefore, alter the vascular response of smokers, since the nitric oxide (NO) pathway, adrenergic and cholinergic systems are affected. Although epinephrine is considered the safest vasoconstrictor drug in patients with cardiovascular disease by The American Dental Association,9 patients receiving betablocker treatment who smoke cigarettes must be treated differently.The number of cigarettes show a positive correlation with higher blood pressure values but not with heart rate.10 In order to increase the knowledge about the safety of epinephrine and felypressin, this study attempted to test them isolated in intravascular administration to simulate the maximal error in local anesthesia, providing information for the formulation of safer local anesthetic solutions. Therefore, the aim of this study was to evaluate and compare the effects of direct intravenous injection of epinephrine and felypressin on blood pressure of smoker or non-smoker normotensive, hypertensive and atenolol-treated hypertensive rats.Felypressin may be a safe alternative vasoconstrictor in such populationce since it is a non-adrenergic vasoconstrictor. There is no reported interaction between cigaretes smoking and vasopressin. A previous study showed reduced hypertensive effect of felypressin in rats treated with atenolol.Faculdade de Odontologia de Bauru facilities were used in all groups of this study. The experimental hypertension method, indirect and direct BP measurements, were performed as previously described10. All rats received a normal diet, free water and food access and were submitted to 12 hour light/dark cycle. Rats weighing 110 to 150 g were anesthetized with an injection of ketamine  plus xylazine . The left renal artery was isolated, and a 0.25 mm gap silver clip was installed around it, and the right kidney was completely removed. 40,000 IU of small-animal antibiotic  was injected. It is worth mentioning that surgery for clips implantation in the renal arteries was performed in 10 animals per group, that is, 120 rats. However, each groups consisted of 6 animals, since part of the rats did not have systolic blood pressure above 150 mmHg. Therefore, 72 was the total number of animals used in the study and there were no criteria for the definition of this sample, being defined by convenience.For the present study, all norms for animal research were reviewed and approved by the institutional review board before the experiments (protocol #010/2010). Male Wistar rats weighing 140 to 320 g provided by 11. One day after hypertension induction, the rats were intoxicated one time a day (10 cigarettes per exposure period), 6 days a week. The exposure protocol consisted of confining 10 rats in the inhalation chamber during 10 min of compressed air ventilation (10 L/min).Passive smoking was performed based on previous emphysema induction studies1K1C rats were heated in individual cages containing an electrical resistance and tail pneumatic cuffs were installed and connected to a digital system for indirect blood pressure record . Rats that presented systolic blood pressure equal to or higher than 150 mmHg in the indirect measurement 15 days after clip surgery were accepted in the hypertensive group or treated with atenolol  administered by gavage in 1mL for 2 weeks.All groups had blood pressure measured directly for 28-35 days after clip surgery, or the equivalent time in the control group: after ketamine/xylazine anesthesia, a saline-filled polyethylene catheter PE-50  with an occluded external extremity was implanted in the left carotid artery and in the right jugular vein. The arterial catheter was connected to a pressure transducer coupled to an invasive blood pressure recording system, using appropriate software . The experiments of intravenous injection of vasoconstrictor drugs were performed with anesthetized rats right after catheter implantation. A scheme of the experiments design are detailed in ®- HipolaborFarmacêuticaLtda - Belo Horizonte, Minas Gerais, Brazil) diluted in saline solution was injected at the doses of 80, 160, 320, 640 and 1,280 ng in bolus through tin venous catheter to obtain dose-response curves. Felypressin alone  was used at doses of 0.125, 0.25, 0.5, 1, 2 and 3mIU. Intravenous injections in random order were performed after a 3-min interval for each response to stabilize blood pressure. Animals were euthanized with intravenous injection of excessive doses of the anesthetic drug thiopental . The following parameters were analyzed using PAM values (PAM = 1/3 Systolic Pressure + 2/3 Diastolic Pressure): minimal hypotensive response, maximal hypertensive response and response duration. Duration was determined using global pressure alterations, since epinephrine has a complex blood pressure response where there is a hypertensive peak followed by hypotensive response and normalization; previous studies have clarified this pattern10. Heart rate was recorded 30 s after the injection during one min to avoid bias caused by longer duration or great blood pressure changes since the program used pulsatile pressure to determine these parameter. In order to compare epinephrine and felypressin, doses that corresponded to 1, 2, 4 and 8 local anesthetic cartridges which would have been administered to the rats, were used. The following formula was used: D = 18,000 (for epinephrine*) or 54 mIU (for felypressin*) x 4,286 x 10-3 (a weight correction from humans (70 kg) to rats (300 g).Exogenous epinephrine  for data with normal distribution according to Kolmogorov-Smirnov test. In cases where normal distribution did not occur in one group or more, data were presented as Median ± interquartile interval.When more than one response was obtained from the same animal, repeatd -measures one-way analysis of variance was used (Repeaed- measures One-Way ANOVA). To compare complete curves from two or more groups, repeaed- measures Two-Way analysis of variance was used (Repeaed- measures Two-Way ANOVA). When there was a significant difference between the doses in each curve or in independent groups and normal distribution, comparison was performed by Holm-Sidak’s or Tukeyhodtest. For non-parametric results, Mann-Whitney and Kruskal-Wallis tests were used. The level of significance in this study was set at 5% (p < 0.05). All tests were performed using STATISTICA Software (StatSoft South America).Basal blood pressure values during the first five minutes are summarized in Maximal hypertensive response curves for epinephrine and felypressin, smokers vs. non-smokers, are shown in 1-receptors. Felypressin showed a significant reduction in heart rate for non-smoker, normotensive rats when compared with basal values , smoking cigarettes has a direct impact on atherosclerosis formation and increases cardiovascular disases risk.4 The association of hypertension and cigarettes smoking represents a delicate case for vasoconstrictor use. Felypressin response duration was significantly higher than epinephrine’s in all groups, which was expected since vasopressin half-life is approximately 17-35min,16 while epinephrine has a short half-life due to metabolism and synaptic reuptake.There is a complex cardiovascular response to nicotine because of ganglionar nicotine receptors which influence autonomous sympathetic and parasympathetic nervous systems. This response includes increase in catecholamine release and altered lipids metabolism which explains increase in cardiovascular disease development on in smokes.17. Nicotine-free cigarette smoke extract administered by subcutaneous injection induced endothelial dysfunction, increased blood pressure values and reduced acetylcholine-induced vasodilatation.18 Although the chemical component responsible for epithelial dysfunction is not clear, cigarettes smoke extract reduces vascular relaxation by increasing oxidative stress and reducing NO bioavailability.19 Smokers also showed altered lipoprotein metabolism, increased levels of oxidized low density lipoprotein (LDL) which may contribute to vasoconstriction.Cigarette smoking increases blood vessel stiffness by different pathways, including oxidative stress increase of endothelin-1 production and formation of smooth muscle cell.21 Our study showed a significantly reduced minimal hypotensive response on the smoker normotensive group (Chronic smoking impairs NO synthesis and enhances production of reactive oxygen species, while nicotine administration leads to hypertension due to increased sympathetic nervous system.ve group . This rein bolus via intravascular route in hypertensive rats but there were no deaths. Our results support vasoconstrictor safety in associated vascular problems, mostly especially felypressin seems to be promising vasoconstrictor to smoker patients since there is no interaction with the sympathetic nervous system.Epinephrine and felypressin dosage corresponded to the content of 0.5 to 16 local anesthetic cartridges administered


M1-PI and M1-FVP were associated with decreasing cognitive function . In summary, this supports an association between arterial pulsatility and SVD in stroke patients, and provides a potential target for further research and preventative treatment. FVP may become a useful biomarker for assessing pulsatile stress with PCMRI and 4D flow MRI.Cerebral small vessel disease (SVD) is a major cause of stroke and cognitive impairment. However, the underlying mechanisms behind SVD are still poorly understood. High cerebral arterial pulsatility has been suggested as a possible cause of SVD. In population studies, arterial pulsatility has been linked to white matter hyperintensities (WMH), cerebral atrophy, and cognitive impairment, all features of SVD. In stroke, pulsatility data are scarce and contradictory. The aim of this study was to investigate the relationship between arterial pulsatility and SVD in stroke patients. With a cross-sectional design, 89 patients with acute ischemic stroke or TIA were examined with MRI. A neuropsychological assessment was performed 1 year later. Using 4D flow MRI, pulsatile indices (PI) were calculated for the internal carotid artery (ICA) and middle cerebral artery . Flow volume pulsatility (FVP), a measure corresponding to the cyclic expansion of the arterial tree, was calculated for the same locations. These parameters were assessed for associations with WMH volume, brain volume and cognitive function. ICA-FVP was associated with WMH volume ( Cerebral small vessel disease (SVD) is a major cause of stroke and cognitive impairment. It is estimated that 20–42% of ischemic strokes are of small vessel origin , and conA new promising technique able to quantify cerebral arterial pulsatility is 4D flow MRI, which measures blood flow in three dimensions time-resolved over the cardiac cycle. The technique measures blood flow rate in any cerebral blood vessel down to a diameter of a few millimeters . In addiWe hypothesized that in stroke, high cerebral arterial pulsatility would be associated with more WMH, cerebral atrophy, and cognitive impairment. The aim of this study was to investigate the cross-sectional relationship between arterial pulsatility and SVD in patients with ischemic stroke and transient ischemic attack (TIA).n = 48). Pulsatility measures in proximal and distal cerebral arteries were analyzed for correlations to three main outcomes: WMH volume, total brain volume (TBV), and neuropsychology and adjusted for risk factors.Eighty-nine patients with acute ischemic stroke or TIA were divided in two groups: with or without associated SVD. MRI including 4D flow MRI was performed within the first week and neuropsychological tests 1 year after the event  during 2013–2015. Due to fire safety regulations at the research MRI facility, bedridden patients were not included. Exclusion criteria included previous stroke ipsilateral to the current event, remaining disability from a previous stroke  and previous disease of the central nervous system. In addition, patients with any MRI contraindication, systolic blood pressure (SBP) > 180 mmHg, mini-mental state examination < 23 points or inability to understand oral information and/or provide informed consent were excluded. In total, 157 patients were included.At initial presentation, a clinical evaluation was performed by a stroke physician including medical history, cardiopulmonary- and neurological examination, National Institutes of Health Stroke Scale (NIHSS), standard blood tests, ECG, computed tomography of the brain (CT) and CT angiography (CTA), or cervical ultrasonography. Use of antihypertensive medications were recorded by class . Examination with Holter monitor and transthoracic- or transesophageal echocardiography was performed on clinical indication. MRI studies were performed at mean 4 (3) days after symptom onset. Finally, an etiologic classification according to TOAST was performed using a validated, computerized tool –22.n = 157), we excluded patients aged below 50 years (n = 7) with CAS > 70% (n = 24) and patients without stroke or TIA within the last 7 days (n = 5). Among remaining patients (n = 121), 17 did not have a complete MRI examination and a further 15 were excluded for technical reasons, such as motion artefacts or corrupt data. The final study population thus contained 89 patients.From the initially included  days), patients were offered a follow-up examination including neuropsychological testing. This later date was selected to avoid acute, reversible effects from the cerebrovascular event. Forty-eight (53.9%) patients participated. Patients with vascular cognitive impairment typically present with frontal lobe deficits such as impaired executive functions, psychomotor speed, and attention . With th−1; TR/TE, 6.5/2.7 ms; flip angle, 8°. Dynamic images were reconstructed by retrospective gating from the recorded peripheral pulse signal by use of temporal interpolation similar to view sharing in Cartesian acquisitions. Besides 3D velocity information for the 20 reconstructed time positions, a time-average composite complex difference image was reconstructed to provide an angiogram.MRI studies were performed at a 3 T scanner  with a 32-channel head coil. T1- and T2-weighted, FLAIR, diffusion- and susceptibility-weighted images were obtained. 4D flow MRI data were acquired by a balanced five-point PC-VIPR sequence , 26, covUsing SPM 12 , the intracranial space was segmented into grey matter (GM), white matter (WM), and cerebrospinal fluid (CSF). Results were visually inspected for accuracy; no manual corrections were needed. Intracranial volume was calculated by summing GM, WM, and CSF. Total brain volume was calculated by summing GM and WM.https://www.statistical-modelling.de/lst.html) for SPM [WMH volumes were segmented by the lesion prediction algorithm as implemented in the Lesion Segmentation Toolbox version 2.0.15 . The STRIVE definition of SVD on conventional MRI includes white matter hyperintensities, small recent subcortical infarcts, lacunes, and cerebral microbleeds [Structural MRI data were reviewed for lesion sizes, locations, and features of SVD. Visual rating of WMH according to the Fazekas scale was performed . To asserobleeds . For theR–R interval was performed in both measures to account for the assumption that individuals with higher heart rates are exposed to more pulsatile stress over time given similar pulsatile expansion in each heart cycle. All measurements were made bilaterally. For each segment, the mean PI and FVP of the right and left sides was used. If a pulsatility measure was missing for a paired artery, the measure of the contralateral artery was used.To assess blood flow in the 4D flow MRI data, a centerline processing scheme was used. It has been previously described in detail . Total ct test or Kruskal–Wallis H-test. Multivariable analysis was performed using generalized linear modeling (GLM). For modeling skewed data such as WMH volume, gamma distribution with log link was used. For normally distributed dependent variables, we used linear distribution with identity link. To limit the number of comparisons, M3 pulsatility was not used in the multivariable analysis. Pulsatility variables were entered one at a time. Three GLM models were thus created, using WMH volume, TBV, and cognitive function as dependent variables, adjusting for age, sex, MAP, hypertension, and tCBF (basic model).Statistical analysis was performed in SPSS 24 . Values are mean (SD) if not otherwise specified. Correlations between continuous variables were assessed using Pearson correlation and Spearman’s rho as appropriate. Relationships between categorical variables were assessed using Fisher’s exact test. Relationships between categorical and continuous variables were examined using independent samples α was set at 0.05.In a second step, the models including all patients  were additionally adjusted for antihypertensive drugs (by class). The model for cognitive function was additionally adjusted for WMH volume and TBV. A subgroup analysis was performed in patients with SVD. This analysis was also performed using the basic model and used WMH volume and TBV as dependent variables. Patients having completed the neuropsychological examination were deemed too few to use cognitive function as a variable in this analysis. Finally, as periventricular and deep WMH may have different pathogenesis, an ordinal logistic regression model was created to assess these separately using the periventricular and deep scores on the Fazekas scale as dependent variables. This model also adjusted for age, sex, MAP, hypertension, and tCBF. Of 89 included patients, 64 71.9%) were diagnosed with ischemic stroke, remaining 25 (28.1%) had TIA  and ICA-FVP was associated with decreasing DBP . There were no significant associations between PI and DBP . Women had higher ICA-PI  and M1-PI . This difference remained significant after adjusting for age. PI and FVP were correlated in ICA and M1  but not in M3.ICA-PI, M1-PI, M3-PI, and ICA-FVP were associated with age  while M1-FVP and both measures of PI were not. If antihypertensives were added to the model, both ICA-FVP and M1-FVP were associated with WMH volume . There was no association between arterial pulsatility and either periventricular- or deep WMH as represented by their respective Fazekas score.In the multivariable models, ICA-FVP was associated with WMH volume . If WMH volume and TBV were added to the model M1-PI, remained associated with decreased cognitive function , while M1-FVP did not. The best-fitting basic model for each outcome is presented in Table There were no associations between any measure of arterial pulsatility and TBV. Results were unchanged if antihypertensives were added. M1-PI and M1-FVP were associated with decreasing cognitive function . In addition, both ICA-FVP and M1-FVP were associated with decreasing TBV . PI was not associated with either WMH or TBV. Table In the SVD subgroup, ICA-FVP was independently associated with WMH volume . This difference was no longer significant after adjusting for age. There was no difference in pulsatility between stroke versus TIA or between different etiologies or lesion locations. There were no correlations between NIHSS score and arterial pulsatility.M1-PI was increased in patients with SVD . Increased FVP, a new parameter measuring cyclic expansions of the vascular tree, was associated with increased WMH volume, decreased cognitive function and, in patients with associated SVD, lower TBV. The most commonly used parameter for arterial pulsatility, PI, was only associated with cognitive function.4D flow MRI is a relatively new technique for measuring intracranial flow. We have previously shown that 4D flow measurements are consistent with traditional phase-contrast MRI in both young and elderly subjects, and that good agreement between the modalities also applies to pulsatility measures , 32. PI n = 100) found cross-sectional relationships between M1-PI and WMH [There was an association between FVP and WMH. This is a novel finding, as FVP has not been measured in this context previously. There is steadily increasing evidence of a relationship between WMH and high cerebral pulsatility, spanning a variety of modalities, anatomical measuring points, and populations. In a retrospective, hospital-based cohort of 450 patients, baseline M1-PI was found to predict WMH expansion independent of traditional risk factors . In pati and WMH , 15. OurWe also found a negative correlation between arterial pulsatility measured in the acute phase, and cognitive impairment 1 year later. This relationship is sparsely studied, but our results are consistent with previous studies in the elderly population and in patients with acute lacunar syndromes , 17. TheIn stroke patients with associated SVD, we found a negative association between FVP and TBV. This correlation was not significant in the full sample, nor using pulsatile index. This relationship has not been previously studied in patients with stroke, but data from the AGES-Reykjavik population study and a previous study in elderly from our group support a relationship between cerebral arterial pulsatility and brain volume , 30. TheSeveral mechanisms have been put forward to explain the relationship between cerebral arterial pulsatility and brain structure and function. In one, increased aortic stiffness and impedance-matching with the carotid arteries enables transfer of increased arterial pulsatility into the cerebral microcirculation , 14. An Cerebral veins and venules have been less explored in the setting of SVD. There is some evidence to suggest venous collagenosis may be associated with WMH , 41. TheIt has previously been assumed that increased WMH causes increased cerebral arterial pulsatility by way of increased flow resistance. However, several studies have found that cerebral arterial pulsatility is more closely associated with upstream factors such as aortic stiffness, aortic pressures, and impedance-matching at the aortic–carotid junction , 14. ThiStrengths of the study include prospective recruitment, use of FVP in addition to PI, performing a comprehensive, validated neuropsychological test battery, for the first time assessing the relationship of pulsatility and atrophy in this population and performing the MRI examination in a clinically relevant situation, within the initial hospitalization. Moreover, 4D flow MRI is feasible to perform as part in routine management of stroke patients as measurements are made entirely in post-processing and can be automatized , 44.This study also has limitations. As WMH, TBV, cognitive function, hypertension, and cerebral arterial pulsatility are all closely associated with age, causative associations are difficult to find. This particularly applies to wide-range populations and cross-sectional studies such as this. This implies that relevant associations between these variables may be underestimated. The sample size, although similar to previous studies in the field, was insufficient to detect weaker correlations. Patients with severe hemodynamic alterations  were excluded, as measured pulsatility was not deemed representative of their long-term pulsatility exposure. Results may, therefore, not be generalizable to these patients. This study did not account for venous pulsatility, which also may be associated with WMH in stroke patients , somewhaNew and clinically relevant findings reported in this study are associations between the novel parameter FVP and both WMH and cognitive function. FVP was more strongly associated with features of SVD compared to PI and may be a useful biomarker in future studies of cerebral pulsatility. The cross-sectional design limits conclusions regarding causality. However, our results support an association between arterial pulsatility and SVD in stroke patients, and provides a potential target for further research and preventative treatment. This study also shows that 4D flow MRI could be a suitable method for flow assessment in clinical routine and in large cohorts.


Self-measured blood pressure monitoring programs (BPMPs) are effective at controlling hypertension. We examined implementation of self-measured BPMPs at 5 Hawaiʻi-based Federally Qualified Health Centers (FQHCs). In a process evaluation of these programs, we found that FQHCs developed protocols for self-measured BPMP recruitment and enrollment and provided additional supports to account for their patients’ psychosocial needs to achieve blood pressure control, such as lifestyle change education and opportunities through referrals either to on-site or other programs . Common barriers across sites included insufficient material support for blood pressure monitors and data collection; funding, which affects program sustainability; and the lack of an “off-the-shelf” self-measured BPMP intervention. Policy makers and funding organizations should address these issues related to self-measured BPMPs to ensure implementation success. Self-measured blood pressure monitoring programs (BPMPs) are effective in helping people with hypertension control their blood pressure.This article explores the experiences of 5 Hawaiʻi-based Federally Qualified Health Centers (FQHCs) in implementing self-measured BPMPs. Because no nationally recognized self-measured BPMP curriculum existed at the time of this evaluation, the purpose of this article was to understand how FQHCs designed and implemented self-measured BPMPs in practice.Policy makers, funding organizations, and intervention designers can draw on these experiences to make improvements to self-measured BPMPs in terms of support and toward the development of a standardized intervention curriculum.Self-measured blood pressure monitoring programs (BPMPs) are interventions for patients to track their blood pressure at home or in other nonclinical settings. They are used to diagnose high blood pressure, improve blood pressure control, and reduce the risk of related conditions, including heart disease, heart attacks, and stroke . CompareIn 2014, the Centers for Disease Control and Prevention (CDC) awarded funds to the Hawaiʻi Department of Health (HDOH), Hawaiʻi Primary Care Association (HPCA), and 9 Federally Qualified Health Centers (FQHCs) to increase use of self-measured BPMPs with clinical support . In 2015www.cdc.gov/dhdsp/docs/logic_model.pdf). This evaluation was approved by the University of Hawai‘i at Mānoa institutional review board.Evaluators from the University of Hawaiʻi at Mānoa were contracted to provide a process evaluation that qualitatively assessed common self-measured BPMP components and that assessed barriers and facilitators at sites implementing the program. HPCA identified 5 FQHCs with self-measured BPMPs at varying levels of maturity; these FQHCs represented different practice settings  and patient population sizes . Health centers selected staff familiar with their self-measured BPMPs to participate in semi-structured video or telephone interviews, conducted in June and July 2018. Nine providers participated , and allAcross the 5 FQHCs, the main program goals were to confirm a hypertension diagnosis and control blood pressure among those with diagnosed hypertension. The primary ways programs sought to achieve blood pressure control were through blood pressure monitoring and lifestyle change programs. We present the themes that emerged from interviews.Ola Hou (hula for hypertension), and the National Diabetes Prevention Program (NDPP). Patient-centered practices, like working with patients to develop individual goals for controlling blood pressure, were important. One provider said, “Shared decision-making is, I think, progressively getting more incorporated into the management of the team as well as the providers.”Self-measured BPMP programs started at various times. One site started in September 2016 and 3 sites started in October 2016. The remaining site had an existing self-measured BPMP that started before the grant in 2015, and it used grant funds to maximize its community care model with CHWs. In addition to hiring support staff at all 5 centers, grant funds were used for additional program supplies . Interviewees said staff, existing program curricula related to blood pressure management, and patient-centered practices were important program inputs. All 5 FQHCs engaged CHWs or health educators in self-measured BPMPs, together with pharmacists, nurses, care coordinators, patient navigators, medical assistants, social workers, and/or nutritionists. The American Heart Association donated monitors, which facilitated the creation of a monitor loan program for patients who could not afford to purchase them, and provided educational materials. Other existing patient educational materials used by FQHCs included resources from HDOH, a culturally tailored intervention called All FQHCs enrolled current patients with hypertension, although 3 sites also used their self-measured BPMPs to formally diagnose hypertension. FQHCs mainly used a systolic/diastolic threshold of 140/90 mm Hg to determine eligibility, and 1 center also used 150/90 mm Hg for its patients who were older than 60. All FQHCs developed workflows for recruitment, which included internal bidirectional referral systems and electronic health record (EHR) algorithms to identify patients with undiagnosed hypertension. Participants were also recruited via existing programs at FQHCs, such as NDPP classes . One sitFQHCs used many of the same intake and enrollment procedures. Potential participants complete readiness assessments and program introductions with their PCP or self-measured BPMP staff assigned through the EHR. The level of patient assessment differed by site. One site asked permission of potential patients to schedule a time to explain the process. Another site conducted 3 different patient assessments because many of their clients had other underlying psychosocial issues, such as houselessness or mental illness: “We've had times . . . where [the patients] come in, and then they don't really know what they're here for. Then they don't want to do it.” After assessment, patients who were willing and able to participate were formally enrolled in the program.At 4 FQHCs, patients signed a rental agreement for a loaner blood pressure monitor. A fifth FQHC provided reduced-price, Bluetooth-enabled monitors for purchase, so data could be transferred from the monitor directly into the clinic’s health information system. This clinic’s advanced practice registered nurse said, “We talk with the patient about the cost of the monitor being $35 and that it’s theirs. They can use it as much as they want, even that they could have 2 people use it in their household.” Enrollment and setup sites included both the FQHC and patient homes. Clinics encouraged participants to take their blood pressure twice per day, although some patients only measured once per day. For sites with loaned monitors, self-measured BPMPs were conducted for 3 to 6 months; the FQHC that sold monitors had no end date for its program. Staff at all sites trained patients on the use and proper placement of the monitor cuff, proper posture during a blood pressure reading, and how to record the reading. Patients often logged their blood pressure readings by hand, and these data were then collected by staff either in the office or at participants’ homes. Self-measured BPMP staff manually calculated average blood pressure and then entered the data into the EHR. Bluetooth-enabled monitors used at 1 site allowed all blood pressure readings of patients to be digitally stored and electronically collected by the site’s staff. PCPs and self-measured BPMP staff used the data to confirm hypertension or titrate medication as appropriate.All 5 FQHCs included additional blood pressure education or lifestyle change components as part of their self-measured BPMPs. All sites provided diet-related education, including menu planning, food preparation demonstrations, referrals to nutritionists, or dietary information. Goal setting and motivational interviewing were also used by FQHCs to address barriers to lifestyle change and blood pressure monitoring. One site used its behavioral health team to address issues that affect patients’ weight and hypertension:“We will utilize [behavioral health specialists] to meet with patients to discuss goals of wanting to lose some weight and some motivational cognitive behavioral therapy . . . to help with some patients with multiple chronic diseases. These patients sometimes also have some behavioral health issues that we need to address as well.”Ola Hou, tobacco cessation, or referrals to dietitians.Sites also reported adding in physical activity supports, including hula classes, group bicycle rides, and using on-site gyms or wellness programs. Some sites took advantage of existing on-site programs including NDPP classes, Various barriers to implementing self-measured BPMPs and how sites overcame them were discussed . TechnolProgram reach was stymied by a lack of provider referrals because of competing demands. One staff member said, “I hear it from other programs, too, that they don't get a lot of referrals in general. From what I hear, it’s that [PCPs] have so many other things to do in a visit or whatnot, that this may not be their top priority type of thing.” Staff at 2 different sites mentioned that turnover of PCPs and self-measured BPMPs staff affected capacity, with one saying, “Staff turnover in the recent past has led to backlog of referrals . . . the maximum capacity is 2 patients per day.” One site had started their program using an in-house pharmacist; however, the main funding for that position ended, and program operation was moved to other health education staff. Turnover, although challenging, was partially addressed through presentations of self-measured BPMPs to new PCPs.In addition to other systemic barriers, interviewees frequently mentioned the lack of an “out-of-the-box” self-measured BPMP curriculum, which led program staff to combine materials from a variety of sources. Systemic facilitators included funding to initiate self-measured BPMPs, technical assistance and shared capacity-building with other implementing sites, and availability of existing educational materials. Another barrier mentioned was the lack of an agreed-upon hypertension diagnosis standard ,15 amongThis process evaluation identified several lessons learned and potential recommendations for policy makers and funding organizations. Foremost, recruitment, scaling, and sustainability were limited by the lack of material supports  for program implementation, and staff turnover was a major barrier. Funding for other self-measured BPMP positions, like CHWs, is often grant-based, which can lead to burnout and contribute to turnover . Four FQFunding organizations should address the lack of material resources, challenges to remote data collection and monitoring, program reimbursement, and the need for cost-effective health information technology to improve self-measured BPMP uptake and support program sustainability, especially for organizations with populations like those served by FQHCs. In 2018, Hawai‘i FQHCs served 157,097 patients, of whom 22,509 had hypertension; of those, 39% had yet to achieve blood pressure control , demonstFive Hawaiʻi-based FQHCs implemented self-measured BPMPs that strategically addressed patients’ psychosocial and health needs. Systemic barriers hindered the sustainability of self-measured BPMPs at some sites and access to data, which hindered an outcome evaluation of these efforts. Policy makers should consider developing off-the-shelf self-measured BPMPs and provide material support to implementation sites through blood pressure monitor reimbursement and further financial support to maintain clinic staff.


Serum uric acid (sUA) has been associated with cardiovascular risk. Although the recent mechanistic hypothesis poses the basis for the association between sUA and left ventricular mass index (LVMi), the issue remains poorly investigated in a clinical setup. Through a retrospective analysis of the database of the departmental Hypertension Clinic of University Hospital of Salerno Medical School, we identified 177 essential hypertensives , free from uric acid-modulating medications and severe chronic kidney disease, and whose sUA values, anthropometric, clinical, and echocardiographic data were available. In the studied cohort, the average duration of hypertension was 8.4 ± 7.1 years. LVMi associated with classical determinants, such as age, blood pressure, and kidney function, although after multivariate correction, only age remained significant. Also, sUA correlated positively with LVMi, as well as body size, metabolism, and kidney function. In a multivariate analysis, sUA confirmed the independent association with LVMi. Also, levels of sUA >5.6 mg/dl are associated with larger cardiac size. We confirmed our data in a replicate analysis performed in a larger population  from an independent clinic. Our results demonstrate that sUA increases with LVMi, and a cutoff of 5.6 mg/dl predict larger LV sizes. Our data suggest that hyperuricemia might help to stratify the risk of larger cardiac size in hypertensives. Serum uric acid (sUA) is the final product of purine catabolism; its levels depend on the equilibrium of production and elimination, which occurs through the kidney. By routine, the normal distribution of sUA among the general population is considered below 6 mg/dl in women and 7 mg/dl in men . HyperurIn recent years, sUA has become an important parameter to consider when assessing cardiovascular risk. Indeed, sUA is associated with insulin resistance, hypertension, diabetes mellitus, dyslipidemia, obesity, metabolic syndrome, renal dysfunction, and hypothyroidism –5, whichRecently, Kuwabara et al. showed that in the Japanese population, having higher sUA could be a risk for hypertension, dyslipidemia, and chronic kidney disease (CKD) .Moreover, we reported that the optimal cut point for sUA to discriminate cardiovascular disease (CVD) mortality was 5.6 mg/dl  in populOur study aims to investigate the relationship between sUA and cardiac structural and functional variables in a cohort of hypertensive patients.The population enrolled in the departmental Hypertension Clinic of University Hospital of Salerno Medical School is included in a central electronic database , which contains separate electronic sheets for medical history, physical examination, clinical data, laboratory tests, electrocardiogram, and cardiac and vascular ultrasounds.The database was interrogated to extract data of patients according to the following inclusion criteria: patients visited consecutively over a period of 3 months, with at least an average follow-up of 3 years, both males and females, age 18–80, with blood pressure <140/90 mmHg in office, on active antihypertensive treatment. We excluded those patients that were actively treated with diuretics , with sUA lowering agents, pregnant women, patients diagnosed with gout, malignancies, rheumatic disease, in chronic treatment with anti-inflammatory or anti-pain agents, and no use of daily doses of alcohol>3 drinks per day. Patients with chronic kidney disease at stage 4 and higher were also excluded. The diagnosis of hypertension was based according to current guidelines , which has been in use for almost 40 years . Patienta priori approval by the institutions' human research committee (NCT03305276). The validation group data were obtained from the anonymized database of a previously approved, completed trial .Informed consent was obtained from each patient, and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in The visit includes an update of anamnestic data and medical history with particular attention to lifestyle habits and pharmacological treatments, physical examination , and standard electrocardiography.Blood pressure (BP) measurement was obtained with an automated oscillometer , validated according to international standardized protocols, and adequately maintained to verify calibration. Cuff placement was preceded by the selection of the appropriate cuff size for the patient's arm circumference; the lower end of the cuff was 2 to 3 cm above the antecubital fossa. The BP reading was obtained in the supine position (after a resting period of at least 10 min), in sitting and standing positions; the cuff was at the heart level, whatever the position of the patient. At least two BP measurements were recorded in every position (timed 1–2 min apart), and additional measurements were obtained if the first two assessments were largely different. In this study, we considered the average BP in the sitting position according to the current guidelines . In subjVenous blood samples were collected in the morning after an overnight fast as a general rule. Blood chemistry was evaluated according to standardized methods by trained personnel. sUA levels were determined using the uricase-peroxidase system. Triglycerides and total and HDL cholesterol were assayed enzymatically, while LDL cholesterol was calculated with the formula of Friedewald. Serum glucose was measured using the glucose oxidase method. The estimated glomerular filtration rate (eGFR) was calculated by the Modification of Diet in Renal Disease (MDRD) equation.2.7  with M-mode, 2D, pulsed, and color-flow Doppler within 4 months from the first visit. To eliminate the confounding effect of gender on cardiac size, in this study, LVMi was adjusted for height 2 test. Linear univariate regression analyses, with confidence intervals, were tested on sUA and LVMi; multivariable regression analyses were performed on the significant continuous and categorical variables. Statistical analysis was performed using SPSS software for Windows, version 26.0 .The data are expressed as frequencies and percentages for qualitative variables and as mean ± standard deviation (SD) for quantitative ones. Using ANOVA, we analyzed continuous variables; categorical data were compared using the χWe enrolled 300 hypertensives consecutively admitted to our clinic from February to May 2017; we followed up for 12 months to collect all clinical, cardiac US, and serum biochemistry data. After 1 year of follow-up, 31 patients were lost, and 92 were discarded for the incompleteness of the data. The analysis was therefore completed on 177 patients. The clinical, biochemical, and cardiac ultrasound (US) parameters of the study patients are summarized in LVMi was significantly and directly correlated with age, serum glucose, blood pulse pressure, and kidney function . Interesp < 0.009; (95% CI: 0.539–3.659)]. Furthermore, sUA levels displayed a significant correlation with gender, metabolism , and kidney function   .Since previous literature had demonstrated that sUA might impact the outcome “death” on top of other determinants , also inRecently, we have proposed lower limits of sUA (5.6 mg/dl) to identify the increased risk of CV death . To veriTo overcome some of the small sample size limitations of our study, we sought the collaboration of the Hypertension Outpatient Clinic of the Federico II University, which provided data regarding the first access to their database of 1,379 hypertensives selected out from a pool with over 25,000 patients, using the same inclusion criteria. The available clinical characteristics are illustrated in We then performed a correlation analysis between sUA and LVMi in this larger population, confirming the association between the two parameters, with a similar amplitude than that observed in the original smaller population . In the Our results show for the first time in a real-life situation that sUA is in direct correlation with the LVMi, independently from other confounders. Furthermore, the use of the newly proposed cutoff of 5.6 mg/dl can help to predict the hypertensive population with a larger cardiac size. Our results agree with the growing role that this biochemical parameter plays in the definition of the CV risk of events in the hypertensive population.R2, thus indicating that the two phenomena (sUA and LVMi), although associated, have distant mechanisms underlying. Nevertheless, the use of sUA in the management of hypertension might be helpful to identify patients with TOD.Our data have been confirmed in two independent populations admitted at the University of Salerno and the Federico II University Hypertension Clinics. Apart from the confirmation of all the major observations, it is interesting to note that the association between sUA and LVMi comes with very low levels of The precise mechanism underlying the relationship between sUA and LVMi is still undetermined. It is possible to advocate pathophysiological mechanisms linking the two phenotypes. It has been reported that sUA increases tumor necrosis factor-alpha, stimulates mitogen-activated protein kinases, and activates the renin–angiotensin system, all of which are known to promote cardiac hypertrophy , 18. AltThe need for biomarkers for the stratification of CV risk among hypertensives is a sensitive issue. Indeed, in the general definition of hypertension, we include multiple intermediate phenotypes: males and females, easy and difficult to treat, young and old, lean and obese and so on , 25. In The association between sUA and LVMi was previously shown in a different condition. In 540 patients with CKD, sUA directly correlated with LVMi ; similarNakanishi et al. demonstrated that in a sample of the general population without overt cardiac disease, elevated sUA was independently associated with subclinical LV dysfunction, assessed as abnormal LV global longitudinal strain (GLS). Interestingly, the authors do not report the association between sUA and classical US parameters of LV function such as ejection fraction . Our resSome studies have shown that sUA is related to markers of increased vascular damage, such as a low ABI  and highA corollary in our study is the significant correlation of sUA with metabolic parameters such as BMI, weight, HDL, sGlucose, and TG . It is nIndependently from BMI, metabolic parameters correlate with sUA. Hikita et al. investigated the relationship between sUA, body fat distribution, and metabolic syndrome, and showed a significant direct correlation with triglycerides, visceral fat, and the Homa index . AccordiLVMi assessment by echocardiography could be considered a limitation due to lower sensitivity compared to more precise technological assessments. On the other hand, the cardiac US is more accessible for the larger part of hypertensive patients, making our results more relevant for daily practice. We followed up the patients for 12 months to collect all clinical, cardiac US, and serum biochemistry data, and this could be considered a limitation since the data were not collected at the same time; we calculated that from the first visit to the collection of the data elapsed an average time of 52 ±89 days for serum data and of 11 ±65 days to execute the cardiac US. We believe that this time is close enough to consider the collection of data to be contemporary.In summary, our results in a small population and their replication in a larger cohort demonstrate that sUA directly correlates with LVMi and that a cutoff of 5.6 mg/dl can identify patients with larger left ventricular mass. Our data suggest that hyperuricemia is an early marker of increased left ventricular mass that can be used to identify a hypertensive population with cardiac TOD.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Comitato Etico Campania sud. The patients/participants provided their written informed consent to participate in this study.VV, MC, and GI: conceptualization, formal analysis, investigation, resources, writing – original draft, and writing – review & editing. VV, AP, NV, FM, FCi, RG, RF, PM, CM, MM, RI, FR, FCe, MC, and GI: data curation. All authors contributed to the article and approved the submitted version.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.


Heart failure (HF) involves complex remodelling leading to electrical and mechanical dysfunction. We hypothesized that machine learning approaches incorporating data obtained from different investigative modalities including atrial and ventricular measurements from electrocardiography and echocardiography, blood inflammatory marker [neutrophil‐to‐lymphocyte ratio (NLR)], and prognostic nutritional index (PNI) will improve risk stratification for adverse outcomes in HF compared to logistic regression.Consecutive Chinese patients referred to our centre for transthoracic echocardiography and subsequently diagnosed with HF, between 1 January 2010 and 31 December 2016, were included in this study. Two machine learning techniques, multilayer perceptron and multi‐task learning, were compared with logistic regression for their ability to predict incident atrial fibrillation (AF), transient ischaemic attack (TIA)/stroke, and all‐cause mortality. This study included 312 HF patients . There were 76 cases of new‐onset AF, 62 cases of incident TIA/stroke, and 117 deaths during follow‐up. Univariate analysis revealed that age, left atrial reservoir strain (LARS) and contractile strain (LACS) were significant predictors of new‐onset AF. Age and smoking predicted incident stroke. Age, hypertension, type 2 diabetes mellitus, chronic kidney disease, mitral or aortic regurgitation, P‐wave terminal force in V1, the presence of partial inter‐atrial block, left atrial diameter, ejection fraction, global longitudinal strain, serum creatinine and albumin, high NLR, low PNI, and LARS and LACS predicted all‐cause mortality. Machine learning techniques achieved better prediction performance than logistic regression.Multi‐modality assessment is important for risk stratification in HF. A machine learning approach provides additional value for improving outcome prediction. Heart failure (HF) is a growing epidemic and is estimated to affect around 26 million globally.The use of a combination of different risk markers can provide important, incremental pieces of information for prognostication and potentially can better guide treatment strategies in HF patients. These markers include traditional echocardiographic parameters such as left ventricular (LV) ejection fraction (LVEF) and global longitudinal strain (GLS),This study received ethical approval from The Joint Chinese University of Hong Kong—New Territories East Cluster Clinical Research Ethics Committee . It is based on the raw datasets that have already made available by our group in an online repository.3 to peripheral lymphocyte count/mm3. The PNI was calculated by 10 × serum albumin value (g/dL) + 0.005 × peripheral lymphocyte count/mm3.The following clinical details were obtained: age, gender, smoking status, diabetes mellitus, hypercholesterolaemia, coronary artery disease, hypertension, baseline atrial fibrillation (AF), and anti‐hypertensive and anti‐coagulation medications. Complete blood count was performed using automated haematology analysers. Biochemical data such as sodium, potassium, urea, creatinine, and albumin levels were also determined. Neutrophil‐to‐lymphocyte ratio (NLR) was given by the ratio of peripheral neutrophil count/mmP‐wave variables were measured manually from patients who were in sinus rhythm at baseline. Two investigators measured the following parameters from the ECGs: (i) mean PWD was calculated from values obtained from leads V1, II, III, and aVF; (ii) amplitude of the P‐wave was measured from lead V1; (iii) partial or advanced inter‐atrial block (IAB), defined as PWD ≥ 120 ms in the absence or presence of biphasic P‐waves in the inferior leads, respectively; (iv) P‐wave dispersion, defined as the maximum difference in PWD between the leads V1, II, III, and aVF; and (v) P‐wave terminal force in V1 (PTFV1), defined as the area subtended by the terminal negative component of a biphasic P‐wave in lead V1, with the area calculated by multiplication of the duration and depth of the waveform.Comprehensive transthoracic echocardiography was performed using a cardiac ultrasound system with digital storage capacity . Left atrial (LA) diameters, LV diastolic diameters, the thickness of the interventricular septum, and thickness of the LV posterior wall were measured according to the American Society of Echocardiography guidelines. Conventional parasternal short‐axis views at the basal, middle, and apical levels and apical four‐chamber, two‐chamber, and three‐chamber views were obtained. Three consecutive cardiac cycles in sinus rhythm were digitally stored for subsequent analyses. All the images were obtained at a frame rate of 60–90 frames per second.LA area was measured with planimetry for four‐chamber and two‐chamber views by tracing the endocardial border, excluding the confluence of the pulmonary veins and the LA appendage. LA volume was measured at end‐systole, before P‐wave, and end‐diastole. STE enables quantification of LA function with relatively high fidelity and accuracy.P < 0.10 were further included in a multivariate model. Crude and adjusted odds ratios were reported in 95% confidence intervals. To develop a scoring system, the significant variables in the final multivariate logistic regression model were included. Briefly, a point assigned to a variable would be equivalent to the halved value of adjusted odds ratio, rounded up to the nearest integer. The diagnostic performance of risk variables was evaluated by Harrel's C‐statistic and receiver operating characteristic curve using cut‐off values determined by Youden's J statistic. The multi‐task learning model consists of common knowledge sharing layers and task‐specific knowledge sharing layers.Outcome measures include incident AF, transient ischaemic attack (TIA)/stroke, and all‐cause mortality. Descriptive statistics were presented as number (percentage) or median [interquartile range] as appropriate. Kruskal–Wallis test was applied for comparisons of differences between groups. The relationship between clinical and laboratory parameters and study outcomes was explored using univariate logistic regression. Variables with P‐value < 0.05 was considered statistically significant.Statistical analysis was performed using Stata (Version 13.0). Comparisons between groups were made using Fisher's exact test or Kruskal–Wallis ANOVA for categorical and continuous variables, respectively. A two‐sided n = 312), the median age was 64 [55–73] years, and 235 (75%) were male. The baseline characteristics, laboratory information, and ECG and echocardiographic measurements are shown in 3, yielding a neutrophil‐to‐lymphocyte ratio (NLR) of 4.41 [2.78–7.82]. Albumin took a median level of 35.1 [30.2–39.0], yielding a PNI [given by 10 × serum albumin value (g/dL) + 0.005 × peripheral lymphocyte count (per mm3)] of 35.0 [30.2–39.0]. A total of 22 and 54 patients received implantable cardioverter‐defibrillators.In our HF cohort . Increased risk of TIA/stroke was associated with age, smoking, type 2 diabetes mellitus, and high N2AC score (P < 0.05). Moreover, all‐cause mortality correlated with age, hypertension, type 2 diabetes mellitus, mitral or aortic regurgitation, LA diameter, LVEF, abnormal P‐wave terminal force in V1, partial IAB, chronic kidney disease, urea, creatinine, albumin, high NLR in Quartile 4, PNI, average ventricular GLS, LA reservoir, conduit, and contractile strain (P < 0.05). The area under the curve values from receiver operating characteristic analysis for incident AF, stroke, and all‐cause mortality are shown in New‐onset AF was associated with age and median LA reservoir and contractile strain  was created, combining NLR at Quartile 4, PNI at Quartiles 1 and 2, age > 62.5 years, and creatinine > 119.5. N2AC scores of 2, 3, and 4 were associated with 3.28 [1.25–8.61], 5.94 [2.20–16.05], and 25.00 [5.48–114.10], respectively, higher odds for all‐cause mortality.Variables that achieved n = 250) while using the remaining 20% (n = 62) samples for testing. To better test the model's out‐of‐sample prediction ability, five‐fold cross‐validation was adopted. The computation results are evaluated with several widely used metrics , as shown in A convolutional network‐based, multi‐task learning method was then used to predict outcomes of incident AF (Task 1), TIA/stroke (Task 2), and all‐cause mortality (Task 3)  samples are difficult to obtain. For instance, we only have 312 patients in our HF dataset. In this case, shallow learning models, let alone deep models, are constrained by limited training samples. To overcome this data insufficiency problem, multi‐task learningIn this study, we had three prediction tasks: incident AF (Task 1), TIA/stroke (Task 2), and all‐cause mortality (Task 3), and the three tasks are related to each other. We used a convolutional network‐based multi‐task learning method, in which we design a common knowledge sharing layer and a task‐specific knowledge sharing layer to jointly capture the important relevant information among the three prediction tasks. The deep multi‐task learning method is not sensitive to data insufficiency and can improve the overall performance of all three prediction tasks. The experimental results of our study demonstrate that the deep multi‐task learning model is an efficient approach to jointly achieve overall performance improvement for the prediction of multiple tasks/outcomes by exploiting complex and informative interactions among dependent variables in HF.The main strength of our study is the relatively large sample size involving >300 patients with comprehensive ECG and echocardiographic measurements supplemented by laboratory data. However, it is limited by the single ethnicity of the study subjects. Future studies are needed to validate our findings and models in external cohorts involving other ethnicities. Moreover, it is well‐recognized that HF with mid‐range EF (HFmEF) may have a different disease course compared to HF with reduced EF patients, and our sample size for the HFmEF group was small. The latter group will need to be examined separately in the future. Finally, the convolutional network‐based multi‐task learning method we use provides highly accurate risk predictions, but it fails to generate the importance ranking of specific parameters among clinical, demographic, ECGs, and so forth for the predictions. Therefore, it is of great interest to develop an interpretable deep multi‐task learning model for risk stratification in HF.Multi‐modality assessment using baseline variables, laboratory, ECG, and echocardiographic indices is important for risk stratification in HF. A machine learning approach provides additional value for improving outcome prediction.None declared.This study was supported by Theme‐based Research Scheme project of the Research Grants Council of Hong Kong to QZ (T32‐102/14‐N).Table S1. Univariate analysis for new onset atrial fibrillation.Table S2. Univariate analysis for transient ischemic attack (TIA)/stroke.Table S3. Univariate analysis for all‐cause mortality.Table S4. Univariate analysis of atrial strain variables for new onset atrial fibrillation.Table S5. Univariate analysis of atrial strain variables for transient ischemic attack (TIA)/stroke.Table S6. Univariate analysis of atrial strain variables for mortality.Table S7. Univariate analysis of ventricular strain variables for new onset atrial fibrillation.Table S8. Univariate analysis of ventricular strain variables for TIA/stroke.Table S9. Univariate analysis of ventricular strain variables for all‐cause mortality.Table S10. Comparative of diagnostic performance between logistic regression, multilayer perceptron and multi‐task learningClick here for additional data file.


Introduction: Esophageal varices bleeding (EVB) in liver cirrhosis is an important cause of mortality and morbidity. We aimed to study the relationship between systolic pulmonary artery pressure (sPAP) and EV grade and EVB.Methods: A total of 229 patients, 183 male and 46 female, who were determined to have EV in the upper gastrointestinal tract endoscopy and who had a transthoracic echocardiogram (TTE) were included in this study.Results: The frequency of pulmonary hypertension (PHT) and EVB was determined to be 16% and 45%, respectively, in our study, and 20% of those who had bleeding had PHT; 70.3% of the cases with PHT were determined to have grade III varices while this rate was lower at 52.9% in cirrhosis without PHT. A significant correlation was determined between Model for End-Stage Liver Disease (MELD) score, Child-Turcotte-Pugh score, platelet, albumin, and sPAP in those without a history of bleeding (p<0.05).Conclusion: An increase in the rate of grade III varices has been noted along with the prevalence of PHT in patients with portal hypertension. It has been determined that the increase in PAP is associated with an increase in the MELD score, which is closely associated with mortality and morbidity. Therefore, this positive relationship between the MELD score and PHT may lead to an increase in the frequency of advanced-stage EV. Liver cirrhosis (LC) is caused by long-term or repeated damages to liver tissues due to one or more reasons. These repeated damages cause an increase in intrahepatic vascular pressure along with the formation of generalized hepatocyte necrosis, fibrous tissue hyperplasia, and regenerative nodules. Portal hypertension (PH) occurring due to increased intrahepatic vascular resistance in cirrhosis is observed due to the combined effect of the damage occurring in hepatic sinusoids in addition to the disruption of the balance between vasodilator and vasoconstrictor substances .Numerous spontaneous portosystemic shunts and esophageal varices (EV) may occur as a complication of long-term PH in patients with LC . The preHeart performance and liver function are closely related. The dysfunction of one organ often leads to functional impairment in the other organ . When coAn important factor causing PHT is chronic and/or acute pulmonary embolism (PE). Since there are studies indicating that the risk of venous thromboembolism (VTE) in patients with cirrhosis is twice as high in non-cirrhotic patients, this should not be ignored . Low levThere are many cardiac pathologies that can lead to liver disease; however, the common physiology for most of them is chronically high central venous pressures. The long-term increase in these pressures may clinically manifest as cardiac cirrhosis . Hyper-dWe tried to evaluate the effects of sPAP, which is an indicator of right heart pressure, on esophageal varices bleeding (EVB).PatientsThis study was carried out between 2016 and 2019 by scanning the files of the patients with cirrhosis listed for liver transplantation at the liver transplantation center gastroenterology outpatient clinic, online data of the hospital, and their endoscopy records. It was planned to include the patients who had EV detected in upper gastrointestinal tract endoscopy and who had transthoracic echocardiogram (TTE) in the study. Patients under 18 years of age and those without EV detected in endoscopy were excluded from the study. A total of 296 patient files were scanned retrospectively; 55 patients without echocardiography and 12 patients below the age of 18 were excluded, and 229 patients were included in the study. The ages, genders, cirrhosis etiologies, systolic PAP (sPAP) in TTE, varices grade in endoscopy, EV bleeding histories in the last year, and laboratory values of the patients were recorded. Model for End-Stage Liver Disease (MELD) and Child-Turcotte-Pugh (CP) classification scores were calculated by evaluating the clinical information and laboratory results over recorded patient files.Pulmonary artery pressures and endoscopysPAP values estimated according to the measurements made based on the recommendations of the American Echocardiography Association  and fromStatistical analysis2) test. Spearman's correlation analysis was carried out for the relationship between PAP, laboratory data, MELD score, and CP score. A p-value of <0.05 was considered to be statistically significant.The data were analyzed using Statistical Package for the Social Sciences, version 21 . The conformance of continuous variables to normal distribution was evaluated using visual (histogram and probability plots) and analytical (Kolmogorov-Smirnov/Shapiro-Wilk tests) methods. In the part of the descriptive statistics, categorical variables are provided in numbers and percentages, data conforming to normal distribution are provided with arithmetic mean and standard deviations, and data not conforming to normal distribution are provided with median (minimum-maximum) values. The continuous variables between the independent groups were analyzed by independent Student's t-test and Mann-Whitney U test, whichever is appropriate. The comparison analysis for categorical variables between independent groups was carried out using the Pearson chi-square  male and 46 (20.1%) female, were included in the study. The mean age of the whole group was 53.58±8.93 years. There was no statistically significant difference in the mean age between male  and female  (p=0.690). The prevalence of EVB and PHT in our study group was 45% and 16%, respectively. EVB was observed in 20% of cases with PHT. Clinico-demographic, laboratory and echocardiographic findings according to the presence of PHT are summarized in Table The correlation analysis carried out between sPAP and laboratory parameters, CP and MELD scores according to bleeding status is summarized in Table The liver usually has a fragile balance with low-pressure blood flow and is easily affected by pressure changes. Any factor affecting drainage from the liver to the caval system will contribute to the disruption of this balance. As a result, the pressure increase in the caval vein, and the hepatic vein as a reflection of this may cause tissue damage. In an animal model where the caval vein was clamped, obstruction was shown to trigger liver fibrosis without a clear inflammatory process  . SimilaPortal hypertension and related complications may progress with the contribution of a hyper-dynamic syndrome characterized by an increase in right cardiac pressures in LC . The anaWe observed in our study that the prevalence of PHT was 16% and that the prevalence was high in patients with cirrhosis and PH findings in line with the literature . In our The MELD score was higher in the PHT group compared to those without PHT (p=0.007). This situation can be interpreted as an indicator of negative effects of cardiac functions on the liver and worsening the disease prognosis.The limiting factor of the study is that the pulmonary artery is not measured by right heart catheterization, which is the gold standard method.The prevalence of PHT has increased in patients with PH. Although no significant relationship was found with EV bleeding, it should be noted that the increase in the MELD score, which is an indicator of mortality and morbidity, may be associated with PHT and thus, the patients should be closely monitored for treatment at the appropriate time. Prospective studies using the right heart catheterization are needed to clarify the relationship between PHT and esophageal varice bleeding.