Several studies showed that blood pressure and lung function are associated. Additionally, a potential effect of antihypertensive medication, especially beta-blockers, on lung function has been discussed. However, side effects of beta-blockers have been investigated mainly in patients with already reduced lung function. Thus, aim of this analysis is to determine whether hypertension and antihypertensive medication have an adverse effect on lung function in a general adult population.Within the population-based KORA F4 study 1319 adults aged 40-65 years performed lung function tests and blood pressure measurements. Additionally, information on anthropometric measurements, medical history and use of antihypertensive medication was available. Multivariable regression models were applied to study the association between blood pressure, antihypertensive medication and lung function.2: 0.65) and forced vital capacity values . Furthermore, a detailed analysis of antihypertensive medication pointed out that only the use of beta-blockers was associated with reduced lung function, whereas other antihypertensive medication had no effect on lung function. The adverse effect of beta-blockers was significant for forced vital capacity , while the association with forced expiratory volume in one second showed a trend toward significance . In the same model high blood pressure was associated with reduced forced vital capacity (p = 0.01) and forced expiratory volume in one second (p = 0.03) values, too.High blood pressure as well as antihypertensive medication were associated with lower forced expiratory volume in one second (p = 0.02 respectively p = 0.05; ROur analysis indicates that both high blood pressure and the use of beta-blockers, but not the use of other antihypertensive medication, are associated with reduced lung function in a general adult population. Hypertension is an increasingly important public health challenge worldwide and it is one of the major causes for morbidity and mortality . Thus, t1), and hypertension [Moreover, hypertension has been linked to multiple other diseases including cardiac, cerebrovascular, renal and eye diseases . Beside rtension ,9,6.Furthermore, there are a number of publications discussing the controversial effect of beta-blockers (BBL) on lung function -16. It iThe KORA F4 study is a follow-up of the KORA S4 study, a population-based health survey conducted in the city of Augsburg and two surrounding counties between 1999 and 2001. A total sample of 6640 subjects was drawn from the target population consisting of all German residents of the region aged 25 to 74 years.Of all 4261 participants of the S4 baseline study, 3080 also participated in the 7-year follow-up F4 study. Persons were considered ineligible for F4 if they had died in the meantime , lived outside the study region or were completely lost to follow-up , or had demanded deletion of their address data . Of the remaining 3867 eligible persons, 174 could not be contacted, 218 were unable to come because they were too ill or had no time, and 395 were not willing to participate in this follow-up, giving a response rate of 79.6%. Our study focuses on a subset of 1319 persons aged 40-65 years, because only this age-restricted subset performed both blood pressure measurements and lung function tests. The clinical examinations and interviews were performed at the same day. Overall, the KORA F4 study was conducted between 2006 and 2008.The investigations were carried out in accordance with the Declaration of Helsinki, including written informed consent of all participants. All study methods were approved by the ethics committee of the Bavarian Chamber of Physicians, Munich.1 were taken and percent predicted values were calculated according Quanjer et al. [Lung function examinations, i.e. spirometry, were conducted based on the American Thoracic Society (ATS) criteria  and the r et al. .Blood pressure was measured using a validated automatic device (OMRON HEM 705-CP). Three independent blood pressure measurements were taken with a 3-minute pause after a rest of at least 5 minutes in a sitting position on the right arm. The mean of the last two measurements was used for the current analyses. High blood pressure (HBP) was defined as blood pressure ≥ 140 mm Hg systolic or 90 mm Hg diastolic (with or without antihypertensive medications). Additionally, anthropometric measurements, computer-assisted standardized interviews and self-administered questionnaires on lifestyle and health related factors, medical history and respiratory symptoms were performed. Cardiovascular  and pulmonary diseases  were based on self-reported physician's diagnosis. The smoking status  was assessed by self-report. Education level was defined by the highest graduation . Furthermore, the use of medication within the last seven days before the examination was ascertained by an instrument for database-assisted online collection of medication data (IDOM) . The fol- A. HBP: high blood pressure regardless of its medical treatment- B. HBP or medication: high blood pressure or the use of antihypertensive medication- C. HBP and medication: high blood pressure and the use of antihypertensive medication; treated but uncontrolled hypertension- D. Only HBP: high blood pressure, but no antihypertensive medication; untreated hypertension- E. Only medication for HBP: antihypertensive medication, but no high blood pressure; treated and controlled hypertension- F. Medication for HBP: antihypertensive medication independent of high blood pressureDescriptive analysis for the study population, blood pressure and lung function measures was done using chi-square and Kruskal Wallis tests to determine significance levels. Kruskal-Wallis tests and multivariable linear regression models were applied to study the association between the abovementioned classes of high blood pressure and antihypertensive medication and lung function outcomes. Additionally, high blood pressure and antihypertensive medication were used as individual variables in one regression model. P-values < 0.05 were considered statistically significant for all analyses. All statistical analysis was performed with SAS, version 9.13.Table 1 % predicted  and FVC % predicted  were significant lower  and of FVC % predicted  could be shown for the use of antihypertensive medication irrespective of high blood pressure. Furthermore, an effective blood pressure treatment and an ineffective blood pressure treatment, meaning high blood pressure despite the use of antihypertensive medication, were associated with lower FEV1 %  and FVC % predicted values .In subjects with high blood pressure FEVer Table . A simil1 and FVC % predicted values did not differ between subjects with and without high blood pressure. However, the use of antihypertensive medication irrespective of high blood pressure was associated with a significant reduced FEV1 and FVC % values in women .Similar results for the association between high blood pressure, antihypertensive medication and lung function could be shown in men. In women FEV1 and FVC % predicted values .The descriptive analysis Table  of the a1  and FVC values  after adjusting for sex, age, height, weight, education level, packyears of smoking, pulmonary and cardiac diseases . Furthermore, the adjusted regression models with mutual exclusive categories pointed out that the combination of high blood pressure and the use of antihypertensive medication had the strongest negative effect on lung function (Model 4). Thus, among treated but not controlled hypertensive subjects FEV1 had a lower volume of 160 mL and FVC of 170 mL compared to subjects with no high blood pressure and no antihypertensive medication (each p = 0.02 and p = 0.02). A detailed analysis of antihypertensive medication showed that the use of BBL was associated with reduced FEV1 and FVC values, whereas other antihypertensive medication had no effect on lung function (Model 5). However, it has to be considered that the effect of BBL was significant for FVC (p = 0.03) while for FEV1 the association was of borderline significance (p = 0.07). A further model including BBL, other antihypertensive medication and high blood pressure showed similar negative effects of BBL on FVC (p = 0.04) and FEV1 (p = 0.07). Besides, high blood pressure was associated with reduced FVC (p = 0.01) and FEV1 (p = 0.03) values, too (Model 5a). An additional sensitivity analysis of the models 5 and 6, where we excluded subjects with obstructive lung diseases, showed that the effect of BBL still exists. Although the significance level declined the magnitude effect estimates did not change. For all multivariable regression models the adjusted r-squared value was 0.65 for FEV1 and 0.73 for FVC.The application of multivariable regression models revealed that high blood pressure as well as antihypertensive medication are associated with lower FEV1 for all models. The multivariable regression models for FVC, however, showed a significant interaction between gender and high blood pressure, indicating that high blood pressure has a lower effect on lung function in women compared to men. Further analyses regarding the ratio FEV1/FVC showed no significant association between high blood pressure or antihypertensive medication and the ratio FEV1/FVC.A further sensitivity analysis regarding the possible effect modification by gender showed no gender difference for FEVThe present analysis of a population-based study demonstrates that both high blood pressure and the use of BBL are associated with reduced lung function, whereas other antihypertensive medications have no effect on lung function.1 and FVC between hypertensive subjects that used or did not use beta blocking antihypertensives [Our findings are in line with previous observations that blood pressure and lung function are inversely associated ,6,9. But1 and FVC. Interestingly, the FEV1/FVC ratio was found not to be affected by BBL medication suggesting that the expired volume, FVC, is lowered in proportion. Indeed, the drug-specific effect of BBL medication is more pronounced on FVC than on FEV1. This supports the hypothesis that not airway obstruction, but rather restriction is the more likely mechanism involved in the effect of BBL medication on lung function. For instance, possible effects on the respiratory muscle strength have to be considered. It is well established that beta agonists improve the performance of skeletal muscles [1 and FVC. However, further studies directly addressing this issue are required.Thus, our study might substantially add to the question, whether antihypertensive BBL medication independent of high blood pressure has adverse effects on lung function. Beta-adrenergic receptors (β-ARs) play a key role in the regulation of bronchomotor tone . In the  muscles  and also muscles ,24. The  muscles . Thus, w1 had a lower volume of 160 mL compared to subjects with no high blood pressure and no antihypertensive medication. This finding might be of importance on the population level. One possible explanation for this significant lung function reduction might be an additive effect of both treatment and persistent high blood pressure. However, the cross-sectional study design makes it difficult to disentangle the effects of high blood pressure and antihypertensive medication. Thus, it allows only statements about a single point in time and does not allow evaluating the effect of long-standing high blood pressure. Another explanation for this lung function decrement could be that those with persistent hypertension despite medical treatment have a higher underlying blood pressure compared to effectively treated subject. Moreover, the effects of high blood pressure and antihypertensive medication are highly correlated. A detailed analysis of antihypertensive medication indicates that BBL medication and not any other antihypertensive medication is associated with a reduced lung function. This negative effect of BBL medication still remains, when BBL, other antihypertensive medication and high blood pressure are analysed in the same model. Besides, BBL are the most common prescribed antihypertensive medication and it has to be considered that BBL medication might be prescribed for other indications than hypertension, as for example, coronary heart diseases or heart failure, too. This again suggests that the effect of antihypertensive BBL medication on lung function is mainly ascribed to the medicament and not to the indication. Furthermore, a variety of confounders might affect the association between high blood pressure, antihypertensive medication and lung function. Cigarette smoking is a common risk factor for both impaired lung function and high blood pressure and BMI might have an effect on lung function. However, adjustment for these possible confounders did not influence our results. Moreover, we could show that the association was not affected by the concomitance of pulmonary diseases and that the negative effect of BBL medication on lung function is not modified by obstructive lung diseases. This supports our interpretation that BBL have an effect on lung function in the general population. Besides, our results suggest that there may be an effect modification by gender. We could show that in women the percent predicted lung function values did not differ between subjects with and without high blood pressure. Furthermore, the multivariable regression analysis revealed a significant interaction between gender and high blood pressure. This might possibly indicate that high blood pressure has minor effect on lung function in women compared to men.When reviewing our results, it becomes apparent that from a statistical point of view both high blood pressure and antihypertensive BBL medication have an effect on lung function measurements. But the observed lung function differences between exposed und non-exposed subjects are relatively small, meaning that they have no direct clinical consequence in healthy individuals. However, we could show that among treated but not controlled hypertensive subjects FEVThe large sample size and the population-based setting are a major strength of this study. Furthermore, it is one of few investigations differentiating between the effect of blood pressure and antihypertensive drug treatment on lung function. Nevertheless, this study has some possible limitation. Methodological bias might lead to insufficient lung function measurements. Thus in patients with high blood pressure lung function tests might be stopped earlier, because the respiratory effort might cause an increase in blood pressure. However, we consider this possible bias unlikely to affect our findings. Besides, selection bias might limit the representative status of the population sample included in our analysis. We had to restrict our analysis to subjects aged 40-65 years, because only this age-restricted subset performed lung function tests. However, as this was a random sample, we consider that our population sample is highly representative for this age group of the Augsburg population. Moreover, the cross-sectional study design makes it difficult to make a clear statement about the temporal sequence and causality between high blood pressure, its treatment and lung function. Several prospective studies indicated that high blood pressure is a risk factor for reduced lung function as well as impaired lung function increases the risk for the development of high blood pressure -9,26. BeOur findings are in line with previous observations showing an inverse association between blood pressure and lung function. Furthermore, our analysis indicates that BBL medication and not any other antihypertensive treatment is associated with reduced lung function in a general adult population. Thus, our findings may serve as a basis for experimental testing, as for example by adding measurement of respiratory functions to outcomes of 'hypertensive' trials.The authors declare that they have no competing interests.ES was responsible for the data analysis, interpretation of data and manuscript preparation. JH and ES developed the statistical analysis plan. SK, HS, SG, CM, MH, AP, H-EW, JB, RMH and JH assisted in the interpretation and critical revision of the results. SK, HS, CM, MH, H-EW and AP were responsible for the data. All authors read and approved the final manuscript.


Mild (140 to 159/90 to 99 mmHg) or moderate (160 to 179/100 to 109 mmHg) chronic arterial hypertension does not appear to cause headache. Whether moderate hypertension predisposes patients to headache at all remains controversial, but there is little evidence that it does. Ambulatory blood pressure monitoring in patients with mild and moderate hypertension has shown no convincing relationship between blood pressure fluctuations over a 24-hour period and presence or absence of headache. However, headaches are associated to various disorders that lead to abrupt, severe, and paroxysmal elevations in blood pressure. In this paper, the secondary headaches attributed to acute crises of hypertension and the criteria for diagnosing each of them have been reviewed. These are headaches attributed to pheochromocytoma, hypertensive crisis without encephalopathy, hypertensive encephalopathy, pre-eclampsia, eclampsia, and acute pressure response to exogenous agents. Commonly, an abrupt elevation of arterial blood pressure is responsible for headache rather than the absolute value. HTN attributed headaches are discussed under 5 major categories and for each one definite criteria have been validated [International Headache Classification (IHCD-2)]We will explain each of the items in more detail in this essay.2 It is known as “The tumor of tens”; 10% are extra-adrenal, 10% are bilateral, 10% are malignant, 10% are found in asymptomatic patients, and 10% are hereditary.3 Some of these percentages have changed according to more recent studies.Pheochromocytoma is a catecholamine-producing tumor originated from chromaffin cells that are located in the adrenal medulla and sometimes the extra-adrenal tissues.4 Other characteristic symptoms include visual disturbances, abdominal and chest pain, anxiety, nausea, and vomiting. The evaluation may reveal bilateral papilledema, orthostatic hypotension, and transient EKG changes. Patients usually have a persistent hypertension; although, detection of normal or low blood pressure in pheochromocytoma is not particularly rare.5 For example, patients who have a genetic predisposition to pheochromocytoma tend to be normotensive. Moreover, the tumor is probably smaller in size in this group of patients. These include about 24% of all the patients (contrary to the previously mentioned 10%).6The incidence of pheochromocytoma is 0.5% in patients with hypertensive symptoms. The traditional triad of the disease are episodic headache, sweating, and palpitations.2The most well-known familial syndromes associated with pheochromocytoma are Von Hipple-Lindau (VHL), multiple endocrine neoplasia type 2 (MEN2), and Neurofibromatosis type 1(NF1); all of which have an autosomal dominant mode of inheritance.7 The alternative is to measure plasma metanephrines that is extremely sensitive, and is suggested by some authorities as screening test. It has a sensitivity of about 99%, but the specificity is lower (85%–89%).8 In fact, the detection of excessive catecholamines or their metabolites in the urine or serum is the basis of diagnosis. Imaging studies should be used to localize the tumor.9 CT and MRI are useful in localizing the majority of tumors, except the smaller ones that are usually found in the hereditary form of disease.10 MIBG and PET scan are complementary imaging tools. These techniques are sensitive in bilateral tumors or in situations when the patient is suspicious of malignancy. Furthermore, they are useful when the tumor is greatly suspected in clinical settings, but the inspections have been nonconclusive.6If one suspects the disorder in a patient on the basis of clinical presentations, the next diagnostic step is biochemical testing. The classic test is a measurement of urinary catecholamines and their metabolites, which have a sensitivity and specificity of 98%.Medical therapy has a crucial role in symptomatic treatment, but surgery is essential for the cure.11Prevention of intraoperative catastrophic hypertensive crisis and the hypotension immediately after the surgery must be considered.12 In about 70% of patients the duration of headaches is less than1 hour.As mentioned earlier, headache is an important symptom of pheochromocytoma. 51-80% of patients with pheochromocytoma describe headaches which are often paroxysmal. Paroxysmal headaches are severe, may have a persistent or pulsatile quality, and are usually located in the frontal or occipital region. Headache is typically accompanied by perspiration, palpitations, anxiety, and facial pallor, and is known to occur simultaneously with sudden elevation of blood pressure.1Diagnostic criteria for headache in pheochromocytoma are included in 13 In addition, higher levels of blood pressure are observed in emergent condition. It is estimated that one to two percent of the hypertensive patients experience at least one episode of crisis in their life.14 The majority of patients have a history of established primary or secondary HTN.15Hypertensive crisis is an acute and severe elevation in blood pressure often described as SBP > 180 mmHg, or DBP > 120 mmHg. However, according to the International Headache Classification (IHCD-2), the definition is somewhat different . It is discussed in the two subtypes of hypertensive urgency and hypertensive emergency depending on absence or presence of end organ damage, respectively.16 It is more common in males and African Americans. Patients with uncontrolled HTN may be at a higher risk of developing a crisis, although data is inadequate in this regard.17There is a peak of incidence for HTN crisis between the ages of 40 and 50 years.18Some disorders and medical conditions are related to hypertensive crisis; renal disorders , Cushing's disease, poor medication compliance, cocaine and PCP abuse, abrupt withdrawal of some antihypertensive agents such as clonidine, and etcetera.19The precise mechanism of hypertensive crisis is not well understood. It is presumed that a diffuse vascular constriction caused by humoral factors is the trigger for the hypertensive process. The consequence is vascular endothelial injury and activation of coagulation factors leading to fibrinoid necrosis of the arterioles. Renin-angiotensin system and most vasoconstrictors, such as norepinephrine and vasopressin, add to the process and eventually we have rapid blood pressure elevation and end organ ischemic damage.20 Intracranial hemorrhage, acute aortic dissection, acute MI, and acute kidney injury are rare but serious complications of hypertensive crisis.21Headache, epistaxis, faintness, psychomotor agitation, chest pain, dyspnea, neurologic deficits, and less often arrhythmias and paresthesias are the clinical presentations.Hypertensive crisis needs to be promptly treated in order to prevent lethal complications.18Hypertensive urgencies, once no serious end organ damage suspected, may be managed as outpatients with oral antihypertensive agents. However, hypertensive emergencies necessitate admission to the intensive care unit and aggressive therapy. Short-acting titratable intravenous antihypertensives, including labetalol, esmolol, fenoldopam, nicardipine, sodium nitroprusside, and etcetera, are the drugs of choice. Sodium nitroprusside has the risk of toxicity and should be used cautiously.Headache, as a symptom, has a prevalence of about 20% in hypertensive urgency. It has a bilateral throbbing quality. Helpful diagnostic criteria have been validated for the headaches based on the hypertensive crisis without encephalopathy regardless of the etiology.1Diagnostic criteria for headaches in HTN crisis without encephalopathy are listed in 22Accelerated HTN, also named hypertensive encephalopathy, may result in disturbance of consciousness. It is usually related to hypertensive emergency, as already mentioned. In fact the encephalopathy syndrome  is a type of organ damage in the setting of hypertensive emergency.23Clinical presentation of hypertensive encephalopathy is due to the effect of high blood pressure on the blood brain barrier that impairs its integrity and leads to cerebral hyperperfusion and finally brain edema occurs. In a normal situation, the well-known cerebral autoregulatory effect inhibits the blood brain barrier from damage in a certain range of systolic blood pressure increments. Indeed, the autoregulatory mechanism is active as long as the mean arterial pressure (MAP) is kept in a range of 50-150 mmHg. In chronic hypertensive patients, as a consequence of adaptation, this range is shifted to higher levels of MAP.24In extremely rapid accelerations of blood pressure, MAP exceeds the defined level and we have an orthostatic leakage of plasma across the capillaries. The condition is transient and predominant in posterior cerebral regions and is usually called posterior reversible encephalopathy syndrome (PRES).25 It is mandatory to look for serious complications such as cerebral, cardiovascular, ophthalmic, and renal events.The etiology of hypertensive encephalopathy is almost the same as those for hypertensive crisis without encephalopathy but in a more severe manner. Clinical signs and symptoms of hypertensive encephalopathy and probable accompanying signs and symptoms are listed in ACS: Acute Coronary Syndrome, ARF: Acute Renal Failure, BUN: Blood Urea Nitrogen, Cr: Creatinine, ICH: Intracranial Hemorrhage, LVF: Left Ventricular Failure, PE: Pulmonary Edema, SAH: Subarachnoid Hemorrhage1Apparently, headache can be an important guiding symptom of the disorder and, has a vascular origin. Criteria for headache in hypertensive encephalopathy are listed in 26 It is part of a spectrum known as the hypertensive disorders of pregnancy.27 Pre-eclampsia is characterized by hypertension, abnormal peripheral edema, and proteinuria.Pre-eclampsia affects about 5-8% of pregnancies.28The patient may complain of new persistent epigastric pain and vomiting. In examination, brisk tendon reflexes, and swelling of hands, face, or feet can be detected. A rise in serum creatinine, thrombocytopenia, and liver enzymes are the associated lab data abnormalities.29 The incidence of pre-eclampsia is 9% in obese women in comparison with the 2% risk of incidence among the normal population.30A combination of maternal and placental factors contributes to the condition. Lack of previous pregnancy (nulliparity), obesity, a history of pre-eclampsia, and maternal medical comorbidities  have been posed as the etiology. Patient's age is also a determinant factor; pre-eclampsia is more common before 18 and after 40 years of age.31Pre-eclamptic women are subjected to cardiovascular complications. Studies show an approximately 4-fold increase in the risk of subsequent development of hypertension later in life, and a 2-fold increase in the risk of ischemic heart disease, venous thrombosis, and stroke in pre-eclamptic women.28Magnesium sulfate is the drug of choice for women with pre-eclampsia since it halves the risk of eclampsia.32 Pre-eclamptic headaches can be diagnosed using the criteria listed in 1Neurologic signs and symptoms are common presentations of the disorder, including severe persistent headache, visual defects , confusion, depression of consciousness, and finally may lead to seizures or eclampsia. In this regard the manifestations are much the same as hypertensive encephalopathy.26 The underlying pathophysiology, to some extent, seems to be similar to hypertensive encephalopathy, which is cerebral overperfusion due to failure of autoregulatory response.33 In fact, these two circumstances are part of a spectrum known as posterior reversible encephalopathy syndrome (PRES) which has characteristic features. Vasogenic brain edema is the underlying cause of this syndrome and accounts for the loss of consciousness.32Whenever pre-eclampsia is superimposed by seizure or coma, or both, then it is named eclampsia.24 No reliable serum markers have been identified to predict the risk of eclampsia in pregnant women.34Imaging study, especially brain MRI, shows edema in the cortex and subcortical white matter that predominantly involves the occipital lobes.35 Labor inductions are essentially the definite treatment for eclampsia.It is very important to manage pre-eclampsia appropriately, as soon as the diagnosis is established, in order to prevent its progression to eclampsia, because the latter is harmful for both mother and fetus. There is absolute evidence that early administration of magnesium sulfate lessens the occurrence of eclampsia by more than 50% in pre-eclamptic women. Furthermore, it has been proved that magnesium sulfate is a more efficient drug to control eclamptic seizures in comparison with many antiepileptic drugs.1Headache is a common warning symptom of eclampsia that should be inquired in any pregnant woman visited in perinatal care sessions. Criteria for headache in eclampsia are listed in 36 Criteria related to this type of headache are listed in 1In any patient who complains of headache and we detect a high blood pressure, it is essential to review his/her drugs and ask the patient about cocaine abuse. Acute pressure response to an exogenous agent may cause a hypertensive emergency. The most famous of the agents include cocaine, amphetamines, oral contraceptives, and monoamine oxidase inhibitors (MAOI), especially when interacting with tyramine-containing foods. Hypertensive emergency may also occur following the withdrawal of beta-blockers, alpha-stimulants (e.g. clonidine), or alcohol.


Clinicians are encouraged to take an individualized approach when treating hypertension in patients of African ancestry, but little is known about why the individual patient may respond well to calcium blockers and diuretics, but generally has an attenuated response to drugs inhibiting the renin-angiotensin system and to β-adrenergic blockers. Therefore, we systematically reviewed the factors associated with the differential drug response of patients of African ancestry to antihypertensive drug therapy.Using the methodology of the systematic reviews narrative synthesis approach, we sought for published or unpublished studies that could explain the differential clinical efficacy of antihypertensive drugs in patients of African ancestry. PUBMED, EMBASE, LILACS, African Index Medicus and the Food and Drug Administration and European Medicines Agency databases were searched without language restriction from their inception through June 2012.We retrieved 3,763 papers, and included 72 reports that mainly considered the 4 major classes of antihypertensive drugs, calcium blockers, diuretics, drugs that interfere with the renin-angiotensin system and β-adrenergic blockers. Pharmacokinetics, plasma renin and genetic polymorphisms did not well predict the response of patients of African ancestry to antihypertensive drugs. An emerging view that low nitric oxide and high creatine kinase may explain individual responses to antihypertensive drugs unites previous observations, but currently clinical data are very limited.Available data are inconclusive regarding why patients of African ancestry display the typical response to antihypertensive drugs. In lieu of biochemical or pharmacogenomic parameters, self-defined African ancestry seems the best available predictor of individual responses to antihypertensive drugs. There is a great need for individual treatment options in hypertensive patients of African ethno-geographical ancestry -5. CompaAntihypertensive drugs were the first cardiovascular therapy for which there was wide recognition of differences in clinical efficacy related to ethno-geographical ancestry . PatientGreater knowledge about the potential causes for these differences might lead to more individualized treatment regimens, but to our knowledge, no previous study has systematically addressed why patients of African ancestry may have this specific pattern of responses. The aim of this paper is to provide a systematic overview of the factors associated with the differential drug response of patients of African ancestry to antihypertensive drug therapy.We sought to identify all published or unpublished studies that considered potential explanations for the differential clinical efficacy of different classes of antihypertensive drugs, used as single drug or single drug-based treatment in non-pregnant adults of sub-Saharan African descent with uncomplicated hypertension, defined as the absence of reported clinical heart failure, current stroke or end stage renal disease.ADD1), subunits of G-proteins (GNB3 and GNAS1), the β-1-adrenergic receptor (ADRB1), endothelial nitric oxide synthase (NOS3), and components of the renin-angiotensin-aldosterone (RAAS) system, angiotensinogen (AGT), renin (REN), angiotensin converting enzyme (ACE), the angiotensin II receptor type I (AGTR1 or AT1R), and aldosterone synthase (CYP11B2)  an anP = 0.= 0.15);  variatio+ retention does not appear to be secondary to increased production of aldosterone, deoxycorticosterone, cortisol or 18-hydroxycortisol [+Cl−-cotransporter activity in the renal distal convoluted tubule, blocking sodium reabsorption across the luminal membrane. All sodium absorption throughout the kidney is energetically and osmotically driven by the basolateral sodium pump Na+K+ ATPase [+K+ ATPase to rapidly regenerate ATP in situ[Persons of African ancestry are reported to have a greater tendency to retain salt ,11,96. Tcortisol . The mai+ ATPase . ATP genP in situ. CK is tP in situ  G-6A, AT1R  A1166C, ACE Insertion/Deletion; CYP11B2  C-344 T, and REN (renin) A7174G. Only in women of African ancestry, but not in men or patients of European ancestry, blood pressure lowering was greater with an increasing number of AGT–6A alleles ; and of AT1R 1166A alleles  [In a pharmocogenomic approach, the association between variation in five structural genes encoding components of RAAS and the effect of monotherapy with hydrochlorothiazide 25 mg daily for four weeks, was studied in 255 hypertensive men and women of African and 246 European ancestry, including  = 0.04) .GNB3), which potentially leads to enhanced sodium-proton antiport activity was assessed in men and women of African (n = 197) and European ancestry (n = 190) [GNB3 differed significantly between groups, with the T allele significantly more frequent in patients of African than in European ancestry . In patients of European ancestry, and in men, but not in women of African ancestry, the presence of the T allele was associated with a greater reduction in systolic and diastolic blood pressure with treatment, with mean declines of respectively, 10.2 and 5.9 mm Hg in CC; 13.6 and 7.8 mm Hg in TC; and 16.3 and 10.5 mm Hg in TT genotypes, accounting for 3.1% and 4.5%, respectively, of interindividual variation in the systolic and diastolic blood pressure responses to hydrochlorothiazide [The association between the response to hydrochlorothiazide 25 mg daily for four weeks and a polymorphism (C825T) in exon 10 of the gene encoding the b3-subunit of G proteins (n = 190) . Relativthiazide .+Cl−-cotransporter pathway has been previously implicated in thiazide response, as variations in WNK1 were associated with differential BP response to hydrochlorothiazide [STK39, with a replication sample of 201 hydrochlorothiazide-treated hypertensives from the PEAR study. No polymorphism was significantly associated with blood pressure response [The WNK-SPAK-Nathiazide . Thereforesponse .P <0.01), and there was no significant difference in systolic or diastolic blood pressure response between Trp allele carriers and non-carriers  [In the Genetics of Hypertension-Associated Treatment Study (GenHAT), participants of the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) were studied for the association between α-adducin Gly460Trp polymorphism and blood pressure response to chlorthalidone vs other drugs . Carriers of the Trp allele are reported to have a greater occurrence of salt-sensitive hypertension, and blood pressure response to diuretics was pronounced with the Trp allele, compared to the Gly allele in European ancestry populations . HoweverP >0.05) .GRK2 gene (ADRBK1) and GRK5 Gln41Leu, which are reported to mediate down-regulation of β-adrenergic signaling, were studied in 418 patients (167 of African ancestry) from the PEAR study. The genotypes were not associated with the blood pressure response to hydrochlorothiazide [Also, polymorphisms of the thiazide .YEATS4, a gene probably encoding a transcription factor, over LYZ, encoding lysozyme, as positional candidate genes [Finally, using genome wide analysis, good and poor responders to hydrochlorothiazide of African (n = 194) and European ancestry (n = 195) were compared. Variation in one region on chromosome 12q15 emerged to be significantly associated with blood pressure response, but only in subjects of African ancestry . Follow-te genes . The stute genes , but theACE inhibitors are known to induce less blood pressure lowering in patients of African than in European ancestry . In the High salt intake reduces the blood pressure lowering efficacy of ACE inhibition. With a high salt diet (190 mmol sodium/day) and enalapril studied in 391 subjects (96 of African ancestry), systolic blood pressure reduction in mm Hg (SD) was smaller in patients of African, than of European ancestry  vs. enalapril 146.2 (16.4); difference −10.3 for African, and placebo 159.2 (13.4) vs enalapril 144.2 (17.5); difference −15.0 for European ancestry groups).With low salt (88 mmol sodium/day), blood pressure was lower, but the difference persisted  vs enalapril 137.2 (19.2) difference −7.7; European ancestry placebo 145.1 (17.1) vs enalapril 132.4 (16.2), difference −12.7) . Drug efCYP3A4 A392G, CYP3A4 T16090C or CYP3A5 A6986G genotypes and time to reach target mean arterial pressure among men or women randomized to a low or usual mean arterial pressure.In the ramipril arm of the AASK study , there wThe main mode of action of ACE inhibition is well known, the drugs reduce the activity of angiotensin converting enzyme, and eventually, angiotensin, aldosterone and salt retention. In addition, ACE inhibitors promote NO synthesis in the endothelium .A repressed RAAS system occurs with greater frequency in persons of African ancestry ,35. TherRegarding the intracellular effect of ACE inhibitors, the drugs were observed to have an ACE independent effect , and parG6PD is the first and rate-limiting enzyme of the pentose phosphate pathway, thus serving as the principle source of cellular nicotinamide adenine dinucleotide phosphate-oxidase (NADPH), a cofactor for NO synthase. Vascular endothelial cells constitutively express nitric oxide synthase that forms NO in the presence of oxygen from the semi-essential amino acid L-arginine. NO synthase binds NADPH, flavin adenine dinucleotide, flavin mononucleotide, L-arginine, a heme moiety and tetrahydrobiopterin. Tetrahydrobiopterin synthesis itself is also dependent on available NADPH .in vitro[in vitro[in vivo[In line with this, G6PD deficiency, reported in up to 25% of persons of African ancestry , has beein vitro. In addiin vitro,12,72,73[in vitro, with suo[in vivo. HoweverACE gene. The ACE insertion/deletion genotype ACE DD  had a poorer response to lisinopril treatment than to any of the other three drugs in the GenHAT study. However, the effect was small, a difference of 0.85 mm Hg systolic (SE 0.51) and 0.50 mm Hg diastolic (SE 0.28), with “similar” results reported for the subgroup analysis for patients of African ancestry [Pharmacogenomic factors studied include polymorphisms in the lic SE 0., with “sACE, downstream from the ACE insertion/deletion polymorphism: G12269A, C17888T and G20037A. Only participants with a homozygous genotype at G12269A and C17888T, and randomized to the usual mean arterial pressure goal (≤107 mm Hg) reached a blood pressure goal significantly faster than those with a heterozygous genotype  were genotyped at three polymorphisms on P = 0.78; diastolic blood pressure −0.47 (SD 1.74), P = 0.79); while patients with at least one copy of the −217G allele developed respectively a 7.23 (1.55) and 5.38 (1.12) mm Hg decrease (P <0.01). Similarly, in patients with the −20AA genotype no change in blood pressure occurred, whereas in those patients with at least one copy of the −20C allele, systolic blood pressure decreased in response to ACE inhibitor therapy. In line with this, patients with at least one copy of both the −217G and the −20C allele developed substantial decreases in blood pressure  [Finally, in a study including patients of African ancestry (n = 77), functional variants in the promoter region of the angiotensinogen gene (−217G = > A and −20A = > C) were assessed. Patients with the AA genotype of the −217G= > A variant treated with enalapril or lisinopril showed no significant decrease in blood pressure (systolic blood pressure + 0.84 (SD 2.89), P <0.01) .Angiotensin receptor blockers are also less effective in patients of African ancestry as compared to calcium blockers and diuretics . In one The efficacy of systolic blood pressure lowering of β-adrenergic blockade as monotherapy in uncomplicated essential hypertension is not significantly different from placebo in patients of African ancestry, and some trials report significant placebo corrected increase in blood pressure with β-adrenergic blockade in this population group ,92 The mTo our knowledge, there are no environmental factors reported that may help explain the attenuated blood pressure lowering response of patients of African ancestry to β-adrenergic blockade. In the TAIM study, adding sodium restriction (mean 100 mmol/day) to an atenolol regimen  did not enhance the blood pressure lowering effect .P <0.05) [Studies on the differences in the pharmacokinetics of β-adrenergic blockers based on ancestry yielded heterogeneous results. Oral clearance of L-propranolol was reported to be similar , or highP <0.05) , with siP <0.05) ,56. In lP <0.05) . HoweverP <0.05) . On the P <0.05) , while oP <0.05) . Also, mP <0.05) . FinallyP <0.05) ,67.P <0.01 [The attenuated response of persons of African ancestry to β-adrenergic blockers was extensively studied. As renin lowering contributes to the antihypertensive effect of β-adrenergic blockers, these drugs were expected to be less effective in subjects of African ancestry . Indeed,P <0.01 . FinallyP <0.01 .β-blockers are thought to lower blood pressure predominantly through a reduction in cardiac contractility and heart rate. While early studies found a reduced sensitivity to isoprenaline in healthy men of African ancestry , reportsADRB1) genotype Arg 389/Ser 49 in persons of African ancestry, which was associated with greater blood pressure lowering responses to β-adrenergic blockade in other population subgroups [Pharmacogenomic studies focussed on the frequency of occurrence of the responsive β1-receptor (ubgroups .P <0.01) compared with those who carried the variant allele, and Ser49-Arg389/Ser49-Arg389 diplotype demonstrated a decline in blood pressure of 14.7 mm Hg versus 0.5 mm Hg in patients with the Gly49-Arg389/Ser49-Gly389 diplotype, this was independent of ancestry [In one small study, including 40 subjects (10 of African ancestry) patients homozygous for Arg at codon 389 had a nearly three-fold greater reduction in daytime diastolic blood pressure , and found that heart rate reduction was greatest in the Arg389/Arg389 group, intermediate in the heterozygotes, and smallest in the Gly389/Gly389 group; this effect was seen in both ancestry groups. Carriers of the responsive Arg389/Ser49 haplotype, had a 27% greater adjusted reduction in heart rate at maximal exercise . However, differences in sensitivity to the β1-blocker atenolol persisted after accounting for different distributions of functional genetic β1-receptor variants, suggesting that additional factors contribute to the differences found between ancestry groups [In addition, Kurnik y groups .The AASK study yielded conflicting results as time to reach the target mean arterial pressure of 107 mm Hg with metoprolol (329 participants randomized) was not significantly different for Ser49 or Gly49 variants. In contrast with studies in other population subgroups, the “hazard” ratio of reaching goal blood pressure was lower, 0.68 (95% CI 0.50 to 0.93) in individuals with at least one ‘responsive’ Arg389 allele compared to individuals with Gly389/Gly389 .GRK5) codes for a serine/threonine kinase that phosphorylates and desensitizes G-protein-coupled receptors. However, in a study of 154 healthy subjects (69 of African ancestry), GRK5 Gln41Leu polymorphism, present in approximately 40% of the persons of African and 2% of individuals European of ancestry, did not affect the response to atenolol [GRK2 gene (ADRBK1) and GRK5 Gln41Leu polymorphisms, studied in 418 patients (167 of African ancestry) from the PEAR study did not affect the blood pressure response to atenolol [GRK4, were studied in the AASK Study [P <0.01) with Ala142Val. There was no association between GRK4 polymorphisms and blood pressure response to metoprolol in women. Thus, despite extensive research, there is no clear pharmacogenomic evidence why patients of African ancestry may have a differential response to β-adrenergic blockade.Finally, a series of pharmacogenomics studies did not further explain why patients of African ancestry respond less to β-adrenergic blockade. The G-protein-coupled receptor kinase 5  and European ancestry (n = 6) in trimazosin pharmacokinetics, with the latter having a larger volume of distribution, and a longer terminal elimination half-life for the metabolite, 1-hydroxy-trimazosin . FurtherWhy do hypertensive patients of African ancestry generally respond better to diuretics and calcium blockers and less well to ACE and β-adrenergic blockade? Many clinicians use the self-defined ancestry of a patient as a clinical guide to select antihypertensive drugs , but conTo our knowledge, this is the first systematic review on environmental, pharmacokinetic and pharmacodynamic factors that may contribute to the differential clinical response to different types of drugs observed in patients of African ancestry. In this paper, we also addressed genetic variation thought to affect pharmacokinetic and pharmacodynamic mechanisms, of which phase 1 and phase 2 drug metabolism and receptor function have been most extensively studied.However, the magnitude of the effects of variation in single candidate genes on antihypertensive drug responses appears to be very modest, accounting for only a small percentage of total variation in response when reported (<5%). Also, we found considerable heterogeneity in the direction of the effect across sex and ancestry groups. Studies of polymorphisms may reflect inheritance of a locus in linkage disequilibrium with the gene variation. Because linkage disequilibrium is affected by the population’s history, true associations due to linkage disequilibrium may yield conflicting results in two separate populations . No uniq+K+ ATPase and myosin ATPase, to rapidly transfer a phosphoryl group from creatine phosphate to adenosine diphosphate (ADP) in situ, and generate ATP near these ATPases, thereby facilitating ion transport and muscle contractility [Differences in pharmacodynamics were most consistent, mainly related to the pathophysiology and clinical characteristic of hypertension in patients of African ancestry. In this regard, new views have developed that expand the classical pathophysiology of patients of African ancestry to have low renin hypertension ,8. Low ractility ,12,88-90actility . In lineactility ,12,99, aactility . Patientactility , high CKactility ,12,72,73actility , with reactility . HoweverThe main strength of this study is that this is the first systemic review, designed to assess potential causes for the different responses of patients of African ancestry to antihypertensive drugs, including all published papers without language restriction, and considering salt intake, recent development in pathophysiology and pharmacogenomics, as well as resulting differences in pharmacokinetics and pharmacodynamics. Our systematic approach reduces over-interpretation of study data, and increases the transparency and reproducibility of the synthesis .Using this rigid methodology, the data on potential predictors of blood pressure response in patients of African ancestry are far less conclusive than in previously published, non-systematic overviews ,8,98, wiPatients of African ancestry tend to suffer from more severe hypertension, characterized by enhanced vascular contractility and salt retaining capacity, therapy resistance, and higher morbidity and mortality of the condition and its complications. Because of the need for individual treatment options, as well as the increasing objections to the use of ancestry as a surrogate marker for therapeutic responses, we systematically gathered evidence on biomarkers that may predict the response of individual persons of African ancestry to different types of antihypertensive drugs. However, pharmacogenomics yield heterogeneous, insufficient evidence, and the low renin levels found with greater frequency in patients of African ancestry do not, or do not adequately, predict responses to antihypertensive drugs. Finally, there are no convincing clinical data yet of the emerging paradigm that low NO bioavailability and associated high cellular ATP buffer capacity predict the response to specific antihypertensive drugs. Currently, self-identified ethno-geographic ancestry remains the best available predictor of blood pressure lowering responses to antihypertensive drugs.-ngiotensin-aldosterone system; REN: Renin gene; SER: Sarcoendoplasmic reticulum; TAIM: The trial of antihypertensive interventions and management.AASK: The African-American study of kidney disease and hypertension; ACE or gene ACE: Angiotensin converting enzyme; ACE-i: ACE inhibitor; ADD1: Alpha-adducin gene; ADP: adenosine diphosphate; ADRB1: β-1-adrenergic receptor gene; AGT: Angiotensinogen gene; AGTR1 or AT1R: Angiotensin II receptor type I gene; AIM: African index medicus; ALLHAT: The antihypertensive and lipid-lowering treatment to prevent heart attack trial; BP: Blood pressure; Ca-blockers or CaB: Calcium channel blocker; cAMP: Adenosine cyclic 3′,5′-(monophosphate); cGMP: Guanosine cyclic 3′,5′-(monophosphate); CK: Creatine kinase; Creatine ~ P: Creatine phosphate; CYP11B2: Aldosterone synthase gene; EMA: European Medicines Agency; FDA: The Food and Drug Administration; GenHAT: The genetics of hypertension-associated treatment study; GNB3 and GNAS1: G-protein subunits genes; HCT: Hydrochlorothiazide; INVEST-GENES: The International Verapamil/trandolapril study (INVEST) genetic substudy; LC: Light chain; LILACS: Literatura Latino-Americana y del Caribe en Ciencias de la Salud; MAP: Mean arterial blood pressure; MLCP: Myosin light chain phosphatase; NADPH: Nicotinamide adenine dinucleotide phosphate-oxidase; NO: Nitric oxide; NOS3: Endothelial nitric oxide synthase gene; PEAR: The pharmacogenomic evaluation of antihypertensive responses; RAAS: ReninYKS declare to have no competing interests. LMB is an inventor on NL patent WO/2012/138226 (filed).Both authors have made substantial contributions to conception and design. LMB performed the search. Both authors contributed to extraction, analysis and interpretation of the data, and to drafting the manuscript. The authors read and approved the final manuscript and have given final approval of the version to be published.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/11/141/prepub


Previous studies have shown that chronic headache  is characterized by diffuse somatic hyperalgesia, while arterial hypertension (HY) produces somatic hypoalgesia which is only partly attenuated by antihypertensive treatment. The aim of the study was to assess if comorbidity between CH and HY results into an attenuation of the hyperalgesia due to headache.Forty-eight patients of both sexes [28-56 years] with moderate essential hypertension plus chronic headache (HY+CH) were examined. Twenty-two received no treatment for hypertension, the remaining 26 were under therapy, with good control of pressure values. All underwent measurement of a) blood pressure at rest; b) pressure and electrical pain thresholds in the trapezius, deltoid and quadriceps muscle of one side. The results in this group were compared with those of 40 healthy control subjects (C), 52 patients with chronic headache without hypertension (CH) and 190 patients with hypertension without headache (82 without and 108 with treatment)(HY).Immediately before threshold evaluation, untreated hypertensive patients had higher than normal blood pressure levels, while hypertensive patients under treatment, headache patients without hypertension and control subjects had normal blood pressure values. Pain thresholds at all sites in HY+CH were significantly lower than normal and HY in both treated and untreated patients (p<0.001). They were not significantly different from thresholds recorded in CH.Comorbidity between chronic headache and arterial hypertension (with or without antihypertensive treatment) does not involve any attenutation of the typical diffuse hyperalgesia that characterizes chronic headache. These results suggest that the sensitization process behind diffuse hyperalgesia in chronic pain forms such as chronic headache prevails on the hypoalgesia-determining mechanisms of hypertension in comorbid patients.


Hypertension is a risk factor for cardiovascular disease, and the prevalence of hypertension tends to increase with age. Current treatments for hypertension have side effects and poor adherence. Qigong has been studied as an alternative therapy for hypertension; however, the types of qigong used in those studies were diverse, and there have not been many well-designed randomized controlled trials.Our objectives are the following: 1) To evaluate the effects of qigong on blood pressure, health status and hormone levels for pre- or mild hypertension. 2) To test the methodological appropriateness of this clinical trial and calculate a sample size for future randomized trials.Forty subjects with pre- or mild hypertension will be randomized to either the qigong exercise group or the non-treated group. Participants in the qigong group will conduct qigong exercises 5 times per week for 8 weeks, and participants in the non-treated group will maintain their current lifestyle, including diet and exercise. The use of antihypertensive medication is not permitted. The primary endpoint is a change in patient blood pressure. Secondary endpoints are patient health status (as measured by the SF-36 and the MYMOP2 questionnaires) and changes in hormone levels, including norepinephrine, epinephrine, and cortisol.This study will be the first randomized trial to investigate the effectiveness of qigong exercises for the treatment of pre- and mild hypertension. The results of this study will help to establish the optimal approach for the care of adults with pre- or mild hypertension.Clinical Research Information Service KCT0000140 Hypertension is a risk factor for future cardiovascular events, including heart attack, heart failure, and stroke, which are the most frequent causes of death in developed countries ,2. HyperCurrent interventions for hypertension include sodium restriction, pharmacological management, and lifestyle modifications, such as stress management and exercise. However, in clinical practice, hypertension can be difficult to control, due to poor adherence to prescribed interventions . LifestyQigong is a common healing technique in Oriental medicine and has been used clinically for preventing and curing disease, as well as for improving and maintaining overall health . It has Qigong has been found to have effects on various conditions, such as cancer -12, painHowever, well-designed rigorous randomized controlled trials (RCTs) related to the effects of qigong on BP control are still scarce . AlthougThe aims of this pilot study are the following: (1) to evaluate the effects of internal qigong on blood pressure, health status and hormone levels in patients with pre- or mild hypertension and (2) to test the methods and calculate a sample size for future randomized trials to investigate further the clinical value of qigong in controlling hypertension.The study is a 2-parallel group, randomized controlled trial to compare qigong with no treatment for pre- and mild hypertension on the following outcomes: blood pressure, Health Related Quality of Life (HRQOL), clinical symptoms and hormone levels. The study design is depicted in Figure The protocol has been approved by the institutional review boards of Dongeui University, where the study will take place. This study has been registered with the 'Clinical Research Information Service', Republic of Korea, which is a registry in the WHO Registry Network .This study will be monitored by an independent data and safety monitoring board. Advertisements for voluntary subjects will be printed in local newspapers and posted on notice boards in the local community. All of the participants will provide written informed consent.The inclusion criteria are as follows: (1) patient age between 19 and 65 years, (2) systolic blood pressure between 120 and 159 mm Hg and/or diastolic blood pressure (DBP) between 80 and 99 mm Hg as measured in a sitting position, and (3) the absence of objective signs of hypertension end-stage disease.The exclusion criteria are as follows: 1) serious symptomatic cardiac disease, including previous myocardial infarction, angina or heart failure; (2) previous transient ischemic attacks or stroke; (3) secondary hypertension; (4) taking medications that could affect hypertension, such as stimulants, central nervous system depressants; (5) necessity of antihypertensive medications; (6) concomitant illness that precludes participation, including diabetes, cancer, infectious disease, renal failure; (7) pregnancy or the possibility of pregnancy; (8) moderate to high risk of cardiac complications during exercise; or (9) inability to comprehend and complete the study assessments or comply with the study instructions  will initially screen by telephone each potential participant against the inclusion and exclusion criteria. Willing potential participants will be given an appointment at the center for the qigong trial. A screening log will be maintained to record the inclusion/exclusion criteria for all those participants. The CRC will briefly explain the purpose of the study and ask if they have an interest in participating. The CRC will also record basic demographic and medical information.There are no previous clinical trials to evaluate the effect of qigong on pre- or mild hypertension. Therefore, this study is designed as a pilot study to calculate the appropriate sample size for future randomized clinical trials. Each group will include 20 participants, which is the minimum sample size for evaluating the effect of qigong ,18.The subjects admitted to the trial will be randomized to either the qigong group or the non-treated group. Participants will be randomized before the first treatment by an online centralized randomization service. Randomization will be stratified by age and sex.Allocation concealment will be ensured, as the service will not release the randomization code until the patients are recruited into the trial after all baseline measurements are completed.Each patient's medical history, including current medication, surgical history, and the presence of other diseases, will be recorded at baseline. Lifestyle factors, including diet, exercise, smoking, and drinking alcohol, will also be documented. To investigate other risk factors for hypertension, height, weight, waist and hip circumference, and other demographic information will also be measured. Body-fat percentage will be estimated by measuring bioelectrical impedance. A questionnaire for syndrome differentiation will be used based on general condition, sweating, pain, sleeping, breathing, skin and pulse.Outcome assessors will be blind to group allocation and will not be involved in providing intervention. However, it will be difficult to blind the participants because the control group will not receive any intervention.Although there have been several qigong trials for hypertension, the type of qigong used in those trials was diverse, and there has been no standardized qigong exercises for the treatment of hypertension. We have developed a qigong protocol for the treatment of hypertension based on discussions with three qigong professionals.Qigong will be taught by an instructor with expertise in qigong. The participants will visit the clinic and take 3 qigong classes per week for 8 weeks. Each qigong class lasts 30 minutes, including a warm-up (5 min) and a cool-down (5 min) portion. In addition, the subjects will be asked to practice qigong at home for 30 min more than 2 times a week for the duration of the study. The purpose of qigong exercise is to improve kidney and liver function, to improve blood circulation and to lower blood pressure through calming .Subjects will be asked to complete two questionnaires, specifically, the MOS Short Form 36-item (SF-36) (Korean version) and the Measure Yourself Medical Outcome Profile (MYMOP2). These surveys were selected based on the aims of the trial and on their clinical relevance and feasibility. The SF-36 is a widely used, reliable, valid and responsive measure of outcome health survey. The SF-36 consists of eight scales: physical function, role-physical, bodily pain, general health, mental health, role-emotional, social function, and vitality.The MYMOP is a patient-generated outcome questionnaire, which is problem-specific but includes general well-being. MYMOP aims to measure the outcomes that the patient considers to be most important. MYMOP is applicable to all patients who present with symptoms; these symptoms can be physical, emotional or social .Heart rate will be assessed on every visit, and questionnaires will be administered at weeks 0, 4 and 8. Changes in norepinephrine, cortisol, renin, angiotensin, total cholesterol, and triglycerides will be examined through blood tests at weeks 0 and 8. Blood samples will be taken in the morning after an overnight fast to achieve standard conditions with respect to dietary intake.Four weeks after completion of the 8 weeks of qigong exercise, blood pressure, heart rate, and the SF-36 and MYMOP2 questionnaires will be evaluated. The follow-up assessment is designed to evaluate the long-term effect of qigong exercise.Collected data will be recorded on standardized forms. Descriptive statistics will be calculated for dependent and independent variables. This analysis will include summary statistics of demographic information and outcome measures.The primary analysis of the data will be undertaken using the principle of intent-to-treat (ITT). Our ITT analysis will include all participants, including those who are not fully compliant and those missing outcome data. We will evaluate the effectiveness of qigong exercise and no treatment on blood pressure at 8 weeks using an analysis of covariance (ANCOVA).Demographic and clinical characteristics of subjects in the qigong and the non-treated group will be compared upon admission using a 2-sample t-test (continuous data) and chi-square analysis . Nonparametric methods will be used when assumptions of normality are violated. To control for baseline differences between groups, variables that are significantly different at baseline will serve as covariates in the analyses. Data will be analyzed on an intention-to-treat basis. Software will include the Access and SAS version 9.1 programs. The alpha level will be set at < 0.05.Adverse events will be reported to the data and safety monitoring board. Adverse events will be recorded when participants present with complaints at any time and will be based on the questioning of participants. Serious adverse events will be recorded as required by the International Conference on Harmonization Guideline E2A. We will submit the results of the trial for publication in an appropriate journal irrespective of outcome. We will report the trial in accordance with the CONSORT statements.The primary end point for this study is the change in patient blood pressure from baseline to 8 weeks post-therapy. Eight-week changes in hormone levels and health status, as measured by SF-36 and MYMOP2, are secondary end points. The primary comparison is between participants randomly assigned to qigong exercises versus no intervention. Subgroup analyses for age, gender and baseline BP will be conducted by including each classification.Many qigong researchers consider that the qigong effects on the human body are systemic without targeting one particular element, such as BP . TherefoThe standard mercury sphygmomanometer is the most common device used to measure blood pressure . The accThis study will be the first randomized trial to investigate the effectiveness of qigong exercises for the treatment of pre- and mild hypertension. The main focus of this trial is to investigate the role of qigong in reducing the blood pressure of patients with pre- or mild hypertension. This trial will contribute information needed to begin answering important clinical questions regarding the effects of qigong in lowering the blood pressure of patients with pre- and mild hypertension. Although the trial is not sufficiently powered to determine the effectiveness of qigong on hypertension, we will compare the effect size between groups in order to form larger-scale trials in the future.The authors declare that they have no competing interests.JEP conceived of the project, led the design, and wrote the first draft of this manuscript. YL and TSP participated as qigong experts. SHH, JEK, THK, ARK, SYJ, HJP and SMC provided technical advice and wrote the relevant sections of the manuscript. All authors participated in the trial design, commented on drafts of this paper, and read and approved the final manuscript.


Orexin, cardiovascular function, and hypertension. In normal rats, central administration of orexin can induce significant increases in arterial blood pressure (ABP) and sympathetic nerve activity (SNA), which can be blocked by orexin receptor antagonists. In spontaneously hypertensive rats (SHRs), antagonizing orexin receptors can significantly lower blood pressure under anesthetized or conscious conditions. (2) Orexin, respiratory function, and central chemoreception. The prepro-orexin knockout mouse has a significantly attenuated ventilatory CO2 chemoreflex, and in normal rats, central application of orexin stimulates breathing while blocking orexin receptors decreases the ventilatory CO2 chemoreflex. Interestingly, SHRs have a significantly increased ventilatory CO2 chemoreflex relative to normotensive WKY rats and blocking both orexin receptors can normalize this exaggerated response. (3) Orexin, central chemoreception, and hypertension. SHRs have higher ABP and SNA along with an enhanced ventilatory CO2 chemoreflex. Treating SHRs by blocking both orexin receptors with oral administration of an antagonist, almorexant (Almxt), can normalize the CO2 chemoreflex and significantly lower ABP and SNA. We interpret these results to suggest that the orexin system participates in the pathogenesis and maintenance of high blood pressure in SHRs, and the central chemoreflex may be a causal link to the increased SNA and ABP in SHRs. Modulation of the orexin system could be a potential target in treating some forms of hypertension.In this review we focus on the role of orexin in cardio-respiratory functions and its potential link to hypertension. (1)  Mounting evidence suggests that orexin is not only important to sleep-wake cycle and feeding regulation but also to respiratory and cardiovascular regulation. Furthermore, orexin may play role in some types of hypertension.Orexins, also known as hypocretins (Hcrt), are two excitatory neuropeptides, orexin A and orexin B (OX-A and OX-B) or hypocretin 1 and hypocretin 2 (Hcrt1 and Hcrt 2), produced by neurons primarily located in the lateral hypothalamic area (LHA)  in hypothalamic slices prepared from orexin neuron/enhanced green fluorescent protein (EGFP) transgenic mice , the cell bodies of orexin neurons are strictly located in the perifornical area and lateral and dorsal hypothalamic areas , and PVN in Wistar rats  and activates neurons of the lateral paragigantocellular area , e.g., neurons in the hypothalamic PVN and the RVLM  significantly reduced the number of neurons activated by OX-A, while co-application of OX1R and OX2R antagonists completely eliminated orexin A-induced depolarization  plays a crucial role in the regulation of circulation and blood pressure Guyenet, , and mann Figure . Furthern Figure .in vivo have demonstrated that orexin participates in blood pressure regulation. Transgenic orexin deficient animals, both prepro-orexin knockout (pp-OX KO) mice  with RNAi or antagonizing OX1Rs can block blood pressure and HR responses to acute panic stress  or the RVLM in anesthetized SHRs significantly decreased blood pressure  orexin participates in the regulation of cardiovascular homeostasis, (b) exogenous orexins can increase SNA and blood pressure in normal animals, and (c) transgenic orexin deficient animals have lower resting blood pressure, have led two independent groups to test the hypothesis that orexin may participate in the development of neurogenic hypertension in spontaneously hypertensive rats (SHRs)  gene is down-regulated in the adrenal gland in SHR and stroke-prone SHR (SHRSP) relative to normotensive WKY rats. This raises an interesting question of the role of peripheral orexin on cardiovascular function. As mentioned above, orexin neurons are exclusive located in the lateral hypothalamus and send projections to many brain locations. However orexins are found in many peripheral tissues, and the peripheral orexin distributions and functions have been discussed by recent reviews  , or a selective OX2R antagonist (TCS OX2 29) into RVLM can partially block the OX-A induced increased SBP and HR in SIHR  Transgenic orexin deficient animals have a lower resting blood pressure. (2) Blocking OXRs significantly lowers blood pressure and SNA in adult SHRs. (3) PP-OX mRNA and gene expression are upregulated in the CNS in hypertensive rats and mice. Based on these findings we suggest that an overactive orexin system in the CNS may participate in the pathogenesis and maintenance of high blood pressure in certain forms of hypertension. Further, modulation of the orexin system could be a potential target in treating some forms of hypertension.In normal animals, activation of OXRs by orexin in the CNS or in areas critically involved in SNA regulation, e.g., the RVLM and spinal cord, induces sympathetically mediated hypertension and tachycardia, which can be attenuated by OXR antagonists. Transgenic orexin deficient animals have a lower resting blood pressure. Spontaneously hypertensive rats and mice may have an overactive orexin system as (1) blocking OXRs produces significant anti-hypertensive effects in SHRs, (2) the expression of OX-A mRNA in increased in RVLM in SHRs and (3) the pp-OX/Hcrt gene is upregulated in hypothalamus in hypertensive BPH/2J mice. Orexin is important in the regulation of SNA and blood pressure and an overactive orexin system may be pathologically linked to the development of neurogenic hypertension.1R and/or OX2R mRNA is also found abundantly in many respiratory nuclei in the brainstem with a pattern matching that of OX-containing axon terminals  in the RTN significantly reduced the respiratory response to hypercapnia (7%CO2) with a substantial effect in wakefulness ; the CO2 chemoreflex was not significantly changed in sleep in the dark period and wakefulness and sleep in the light period of the diurnal cycles  Orexin may be a link between breathing and sleep-wake status.In summary: (1) Orexin neurons are intrinsically chemosensitive and send projections to other central chemoreceptor sites, e.g., the RTN and medullary raphe. (2) Orexin may regulate breathing and central chemoreception directly and/or indirectly by recruiting other brainstem chemoreceptor sites, e.g., the RTN and medullary raphe. (3) Orexin modulation of the COAnatomically, many cardiovascular and respiratory related nuclei are closely intertwined within similar regions of the brain, or are even synaptically connected. Many of these nuclei are part of the respiratory-sympathetic network that is critical to the regulation of respiratory and sympathetic activity and blood pressure  induced greater increases in ventilation (E), blood pressure and SNA than did hypoxia (10%O2/93%N2)  Many putative central chemoreceptors sites, e.g., the RTN, NTS and medullary raphe, are involved in the regulation of SNA and blood pressure. (2) Activation of central chemoreceptors by hypercapnia significantly increases blood pressure, SNA and respiration with and without peripheral chemoreceptors. These studies suggest that the hypercapnic induced increase in ABP is due to sympatho-excitation via activation of the central chemoreceptors. The central chemoreceptors directly or indirectly regulate sympathetic vasomotor tone and blood pressure, and can activate the sympathetic outflow in a tonic manner independent of the effects on the central respiratory pattern generator  channels in young pre-hypertensive SHRs , or hyperoxic hypercapnia (7%CO2/93%O2) when peripheral chemoreceptors are suppressed, is significantly higher in both wakefulness and sleep than that of the normotensive WKY control rats , ABP remains significantly above the normal even at 21 days post CSD  Can antagonism of OXRs be a target to treat such an augmented CO2 response and the associated hypertension in SHR? At present, we have found that antagonism of both OXRs using an orally administered dual orexin receptor antagonist, Almxt: (1) significantly reduced the exaggerated CO2 chemoreflex in SHR to the same level as measured in the control normotensive WKY rats  The orexin knockout mouse has a decreased respiratory hypercapnic chemoreflex as well as a lower resting ABP  while SHRs have severe hypertension, a hyperactive central hypercapnic reflex, and possibly an overactive orexin system. Blocking both orexin receptors in SHR can normalize the exaggerated hypercapnic chemoreflex and significantly lower blood pressure, which suggests the overactive central chemoreceptors may be an important link in neurogenic hypertension with orexin as mediator in SHRs.Orexin knockout mice have both a severely attenuated hypercapnic chemoreflex and lower resting blood pressure, while SHRs have severely increased blood pressure and enhanced peripheral and central chemoreflexes with a possibly upregulated central orexin system. Antagonism of both orexin receptors can significantly lower SNA and blood pressure and normalize that central hypercapnic chemoreflex in SHRs. We suggest that overactive central chemoreceptors may be an important link to the development and maintenance of high blood pressure in SHRs with orexin as a key mediator.2 chemoreceptors is associated with sympatho-excitation, hypertension and tachycardia. In SHRs, the overactive central and peripheral chemoreflex may play an important role in the development of neurogenic hypertension. Orexin links the respiratory and sympathetic nervous systems and an overactive orexin system may be the cause of hyperactive central CO2 chemoreflex in SHRs and thus the associated hypertension. Antagonism of OXRs can normalize the overactive CO2 central chemoreflex and significantly lower ABP and SNA in SHRs. Based on the data obtained from SHRs we hypothesize that modulation of the orexin system could be a potential target in treating some forms of hypertension.Activation of central COThe 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.


Following tilt-induced syncope, blood pressure usually recovers rapidly after tilt back to the horizontal position. However, in some patients, hemodynamic recovery is delayed, a condition recently termed “prolonged post-faint hypotension” (PPFH). The mechanism is thought to be mediated by increased vagal outflow rather than exaggerated peripheral vasodilatation and sympathetic withdrawal. To date, no muscle sympathetic nerve activity (MSNA) recordings have been reported in this condition, so we aimed to confirm that neither vasodilatation nor MSNA withdrawal was responsible.To retrospectively select patients with satisfactory recordings of continuous BP and MSNA during tilt-induced syncope. To compare hemodynamic and MSNA profiles in patients with PPFH to patients with normal recovery (NR) after tilt-back.All patients were studied in Christchurch, New Zealand, between 1998 and 2008 using continuous arterial BP monitoring, and microneurographic recordings of MSNA from the right leg. Only patients with satisfactory BP and MSNA data throughout baseline, head-up tilt and presyncope were selected. Stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR) were derived using Modelflow. After baseline measurements, patients were tilted to the head-up 60° position and given GTN spray if asymptomatic after 20 min. Following the onset of presyncope, patients were tilted slowly back to the horizontal. PPFH was defined as systolic BP <85 mmHg for at least 2 min after tilt-back. Measurements were averaged at baseline, early tilt, presyncope, early and late recovery. Within-group comparisons were made between baseline and all other time points. Between-group comparisons were made over all time points.n = 8) and with NR  were selected. Presyncope was provoked by GTN in 4/8 patients in each group. In both groups, MAP remained below baseline during early and late recovery: PPFH 84 ± 5 versus 51 ± 5 and 64 ± 5 mmHg ; NR 104 ± 5 versus 83 ± 5 and 93 ± 5 mmHg . However, MAP and HR were lower in the PPFH group . During early recovery, CO remained below baseline only in the PPFH group (p = 0.001), whereas TPR remained constant in both groups. In both groups, all MSNA indices tended to remain above baseline levels during early and late recovery. PPFH 25 ± 2 increased to 31 ± 6 and 29 ± 4 bursts/min ; NR 23 ± 3 increased to 33 ± 3 and 34 ± 3 bursts/min .Patients with PPFH (7 males, age 46 ± 5 years, PPFH does not appear to be mediated by exaggerated vasodilatation or sympathetic withdrawal. Delayed recovery of cardiac output by increased vagal outflow is a more likely mechanism. Until recently, the mechanism of vasovagal syncope was thought to be dual, vasodilatation mediated by sympathetic withdrawal and bradycardia mediated by vagal activation . The conWe reviewed hemodynamic data from 340 recordings of tilt tests undertaken in the Christchurch Hospital Syncope Clinic from 1995 to 2005. All patients had a history of vasovagal symptoms over the 6 months before tilt. Of these, 203 tilt tests were positive. A positive tilt test was defined as a progressive fall in systolic blood pressure (SBP) below 100 mmHg associated with symptoms of impending syncope. PPFH, defined as SBP <85 mmHg for at least 2 min after tilt back was found in 25 patients (7.4% of tilt tests). From this group, on the basis of satisfactory MSNA recordings during tilt and presyncope (see below), we selected eight PPFH patients, . Nearly all had mild bradycardia during late recovery . However, only two of our PPFH patients had severe bradycardia (HR less than 50 bpm) as in the group described by Wieling et al. [o was performed on a hydraulic tilt-table between 9:00 AM and 1:00 PM in a temperature-controlled room (23°C) according to the Italian protocol [Passive head-up tilt (HUT) to 60protocol . If presThis study was approved by the Canterbury Hospital Ethics Committee.Microneurography needles were positioned for recording MSNA from the right peroneal nerve . The nerNon-invasive beat-to-beat BP was measured at the finger (Finometer Blood Pressure Monitor) with the hand held at heart level in a sling. Invasive BP recordings were undertaken from a 3 French brachial arterial line with a deltrans transducer fixed at mid-atrial level. The measured signal was analogue to digital converted at 200 Hz, and stored on a hard disk for offline analysis. Systolic (SYS) and diastolic (DIAS) arterial pressures were derived from the arterial pressure waveform. Mean arterial pressure (MAP) was calculated from the integral of the arterial pressure wave over one beat divided by the corresponding beat interval. Heart rate (HR) was computed as the inverse of the inter-beat interval and expressed as beats per minute. Beat-to-beat changes in stroke volume (SV) were estimated by modeling flow from the arterial pressure waveform , expressed in ml . CardiacFor each interval, hemodynamic variables were initially averaged over 30-s periods and then averaged (2 × 30 s periods for each minute) for statistical testing. MSNA variables were initially counted and measured over 60-s periods. Values for all variables are expressed as mean ± SE.Baseline: the last 5 min in the supine position before head-up tiltEarly HUT: the steady-state adjustment to orthostatic stress during the 1–3 min of HUT (60–180 s).Presyncope: the last minute before tilt-back to the horizontal position.Recovery: 0–2 and 4–5 min following tilt-back to the horizontal position.The following time intervals were analyzed:t tests and χ2 tests for demography and baseline variables. Changes in variables with time were analyzed using one-way ANOVA for within-group and two-way ANOVA for between-group comparisons.Statistical analysis was performed using unpaired p = 0.6). Five PPFH patients reported protracted symptoms after fainting (feeling unwell for more than 6 h). Tilt time and requirement for GTN provocation were similar between groups.All patients had satisfactory MSNA data during tilt and presyncope, but 4/8 in the PPFH group had incomplete data during recovery. The groups were matched for age and gender. Four patients with PPFH (and 2 with NR) had a life-long history of syncope associated with blood phobia (p = 0.004), and HR (p = 0.023) were lower in the in the PPFH group whereas SV was higher (p = 0.037). For all other variables, including CO (p = 0.89) and TPR (p = 0.128) and indices of MSNA  there were no significant differences between groups.Between group comparisons of haemodynamic parameters across all time points showed that MAP (p = 0.012); TPR 0.92 ± 0.1 versus 1.4 ± 0.3MU (p = 0.049), whereas SV was higher: 103 ± 10 versus 77 ± 4 ml (p = 0.046). HR, CO and all indices of MSNA were similar.Between groups, the PPFH group had lower baseline BP and TPR than the NR group: MAP 84 ± 4 versus 104 ± 5 mmHg (p = 0.043) and 66 ± 2 bpm (p = 0.006) respectively, while SV and CO decreased to 75 ml and 4.9 l/min . TPR tended to increase from 0.92 ± 0.1 to 1.2 ± 0.1MU (p = 0.15). In the NR group, MAP remained constant at 108 ± 5 mmHg (p = 0.2), while HR increased to 84 ± 6 bpm (0.02). SV and CO decreased to 54 ± 6 ml (p = 0.004) and 4.3 ± 0.4 l/min (p = 0.02) while TPR tended to increase (p = 0.1). MSNA indices increased in both groups: PPFH 25 ± 2 to 44 ± 3 bursts/min (p = 0.001), 43 ± 4 to 75 ± 4 bursts/100beats (p = 0.001) and 100 to 154 ± 7% burst area (p = 0.001); NR 23 ± 3 to 41 ± 4 bursts/min (p = 0.001), 35 ± 7 to 59 ± 8 bursts/100beats (p = 0.001) and 100 to 170 ± 13% burst area (p = 0.001).In the PPFH group MAP and HR increased to 92 ± 5 mmHg (p = 0.045) and NR 70 ± 7 mmHg (p = 0.002). In the PPFH group HR increased to 75 ± 6 bpm (p = 0.027), SV fell to 54 ml (p = 0.003), and CO to 4.0 l/min (p = 0.002). In the NR group, SV fell further from baseline to 51 ml (p = 0.012). MSNA indices began to fall but remained above baseline levels in both groups: PPFH 38 ± 5 bursts/min (p = 0.03), 65 ± 11 bursts/100 beats (p = 0.04), and 149 ± 21% burst area (p = 0.06); NR 38 ± 5 bursts/min (p = 0.01), 51 ± 10 bursts/100 beats (p = 0.03) and 157 ± 20% burst area (p = 0.02).MAP fell below baseline levels in both groups: PPFH 68 ± 7 (p = 0.001) and NR 83 ± 5 mmHg (p = 0.001). In the PPFH group, HR fell to baseline at 56 bpm (p = 0.24), while SV and CO remained below baseline at 69 ± 6 ml (p = 0.009) and 3.7 ± 0.5 l/min (p = 0.001). In the NR group SV began to increase but remained below baseline at 62 ml (p = 0.049). All MSNA indices returned to baseline levels in both groups. PPFH 31 ± 6 bursts/min (p = 0.09), 52 ± 11 bursts/100 beats (p = 0.11) and 133 ± 13% burst area (p = 0.16); NR 33 ± 3 bursts/min (p = 0.06), 43 ± 7 bursts/100 beats (p = 0.25), 129 ± 19% burst area (p = 0.16).In both groups, MAP remained below baseline: PPFH 51 ± 5 . In the PPFH group, SV recovered but CO remained below baseline at 88 ± 6 ml (p = 0.178) and 4.6 l/min (p = 0.049), respectively. In the NR group, SV increased back to baseline: 65 ml (p = 0.127). MSNA indices remained at or above baseline levels in both groups. PPFH 29 ± 4 bursts/min (p = 0.02), 48 ± 7 bursts/100 beats (p = 0.05), 133 ± 13% burst area (p = 0.08) and NR 34 ± 3 bursts/min (p = 0.01), 45 ± 8 bursts/100 beats (p = 0.09), 119 ± 10% burst area (p = 0.09).MAP remained below baseline in both groups: 64 ± 5 and 93 ± 5 mmHg, respectively (In summary, MAP and HR were lower at baseline and during recovery in the PPFH group. We also observed that unlike the NR group, CO was depressed through recovery in the PPFH group. Although TPR was lower in the PPFH group at baseline, this was not apparent during recovery and exaggerated MSNA withdrawal was not seen.Our hypothesis, that MSNA would remain increased from baseline values during PPFH, is supported by our findings. TPR remained constant at baseline levels in both groups, while MSNA tended to be elevated. Thus although blood pressure was clearly lower in the PPFH group during recovery, it did not appear to be mediated by an exaggerated withdrawal of MSNA. Delayed recovery of CO and a lower HR throughout recovery secondary to increased vagal outflow is therefore the most likely mechanism for PPFH. These results are consistent with the findings of Wieling et al.  who firsEven though MSNA has been studied extensively during tilt and presyncope , 28, 30,This is a retrospective study, looking at a relatively small group of patients, which was limited mainly by technical difficulties obtaining satisfactory MSNA data. At the time the recordings were made, we were mainly concerned with preserving the recording field throughout presyncope, and so we did not allow our patients to become as bradycardic as the PPFH group previously reported . This ac


Despite the availability of nonpharmacological approaches and pharmacological therapies for hypertension, blood pressure control rates are disappointing all over the world . Among s This special issue presents some papers related to these cardiometabolic risk factors and their involvement mainly in prognosis and treatment of hypertensive patients. Firstly, a very low diastolic blood pressure, with a threshold value of 70 mmHg, was associated with increased all-cause mortality. It has been discussed that blood pressure level is the most important factor in cardiovascular risk evaluation even in hypertensive subjects with important metabolic disorders. The linear relationship between blood pressure and cardiovascular mortality starting from 115/75 mmHg is well known . Neverth Sleep disorders have been increasingly studied in recent years. Obstructive sleep apnea is related to cardiovascular disease and metabolic dysfunction, but sleep duration is a parameter not commonly considered in this association. Indeed, short sleep duration has been previously associated with an increased likelihood for hypertension . In a paThe interaction between hypertension and diabetes seems to be the principal concern to the cardiovascular system. The mechanisms that may increase cardiovascular risk in diabetic hypertensive patients are not completely understood. Oxidative stress and low-grade inflammation resulting in endothelial dysfunction as the first process of atherosclerosis were reviewed in this special issue. These factors may be also relevant in patients with longer duration of type 1 diabetes. In another paper, a cross-sectional study carried out in 20 Brazilian cities demonstrated that less than one quarter of treated type 1 diabetic patients achieved the target values for systolic and diastolic blood pressure. These data indicate that a more aggressive approach of this population is extremely necessary also in developing countries.Nutritional factors involved in the treatment of hypertensive subjects are also discussed in this special issue. Many dietary components, especially sodium, potassium, calcium, and magnesium, are reviewed based on the available evidence. Restriction of daily sodium intake is recommended in several guidelines about hypertension. However, low salt intake has resulted in cardiovascular mortality in some particular groups of patients including diabetic subjects . Potassi Lastly, in a study that enrolled patients with uncontrolled hypertension and criteria for metabolic syndrome, moxonidine therapy resulted in blood pressure reduction and improvement of blood pressure control rates, especially in younger individuals. The pharmacological treatment of hypertension in the context of metabolic syndrome presents many challenges in the daily clinical practice due to several mechanisms involved in this medical condition including the sympathetic nervous system (SNS) hyperactivation. Thus, moxonidine, a selective agonist at the imidazoline receptor subtype 1 which determines a decrease in SNS activity, may be beneficial in this circumstance.  Undoubtedly, hypertension is very commonly associated with other metabolic chronic conditions. In fact, more than 80% of hypertensive patients present one or more concomitant metabolic risk factors. This clinical condition has a growing global prevalence, clearly related to the modern lifestyles characterized by lack of physical activity resulting in overweight or obesity. Hopefully, we believe that this special issue can help to better understand the interaction between raised blood pressure levels and cardiometabolic factors, pointing out the involvement of insulin resistance and RAS/SNS activation as linking factors and also discussing some therapeutic options for this population. Mario Fritsch NevesMario Fritsch NevesAgostino VirdisAgostino VirdisAntonio Felipe SanjulianiAntonio Felipe SanjulianiEduardo Vera TibiriçáEduardo Vera Tibiriçá


Background. Sentinel Data Capture is an IT program designed to collect data automatically from GPs' electronic health record system. Data include ICPC diagnoses, National Health Service disbursement codes, laboratory analysis, and prescribed drugs. Quality feedback reports are generated individually for each practice on the basis of the accumulated data and are available online only for the specific practice. Objective. To describe the development of the quality of care concerning drug prescriptions for diabetes patients listed with GPs using the Data Capture module. Methods. In a cohort study, among 8320 registered patients with diabetes, we analyzed the change in the proportion of medication for uncontrolled cases of diabetes. Results. From 2009 to 2010, there was an absolute risk reduction of 1.35% (0.89–1.81: P < 0.001) in proportion of persons not in antidiabetic medication despite an HbA1c above 7.0. Similarly, there was a 4.51% (3.42–5.61: P < 0.001) absolute risk reduction in patients not in antihypertensive treatment despite systolic blood pressure above 130 mm Hg and 4.73% (3.56–5.90: P < 0.001) absolute risk reduction in patients with total cholesterol level above 4.5 mmol/L and not receiving lipid-lowering treatment. Conclusions. Structured collection of electronic data from general practice and feedback with reports on quality of care for diabetes patient seems to give a significant reduction in proportion of patients with no medical treatment over one year for participating GPs. Due to lack of a control group, we are, however, not able to say if the drop in the proportion of uncontrolled cases is a result of participation in collection of electronic data and feedback alone. Several interventions have been investigated in order to improve quality of diabetes care. Two recent systematic reviews evaluated interventions to improve diabetes management including provider education, point-of-care reminders, audit and feedback, and registries. Both reviews showed improved processes for physician-directed interventions but no improvements in patient outcomes for diabetes , 2. OnlyDanish general practice is considered leading in integrating IT technology in everyday patient care and in the electronic communication with the rest of health care system . In 2006The aim of this is to describe the development of the quality of care concerning drug prescriptions for diabetes patients listed with GPs by use of the Data Capture module.In Denmark health care, contacts are free of charge for the patients and primary health care is organized with self-employed general practitioners (GPs) on contract with 70% pay per fee and 30% pay per capitation. GPs work in singlehanded practices or in cooperation in clinics with 2 or more GPs. Patients must register with a GP or partnership practice of their choice practicing within 15 km of their home and each GP has about 1,600 patients. GPs are gatekeepers of the Danish National Health Service and almost all referrals to specialists and hospitals are made through them.Updated quality reports are generated several times a week and made available for the GPs on the report server, where GPs can access their own data from the clinic online by using the professional digital signature. The GPs have access to updated data on the quality of care from their own practice, and they can identify individual patients that are suboptimal treated  and bencWe classified patients diagnosed with type 2 diabetes into two groups: controlled and uncontrolled diabetes. The criteria for diagnosis and controlling type 2 diabetes are according to the guidelines by the Danish College of General Practitioners . PatientIn all, there were 500.606 patients in DAMD in October 2009 and 14.173 patients were diagnosed with type 2 diabetes before October 2009 and alive during the observation period. The number of included patients for each of the three parameters was: 7988 with two HbA1c measurements, 5805 patients with two blood pressure measurements, and 7123 patients with two cholesterol measurements.P < 0.001) (P < 0.001). For blood pressure regulation, 722 patients were not on medical antihypertensive therapy despite a systolic blood pressure above 130 mm Hg in 2009. After one year, 385 of these were now treated according to guidelines and only 123 patients went from treatment or systolic blood pressure below 130 mm Hg to no medical antihypertensive therapy despite a systolic blood pressure above 130 mm Hg, resulting in a total of 460 patients with high blood pressure not in medical treatment in 2010 and giving a total reduction of uncontrolled cases from 12.44% in 2009 to 7.92% (P < 0.001) in 2010 . In October 2009, 235 persons registered as diabetics with two HbA1c measurements were not in antidiabetic medication despite an HbA1c above 7.0. After one year, 185 of these were now treated according to guidelines, and only 77 of the patients with treatment or HbA1c below 7.0 in 2009 were in 2010 without treatment despite an HbA1c level above 7.0, resulting in a total of 127 persons not receiving antidiabetic medication despite an HbA1c level above 7.0 in 2010. In total, there was a statistically significant reduction in the proportion of persons not on antidiabetic medication despite an HbA1c above 7.0 from 2.94% in 2009 to 1.59% in 2010 (< 0.001) . Concern in 2010 . MultileThe main finding is that implementation of the Data Capture module and electronic feedback of qualitative indicators seems to be associated with improvement of the quality of care for patients with type 2 diabetes when studying quality of drug prescriptions. However, these results should be interpreted with caution due to the lack of a control group, as the observed changes could also be attributed to, for example, time trends. The treatment of diabetes patients in general in Denmark is monitored by the Danish National Indicator Project , and froAnother Danish study  on electDifficulties with proper coding and registration of diabetic patients may be a weakness in this study, where a possible obstacle to the proper coding could be the fear that persons other than the doctor himself might gain insight into his quality of treatment. In the service agreement for the Data Capture module, only the physician and the individual patient had access to view their own data. When more than 4 clinics are pooled, activities can be published but not in a way that it is possible to identify either the patient or the individual doctor. Data from DAMD are in general anonymous for research purposes. However, to specific quality and research projects it may be possible to obtain access to DAMD data. The researcher or quality development person has to seek permission to use data from DAMD from a quality and research committee comprising medical quality representatives from the 5 regions and representatives from the 3 university research units in Denmark.The use of diagnosis coding is voluntary in Denmark. Throughout the country, numerous courses in diagnostic coding have been carried out. A national ICPC background group is in charge of developing courses in diagnostic coding and setting up rules for the way diagnosis coding should be perceived and used as clinically relevantly as possible. In a Danish and an Australian study of vignettes, it appeared that in the coding of chronic disease the interobserver agreement was higher (over 70%), while for single contacts and symptom diagnoses the coding was lower (below 70%) , 13. SinIn this uncontrolled study, structured collection of electronic data from general practice and feedback with quality reports seem to reduce the proportion of type 2 diabetes patients with no medication, despite values for HbA1c, blood pressure, and cholesterol levels above target levels. Data capture and electronic feedback of quality indicators might be a promising tool for quality improvement in general practice.