It is surprising that only about 50 years ago hypertension was considered an essential malady and not a treatable condition. Introduction of thiazide diuretics in late 50s made some headway in successful treatment of hypertension and ambitious multicenter VA co-operative study (phase 1 and 2) started in 1964 for diastolic hypertension ranging between 90 and 129 mmHg and completed by 1971 established for the first time that treating diastolic hypertension reduced CV events such as stroke and heart failure and improved mortality. In the following decade, these results were confirmed for the wider US and non-US population, including women and goal-oriented BP treatment to diastolic 90 became the standard therapy recommendation. But isolated systolic hypertension  was not considered treatable until 1991 when SHEP study (systolic hypertension in elderly program) was completed and showed tremendous benefits of treating systolic BP over 160 mmHg using only a simple regimen using small dose chlorthalidone with addition of atenolol if needed. In the next two decades, ALLHAT and other studies examined the comparability of outcomes with use of different classes and combinations of antihypertensive drugs. Although diastolic BP goal was established as 90 in the late 70s and later confirmed by HOT study, the goal BP for systolic hypertension was not settled until very recently with completion of SPRINT study. ACCORD study showed no significant difference in outcome with sys 140 vs. 120 in diabetics. But recently completed SPRINT study with somewhat similar protocol as in ACCORD but in non-diabetic showed almost one-quarter reduction in all-cause mortality and one-third reduction of CV events with systolic BP goal 120. Over the last several decades, the term “essential hypertension” has become entrenched in our medical vocabulary. We not only use it in our usual medical lingo but the term was actually codified in ICD-9. As a medical community, we do not categorize any other common pathological conditions, such as obesity, NIDDM, or CAD as “essential.”Moreover, in order to distinguish the common variety of hypertension from a specific etiology-related hypertension – so-called secondary hypertension – the most logical alternate term would have been “primary” hypertension. But why and how did the term “essential hypertension” come about? To find the answer, one needs to delve into the history of the pharmacological treatment of hypertension.via the stethoscope, the modern quantitative concept of hypertension – broken into systolic and diastolic categories – came into existence. By the middle of the twentieth century, checking BP by sphygmomanometer became part of the routine physical examination in hospitals and clinics . Even before the Framingham studies, many insurance companies had already begun measuring BP for policyholders’ physical examinations. Furthermore, several studies done by the Actuarial Society of America pointed toward the higher morbidity and mortality associated with higher BP , 7.Yet, throughout the 1960s, the debate continued in the medical community regarding whether a need existed for treating the common variety of hypertension, by then aptly named “essential hypertension” because it was deemed an unavoidable, hence essential, component of the aging process. Attempts to treat hypertension, with the few drugs that were available at the time, often caused more misery and earlier demise for the patients than leaving them untreated. The prevailing attitude in the academic community was expressed in an editorial in the Archive of Internal medicine in 1965 by two professors of medicine from New York.It is common experience that many patients live medically uneventful lives in spite of prolonged and considerable blood pressure elevation. In our study group’s experience with 241 living and continuously employed hypertensive patients, followed from 10–25 years, a so called benign course was the rule, not the exception … A drug that will maintain BP in the normal range in the supine as well as upright position without adverse physiological effects for all 24 hours over a period of years, when and if available, may well make medical history …One needs only to look back at the past 50 years to be amazed and deeply concerned at the worldwide enthusiasm generated by many proposed therapies for hypertension which eventually met their deserved doom – oblivion…Acceptable techniques for obtaining the necessary proof are presently not available. We believe that critical techniques designed for a more precise and scientific answer to the problem under discussion will appear much sooner in an atmosphere of less enthusiasm and more caution in interpreting the results and implication of this form of therapy .To quoteFor more details on this controversy, interested readers are referred to Dr. Moser’s review on the early years of hypertension treatment .Some reconciliation was therefore necessary between the two opposing views: is the common variety of hypertension, or essential hypertension, a benign condition or is it a killer disease? Serendipitously, as it happened for many other important breakthroughs in science, a few lucky developments occurred around the same time and helped in resolving the ongoing controversy.The first Randomized placebo-Controlled clinical Trial (RCT) in the history of medicine was conducted by Medical Research Council (MRC of UK) in 1948 (studying the effectiveness of streptomycin for the treatment of tuberculosis). This provided the tool for scientific proof of efficacy of any treatment .Thiazides and thiazide-like compounds were developed from the sulpha molecule and they were found to have natriuretic properties. First to come was chlorothiazide, followed by hydrochlorothiazide, and then chlorthalidone a few years later. These drugs showed potent hypotensive effects. Small studies demonstrated thiazides’ tolerability and effectiveness of this new group of drugs in lowering BP .Arthur Guyton, the famous renal physiologist, developed his theory of pressure natriuresis and hypothesized that abnormal pressure natriuresis curves can explain all types of hypertension .The Veterans Administration Medical Centers – a chain of federal hospitals dedicated to the care of war veterans – added to their missions of clinical care and medical education the lofty goals of pursuing medical research. Thus, the VA Co-operative research program was started. Having the VA hospital system with many hospitals, scattered across USA, under one authority, made it possible for large multi-center clinical studies to be carried out quickly and with relative ease .All of these lucky developments eventually produced the first multi-center hypertension treatment trial (the first VA Co-operative research study on hypertension), which was published in JAMA in 1967. The major findings of these and other landmark studies that followed in the subsequent 50 years are highlighted in this timeline. Considering the importance of the topic, there had been very few attempts to detail the history of hypertension treatment. Noteworthy are Dr. Moser’s personal account and a more detailed timeline created by Theodore Kotchen .In creating this timeline, I opted to choose studies that were landmark in nature and answered a hitherto unresolved question regarding management of “essential hypertension.” Subsequent studies that reaffirmed these answers or only elaborated on the main theme were mostly omitted to keep the timeline short and readable. For each selected study, we gave the main hypothesis of the study, brief outline of the study methodology and the main result(s) along with a brief commentary as to the historical importance of the study. I have avoided meta-analyses, however, important they may be. We also avoided basic science studies and I have purposefully left out newer experimental therapies like renal sympathetic ablation therapy for resistant hypertension, since it is still evolving.Following are the brief descriptions of the studies that make up the timeline of this review Figure ; Table 1VA cooperative study phase 1 – 1967VA co-operative study on HTN. First Randomized controlled trial of hypertension treatment anywhere in the world. Truly ground breaking study.The Veterans Administration (VA) cooperative study on antihypertensive agents was a major milestone achieved in medicine. This was the first adequately powered placebo-controlled, RCT of antihypertensive therapy . The phaTotal patients – 70 in each groupBP achieved – 91.6 vs. 119.7Events-–Death: 4 in control, 0 in treatment group–Morbid Events: 27 in control, 2 in Rx groupStudy summary:Morbid events included progression to malignant hypertension as evidenced by fundal hemorrhage, CVA, MI, heart failure, and dissecting aneurysm.VA cooperative study phase 2 – 1970This phase of the study examined the benefit of active treatment vs. placebo in moderately severe hypertension (diastolic 90–115).Recruitment for this phase started same time in 1964 as with the first phase group but being less severe disease, and this study needed larger sample size and longer follow-up. They were followed for a longer duration (mean 3.8 years). Using the same active treatment as in the first study, this study achieved an average fall in diastolic BP by 19 mmHg in the treatment group. The results showed significant mortality and morbidity benefits .Inclusion – diastolic BP > 90 < 115Total number – 380 all males (186 vs. 194)Follow-up – average 3.9 yearsMean age – 52.0Rx – HCTZ, reserpine, hydralazineInitial BP – 165/105 vs. 162/104Drop out – 15% equally dividedBP achieved: 138/91 vs. 166/105BP dropped average (treatment vs. control)27.2 vs. 4.2 (+) systolic−17.4 vs. 1.2 (+) diastolicDeaths: 19 vs. 8Total morbid events: 56 vs. 22 (29 vs. 12%)CVA: 20 vs. 8CHF: 11 vs. 0Malignant HTN: 4 vs. 0CAD: 13 vs. 11Study summary:Hypertension Detection and Follow-Up (HDFP) 1979First study to demonstrate benefit in mortality and morbidity by aggressive, goal directed blood pressure treatment with stepwise incremental therapy as opposed to more casual BP management without trying to reach a target BP. This study set the ground rules for future management of BP using incremental therapy – a new concept in managing chronic diseases.Published in 1979, the Hypertension Detection and Follow-Up (HDFP) trial was another land mark trial of antihypertensive therapy and was the first study to demonstrate a mortality benefit of goal-directed, stepped care blood pressure treatment compared to usual care . The stuTotal number: 5485 (Stepped care) vs. 5455 Inclusion: diastolic BP > 90 mmMale:Female – 50:40Intervention: stepped care vs. usual careDrugs: chlorthalidone, reserpine, K-sparing diuretics, methyldopa, hydralazine, guanethidineEntry BP: 159/101 vs. 158/101BP at goal first year: 51.8 vs. 29.4%BP at goal fifth year: 64.9 vs. 43.6%Mortality: (6.4 vs. 7.7%) RRR-17%CVA: 102 (1.8%) vs. 158 (2.8%) RRR 36%CHD: 171 (3.1%) vs. 189 (3.5%)Total CV events: 273 (4.9%) vs. 347 (6.4%)Study summary:Multiple Risk factor Intervention (MRFIT) 1982Not a true antihypertension study per se but BP reduction was one of the 3 risk factors treated.The Multiple Risk Factor Intervention Trial  was an a•Age: 35–37 years•Study randomization: 12,6666428 – Intervention (SI)6438 – Control (UC)Intervention:–Dietary counseling–Smoking counseling–Treatment of HTN–Lower cholesterolDuration: average 7 yearsMortality from CHD: 17.9 vs. 19.3 (per 1000)Total mortality: 41.2 vs. 40.4 (per 1000)p > 0.5.None of the difference is significant The study results played an important role in the direction of hypertension treatment in the ensuing decade. The failure of the study to achieve reduction in mortality in the intervention group was blamed on hypokalemia in some of the thiazide-treated patients and newer antihypertensive drugs were promoted by pharmaceutical industry over thiazide and thiazide such as diuretics like Chlorthalidone. On retrospect, the real cause for failure was that the study was planned prematurely. There was no Statin yet and arrival of Statin in the 90s made all the difference in CAD mortality.MRC trial of treatment of mild hypertension: principal results 1985First definitive study to provide evidence of benefits in treating mild hypertension in younger cohort – men and women aged 35–64 years.The primary objective of the trial  was to sDesign: single blind RCT based almost entirely in general practicesNo of participants: 17,354Active treatment (bendrofluzide or propranolol): 8700Placebo: 8654Duration: 5 yearsp < 0.01Stroke: active treatment (60) vs. placebo (109), Coronary events: active treatment (222) vs. placebo (234)p < 0.05All cardiovascular events: active treatment (286) vs. placebo (352), Mortality from all causes: active treatment (248) vs. placebo (253)Study Summary:The authors concluded that to prevent one stroke 850 individuals would have to receive treatment for a year.European Working Party High Blood pressure in the Elderly (EWHPE) 1986First major study of hypertension in exclusively elderly populationFor the EWHPE trial , 21, 840A non-significant change in total mortality rate (−9%).p = 0.037)Reduction in cardiovascular mortality  and an insignificantDecrease in cardiac mortality .Decrease in cerebrovascular mortality .Decrease in total mortality rate .Decrease in cerebrovascular mortality on treatment .Decrease in cardiac deaths .Decrease in deaths from myocardial infarction  1991First randomized controlled trial to show benefits of treating isolated systolic hypertension which prior to this most remarkable study was considered benign or not amenable to treatment, though isolated systolic hypertension showed more associations with CV morbidities and mortalities per Framingham and other studies. The success of this study opened up the treatment option to 50 million people in US alone.Study results double-blind part of the trial:Up until the 1990s, the benefit of treating isolated systolic hypertension (ISH) was an area of uncertainty. The trial was designed to examine if the treatment of systolic hypertension alone when diastolic BP is normal can be beneficial.Design: double-blind Placebo controlled RCTInclusion: systolic BP > 160 mmHg, diastolic BP < 90 mmHg with age >60 years.Total participants 4736; .Mean systolic at entry BP – 170, mean diastolic – 77Mean age – 72 (57% women)RX; chlorthalidone with a step-up to atenolol or reserpine if neededStep I – chlorthalidone 12.5 mg/day or PlaceboStep II – CTD 25 mg/day or PlaceboStep III – CTD 25 + Atenolol 25 mg/day or PlaceboStep IV – CTD 25 + Atenolol 50 mg/dayStep IV – CTD25 + Reserpine 0.05 mg/dayK supplement PRN for K < 3.5 meq/lAverage follow-up – 4.5 yearsAverage BP at study end (control vs. active RX) – 155/72 vs. 143/65Incidence of stroke – 8.2 vs. 5.2% (RRR 36%)Incident of MI – 141 vs. 106 (RRR 23%)Incidence of CVD – 414 vs. 289 (RRR 22%)Deaths from all cause – 242 vs. 213 (RRR 13%)Treatment of Mild Hypertension study (TOMHS) 1993Randomized controlled trial that compared efficacy of 5 classes of antihypertensive drugs along with non-pharmacologic treatmentsSHEP Study  Summary:The TOMHS trial  was a ran = 234Placebo n = 136Chlorthalidone + nutritional-hygienic advice, n = 132Acebutolol + nutritional-hygienic advice, n = 134Doxazosin mesylate + nutritional-hygienic advice, n = 131Amlodipine + nutritional-hygienic advice, n = 135Enalapril + nutritional-hygienic advice, The six treatment regimens were:Nutritional hygienic advice included increase in physical activity, weight reduction, lowering salt intake, and reducing number of alcoholic drinks.Outcomes: all six groups had sizeable BP reductions with minimal differences between individual Drug intervention groups.Blood pressure: drug treatment vs. placebo (−15.9 vs. −9.1 mmHg for SBP and −12.3 vs. −8.6 mmHg for DBP).p = 0.21).Death or non-fatal cardiovascular event: drug treatment vs. placebo .Other clinical events: drug treatment vs. placebo  1997Randomized controlled trial to determine if Mediterranean type diet with or without salt restriction lowers BP. This is one of the best prospective interventional diet studies in the hypertension research.Up until the 1990s, the non-pharmacological efforts to reduce blood pressure relied on a mix of weight control, reduced salt intake, reduced alcohol intake, and to an extent increase in dietary potassium. Earlier studies examining the relationship between diet and blood pressure found small and inconsistent changes in BP by nutrients such as potassium, calcium, magnesium, protein, and fiber. But most of these studies were retrospective in nature based on diet recall. In 1994, the first phase of the prospective DASH study was initiated .Design: multicenter, prospective, randomized controlled trialParticipants: 459, SBP < 160 mmHg, DBP between 80 and 95 mmHg, 133 hypertensiveIntervention: three sets of diets using prepared mealControl diet, comparable to the average American diet – potassium, calcium and magnesium at the 25th percentile of US consumption. Sodium 3 g.Rich in fruits and vegetables diet – potassium, calcium, magnesium at 75th percentile of US consumption with high fiber. Sodium 3 g.Combination diet – plenty of fruits and vegetables (9–10 servings/day), whole grain cereals, low fat dairy products and reduced saturated and total fat (Known now as DASH diet).All participants were initially fed control diet for 3 weeks (run in phase) followed by randomization for 8 weeks (intervention phase) into one of the diet groups.Resultsp < 0.001).In the hypertensive subset, combination diet reduced SBP and DBP by 11.4 and 5.5 mmHg, respectively, over the reduction by the control diet , this part of the study had 412 participants randomized to DASH or control diet and within each of these 2 categories there were 3 levels of sodium intake: 3.5, 2.3, and 1.2 g daily.High salt + control diet vs. Int salt + control-Sys BP lowered 2.1 mmHgHigh salt + DASH diet vs. Int salt + DASH-Sys BP lowered 1.3 mmHgInt slat + control diet vs. low salt + control-Sys BP lowered 4.6 mmHgInt Salt + DASH diet vs. low salt + DASH Sys BP lowered 1.7 mmHgResults:There was additive BP lowering effect on already lowered BP with DASH diet with every lowered level of salt intake. Not surprisingly, benefit of BP lowering effect of low salt was more pronounced in the control diet. The best BP lowering was in the low salt DASH diet. Compared to the control with high salt diet DASH/low salt reduced BP by 7.1 and 11.5 mmHg in normotensive and hypertensive participants, respectively.Medical research Council: Double-blind randomised trial of modest salt restriction in older people 1997First study to explore effect of salt reduction in older people with normal range BPAt the time of the study, it was well known that high blood pressure could lead to stroke in older people. What was also known was that older people with normotensive blood pressure could also develop stroke. However, no efforts were made to lower the blood pressure in normotensive older people. The MRC study  aimed toDesign: this double-blind randomized controlled crossover trial explored the effect that salt reduction would have on blood pressure in such individuals. The study participants included both normotensive and hypertensive individuals.In all 47 people were parts of the trial of which 18 were normotensive and 29 were hypertensive.In the normal salt intake for the UK population group, supine blood pressure was 163/90 (SD 21/10) mmHg with urinary sodium excretion of 177 (49) mmol/day.p < 0.001) with a urinary sodium excretion of 94 (50) mmol/day.With modest sodium restriction, blood pressure fell to 156/87 (22/9) mmHg .Hypertension Optimal Treatment (HOT) 1998First large randomized control trial to determine if lowering target diastolic blood pressure below 90 mmHg reduces CV events further.Since the second VA co-operative study, diastolic BP target had been 90 mmHg. No large trial was done since then to see if further lowering was beneficial. The Hypertension Optimal Treatment  (HOT) waRandomized control trial across 26 countries18,790 patients in the age group of 50–80Diastolic blood pressure (DBP) between 100 and 1115 mmHgThree target Diastolic BP goal:∘n = 6264)DBP ≤ 90 mmHg (∘n = 6264)DBP ≤ 85 mmHg (∘n = 6262)DBP ≤ 80 mmHg : felodipine 5 mg daily to start and go up to 10 mg, add Ace inhibitor or beta blocker if target not achieved and finally add thiazide diuretic if still above targetAdditionally∘9399 received acetylsalicylic acid∘9391 received placeboFindings∘20.3 mmHg reduction in DBP ≤ 90 mmHg group∘22.3 mmHg reduction in DBP ≤ 85 mmHg group∘24.3 mmHg reduction in DBP ≤ 80 mmHg groupThe final result of the study failed to show any significant difference in outcome between all three groups. However, the actual achieved mean diastolic BP for the ≤90, ≤85, or ≤80 mmHg groups was 85, 83, and 81 mmHg, respectively. The difference in actual achieved diastolic BP degree of blood pressure reduction among the three groups was much smaller than the planned difference of 5 mmHg. So, the study failed to provide the power to detect any difference in protection with varying degrees of blood pressure lowering.United Kingdom Prospective Diabetes Study (UKPDS) 1998Largest and longest trial examining efficacy and outcome of different treatment modalities for T2DM one arm of which examined the treatment for hypertension in T2DM.The United Kingdom Prospective Diabetes Study , 28 was Design: randomized control trialTwo groups:n = 758Tight blood pressure control (target < 150/85 mmHg), n = 390Less tight control group (target < 180/105 mmHg), Results: tight control vs. light controlp < 0.0001).Achieved Mean BP: 144/82 vs. 154/87 mmHg (Reductions in risk of (Tight BP control vs. light BP control)p = 0.0046)Diabetes-related end points (microvascular complications) = 24% Deaths related to diabetics = 32% Strokes = 44% Microvascular end points = 37% Deterioration of retinopathy = 34% Deterioration in visual acuity = 47%  2002Landmark study in African Americans for determining target blood pressure and suitable drug regimen in hypertension control to prevent progressive renal failure. The study failed to show benefits of tight BP control over usual control to slow decline in GFR.Hypertension is the second leading cause of End Stage Renal Disease (ESRD) and African-Americans are six times likelier to progress to ESRD from hypertension as compared to whites . The AfrDesign: 2 × 2 factorial design Randomized control trial.African-Americans18–70 years of age2)Hypertensive renal disease , n = 554Gr. B Usual mean arterial pressure groups (BP 102–107 mmHg), Each group then was randomized to three different classes of antihypertensive agentsn = 441Beta blocker (metoprolol), n = 436Angiotensin converting enzyme inhibitor (Ramipril), n = 217Dihydropyridine calcium channel blocker (Amlodipine), All patients could use diuretics, direct vasodilator, alpha blocker, and central sympatholyitics as needed  to reach goal BP.Outcomes:Lower target BP group vs. usual BP groupAchieved BP∘128/78 mmHg, SD (12/8 mmHg) vs. 141/85 mmHg, SD (12/7 mmHg)Mean (SE) GFR slope∘2/year vs. −1.95 (0.17) ml/min per 1.73m2 per year (p = 0.24)1-2.21 (0.17) ml/min per 1.73 mComposite clinical outcomes risk reduction for lower blood pressure group∘p = 0.85)2% Ramipril vs. metoprolol, 22% Ramipril vs. amlodipine, 38%  with a lower target BP. However, the results suggested that Ramipril was more effective compared to amlodipine in slowing decline in GFR. Superiority of Ramipril over Metoprolol was just marginal.Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) 2002Largest antihypertensive trial. Resolved the question of superiority of any of the newer class of antihypertensive drugs over the old thiazide like diuretic Chlorthalidone.This large trial involving about 42,000 participants were designed to answer the important and lingering question whether newer classes of drugs such as angiotensin converting enzyme inhibitor (ACEI), calcium channel blocker (CCB), and alpha blocker give better CV outcomes than the older drugs such as thiazide diuretics .Design: double-blind randomized control trialParticipants: patients, aged over 55 years with treated or untreated hypertension, with one additional Coronary heart disease risk factor.The participants were from USA and Canada with 35% participants from AA community.Four groups:Chlorthalidone chosen drug representing thiazide/thiazide-like diuretics.Total participants ;n = 9048);Amlodipine represented CCB (n = 9054);Lisinopril represented ACEI (n ~ 9061).Doxazosin represented alpha blocker ; Amlodipine (11.3%), Lisinopril (11.4%);Primary outcomes: Compared with Chlorthalidone, RR of Amlodipine was 0.98 (95% CI 0.90–1.07);Compared with Chlorthalidone RR of Lisinopril was 0.99 (95% CI 0.91–1.08).Key Secondary outcomesAmlodipine vs. Chlorthalidone for heart failure Lisinopril vs. Chlorthalidone∘For CVD ∘For stroke ∘For Heart Failure Based on these findings, ALLHAT study authors concluded that thiazide should be the preferred antihypertensive to start with unless there is clear contraindication. However, it was an optimistic generalization about thiazide as a group and future studies and analysis showed that all thiazides are not similarly effective and the benefits of Chlorthalidone as antihypertensive is not equaled by commonly used hydrochlorothiazide.Australian National Blood Pressure Study (ANBP II) 2003Contemporary to ALLHAT study, done in a different population but with same goal of comparison of thiazide vs. Ace inhibitor as antihypertensive drugThe results of the Second Australian National Blood Pressure Study (ANBP2) followed soon after ALLHAT results were published. This was a randomized, open-label, blinded end point study of 6083 hypertensive patients aged 65–84 years, who otherwise had a relatively low cardiovascular risk profile, with a median follow-up of 4.1 years . InitialAll CV events or death from any cause–p = 0.05HR = 0.89 (0.79–1.00), –p = 0.07CVD: HR = 0.88 (0.77–1.01), –p = 0.16CHD: HR = 0.86 (0.70–1.06), –p = 0.91Stroke: HR = 1.02 (0.78–1.33), –p = 0.33HF: HR = 0.85 (0.62–1.18), Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm ASCOT BPLA 2005After the comparison of individual antihypertensive trials, next series of trials focused on the outcome with different combinations of antihypertensive drugs. ASCOT was one such early trial comparing CCB and ACEI with Beta blocker and thiazide diureticIntervention: enalapril vs. HCTZPublished in 2005 the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA)  was a raDesign: international multi-center randomized control trialParticipants: total 19,257 hypertensives male and female in the age group of 40–79 years, having at least one additional cardiovascular risk factors.Two regimensn = 9639) vs. Atenolol ± bendroflumethiazide (n = 9618)Amlodipine ± perindopril Primary end point – Fatal and non-fatal stroke – Total cardio-vascular events and procedures – All-cause mortality – Incidence of diabetes –  and used hydrochlorothiazide representing the thiazide class . These crucial differences possibly account for different result in ANBP compared to ALLHAT.Conduit Artery Function Evaluation (CAFE) 2006This is a substudy of the ASCOT and this is the only large study that examined the variable effect of different class of drugs on reducing central aortic pressure (as measured by the new non-invasive technique of applanation tonometry) vs. usual peripheral blood pressures. This study gave answer to the lingering question why beta blocker like atenolol was not very effective in reducing stroke in hypertensive patients.The CAFE study  was a laTotal participants 2199.n = 1031)Atenolol based (n = 1042)Amlodipine based ∘Amlodipine Down to 133.2/76.9 (−27.8/−15.7 mmHg)p = 0.2)Difference between two groups: 0.7/1.6 Difference between two groups: 4.3/1.4  2008First randomized trial to demonstrate benefits of treating hypertension in very elderlyPrior to the HYVET  trial, tDesign: randomized control trialInclusion criteria:80 years or olderSystolic blood pressure > 160 mmHgRegimens:n = 1933Active treatment (indapamide with or without perindopril) n = 1912Placebo group, Outcomes:BP in the active treatment group was 15/6.1 mmHg lower than the placebo groupIn the intent to treat analysis, the active treatment group hadp = 0.06)30% reduction in the rate of fatal and non-fatal stroke 39% reduction in rate of death from stroke 21% reduction in rate of death from any causes 23% reduction in the rate of death from cardiovascular causes 64% reduction in the rate of heart failure Side effects: active treatment vs. placebo  2008Large randomized trial that compared two commonly used treatment regimens (ACE + CCB vs. ACE + diuretic)Design: double-blind, randomizedn = 11,506 patients with hypertension with at least one additional CV risk factorsParticipants: n = 5744) vs. Benazepril + Hydrochlorothiazide (n = 5762)Regimens: Benazepril + Amlodipine Benazepril + Amlodipine = 552 (9.6%)Benazepril + Hydrochlorothiazide = 679 (11.8%)2.2% absolute risk reduction with Benazepril + Amlodipinep < 0.001).19.6% relative risk reduction with Benazepril + Amlodipine  trial  exploredAt the end of the study, which was stopped prematurely after attaining a pre-determined end point, the authors concluded that the ACEI and CCB combination was superior to the ACEI and diuretic combination in reducing cardiovascular events in patients with hypertension at risk for CV events.The two major studies, ASCOT-BPLA and ACCOMPLISH, compared the newer and popular regimens (CCB and ACEI) vs. older drugs such as beta blockers and thiazide diuretics. Both were very large studies, but both were open label and sponsored by pharmaceutical companies. One of the major weaknesses in accepting the conclusion of thiazide being less effective than CCB when in combination with another class is that these studies invariably used a weak thiazide diuretic like hydrochlorothiazide. All NIH studies used Chlorthalidone and not hydrochlorothiazide as the diuretic. A recent network meta-analysis had confirmed that Chlorthalidone is much superior to hydrochlorothiazide in efficacy and cardiovascular outcomes. Why these two studies used hydrochlorothiazide when a superior drug, Chlorthalidone was available is open to speculation.Action to Control Cardiovascular Risk in Diabetes (ACCORD) 2010Until ACCORD studies, prevailing wisdom was in diabetic lower the BP is better but this notion was not evidence based. ACCORD trial was designed to answer this very important question.Design: double-blind randomized control trialNo of participants # 4733n = 2362Intensive therapy  n = 2371Standard therapy  Primary outcome = non-fatal MI, non-fatal stroke, or death from any cardiovascular causesThe Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) recommended lowering systolic blood pressure to <130 mmHg in diabetics  tested tMean systolic BP: (IT) 119.3 mmHg vs. (ST) 133.5 mmHgp = 0.20)Primary outcome rate: 1.87% (IT) vs. 2.09% (ST) Annual rate of death (any cause): 1.28% (IT) vs. 1.19% (ST) Annual rate of stroke: 0.32% (IT) vs. 0.53% (ST) Serious adverse events of anti HT therapy: IT – 77 (3.3%) vs. ST-30 (1.3%)  2013First randomized control trial that studied the effect of a Mediterranean diet on Cardiovascular DiseaseThis was a large multicenter study  in SpainTotal participants = 7747Age of participants = 55–80 years, 57% womenMedian follow-up = 4.8 yearsPrimary cardio vascular end point occurred in 288 participantsExtra virgin olive oil = 96 events, adjusted Hazard ratio 0.70 (95% CI 0.54–0.92)Mediterranean nuts = 83 events, adjusted Hazard ratio 0.72 (95% CI 0.54–0.96)Control group = 109 eventsSystolic hypertension intervention trial (SPRINT) 2015The SPRINT study conclusively demonstrated the benefit of lowering systolic blood pressure goal in a non-diabetic population.The SPRINT  study waTotal participants = 9361Intensive Blood Pressure control group (systolic < 120 mmHg) = 4678Standard Blood Pressure control group (systolic < 140 mmHg) = 4683Primary end point was myocardial infarction, acute coronary syndrome, stroke, heart failure, or death from cardiovascular events.At the end of 1 year systolic blood pressure achieved was121.4 mmHg in the intensive treatment group136.2 mmHg in standard control groupMedian follow-up = 3.26 yearsp < 0.001).Primary composite outcome = (1.65 vs. 2.19% per year) intensive vs. standard, respectively. Hazard ratio in the intensive treatment group was 0.75; 95% confidence interval (CI), 0.64–0.89; (p = 0.003).All cause mortality was found to be lower in the intensive treatment group:  throughout the world including less developed countries. Per NHNES survey of 2011–2012, the prevalence of hypertension in the US has remained around 30% – and while awareness of hypertension has reached a laudatory goal of 83% – the control rate is still only 50% (49% for men and 55% for women). These rates are also very similar among all ethnic groups. Therefore, though we have come a long way in the last 50 years in managing hypertension – from calling it essential to finding effective drug therapy for control – we are still short of truly overcoming this common malady of humanity. In fact, the annual number of deaths from HTN in the US still exceeds 30,000. Moreover, our understanding of the pathophysiology of common or so-called “essential” hypertension is still incomplete in many ways. The new discovery of extra-renal deposition of excess sodium in the skin, modulated by macrophages, changed the paradigm of classical Guytonian frame work of salt and hypertension , 40. SimWe know many isolated small communities like Kuna Indians, who continue to follow their ancestral traditions, do not develop hypertension even in their very old age. It is possibly not gene-related, since they develop hypertension when they immigrate to western communities , 45. ThuRegarding immediate clinic management of hypertension, a major unresolved issue is to define the exact clinical utility and wide applicability of ambulatory BP monitoring as well as the role of home BP monitoring. We know that the 24-h average BP per ABPM predicts hypertension outcome better than office BP – the standard used in almost all the trials cited above. We also know for the same level of office BP, people with non-dipping night BP has worse prognosis in CV outcomes . Wider uThere are many other worthy issues related to hypertension that we cannot adequately discuss in this space. We can only say that the great success in refining hypertension treatment, so far in the last 50 years is truly only the beginning of a long journey. The challenge remains for the next generation of clinicians and researchers for further advancement as we better understand human biology.The success of pharmacological treatment of a common human malady like hypertension that affects more than a billion of our fellow human beings is a mega achievement. In the history of modern medicine, only vaccination to prevent infectious diseases, antibiotics for infections, and oral hydration for diarrheal diseases have had similar success and impact on global health.In some ways, the success of treating this common chronic non-communicable disease (NCD) – as WHO has dubbed it – made way for effective planning to manage others. The success of multi-center RCTs for hypertension led to the concept of a very large multi-center study using one single variable intervention (aspirin for preventing CAD or ACE I for systolic heart failure) . In manyIn my experience in teaching medical students and residents, I noticed how little they know about these major breakthroughs in medicine especially cardiovascular medicine in the last quarter of the twentieth century and how the success of pharmacologic treatment of hypertension started this revolution. Once they learned about it, they got a better perspective and better understanding of the evolving nature of the Evidence-Based Medicine. It is these trainees that I had in mind when I decided to create this timeline of the history of hypertension treatment. I hope that the next generation will carry on the spirit of learning and conquer the uncharted territory of this common malady that affects a billion men and women worldwide today.MS planned the review, did the initial literature search in addition to what was already known to him and selected studies to be included. He also wrote the introduction and the conclusion. Most of the short comments on individual studies were written by him. He also selected many of the references that are included. ND helped gathering details of data from selected studies and summarizing them. He also helped creating the figure.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Arterial hypertension is a major public health problem and has increasedconsiderably in young individuals in past years. Thus, identifying factorsassociated with this condition is important to guide intervention strategiesin this population.To determine high blood pressure prevalence and its associated factors inadolescents.A random sample of 1,242 students enrolled in public schools of the city ofCuritiba (PR) was selected. Self-administered questionnaires provided familyhistory of hypertension, daily energy expenditure, smoking habit, daily fatintake, and socioeconomic status. Waist circumference was measured followingstandardized procedures, and blood pressure was measured with appropriatecuffs in 2 consecutive days to confirm high blood pressure. Relativefrequency and confidence interval (95%CI) indicated high blood pressureprevalence. Bivariate and multivariate analyses assessed the association ofrisk factors with high blood pressure.The high blood pressure prevalence was 18.2% (95%CI 15.2-21.6). Individualswhose both parents had hypertension and those with high waist circumference  hadhigher chances to develop high blood pressure.Positive family history of hypertension and high waist circumference wereassociated with high blood pressure in adolescents. These factors areimportant to guide future interventions in this population. A designeffect of 1.5 was added to correct the error related to multistage sample selection,as was a 30% margin for possible losses and refusals. Therefore, the total samplewas estimated in 1,276 adolescents.To estimate sample size, the following parameters were considered: (i) population of115,524 adolescents; (ii) confidence level of 95%; (iii) sampling error of 2%; (iv)arterial hypertension prevalence of 7.4%,The probabilistic sample was selected by use of multiple stages. In the first stage,all public middle and high schools in the city of Curitiba were listed andstratified according to the nine administrative regions of the city. In the secondstage, five schools were randomly selected from each administrative region, and, inthe third stage, a simple random selection of one to three classes at each schoolwas performed. The adolescents received an assent term, and their parents, a consentterm, explaining the research objectives and procedures, to be completed andsigned.The family history of arterial hypertension was obtained with a questionnaire sent tothe adolescent's parents or guardians, which indicated if the biological fatherand/or mother had arterial hypertension.23 The increased value for each sex and age group wasdetermined according to the proposal by Freedman et al.24 as ≥ 90th percentile.The waist circumference was measured at a level midway between the last costal archand the iliac crest, following standard procedures.25the mean value obtained being considered. The individuals were classified intosample quartiles according to sex and age group.The daily energy expenditure  was obtained from a 3-day activity recorddeveloped by Bouchard et al.,26 Theindividuals were classified into sample quartiles according to sex and agegroup.The cardiorespiratory fitness was assessed by using the shuttle run test proposed byLéger et al.Youth Risk Behavior SurveyQuestionnaire, translated and validated by Guedes and Lopes.27 That questionnaire inquires howmany days, in the preceding 30 days, cigarettes were smoked. The individuals wereclassified into three categories as follows: cigarettes smoked 10 to 30 days;cigarettes smoked 1 to 9 days; and no cigarette smoked in the preceding 30 days.To define smoking, the adolescents completed the 28 To maintain data quality, thecases with energy expenditure greater than 6,000 kcal or lower than 500 kcal wereexcluded.29 According tothe American Heart Association, in a proper food intake, total fat intake should be< 30%.30The total fat intake was obtained by completing a food frequency questionnairedeveloped for the Brazilian population by Sichieri and Everhart.31 In the present study, the participants were classified intothe following four socioeconomic levels: I, lowest socioeconomic level (classes Dand E); II, classes C1 and C2; III, classes B1 and B2; and IV, highest socioeconomiclevel (classes A1 and A2).The socioeconomic status was classified according to the criteria established by theBrazilian Association of Research Companies.National High BloodPressure Education Program.4 Before that, arm circumference was measured to enable the choiceof the cuff size .4 In addition, theadolescents were asked about having already had their blood pressure assessedbefore.Blood pressure was measured by using the auscultatory method, following theparameters established in the fourth report of the 4Two blood pressure readings were taken at a 5-minute interval, the mean value beingconsidered in this study. If the readings differed more than 2 mm Hg, the protocolwould be repeated.The Fourth Report on the Diagnosis, Evaluation, andTreatment of High Blood Pressure in Children and Adolescents,4 the cutoff values used, according tosex, age and height percentile, were as follows: arterial hypertension - systolicblood pressure (SBP) and/or diastolic blood pressure (DBP) ≥ 95thpercentile; prehypertension - SBP and DBP values < 95th percentile and≥ 90th percentile. Individuals with blood pressure values >120/80 mm Hg were considered prehypertensive.4In accordance with Adolescents classified as prehypertensive or hypertensive were reassessed at asubsequent visit on the day following the first assessment, in which case the secondblood pressure measurement was considered for the analysis. At both the first andsubsequent visit, blood pressure was measured by only one trained professional toprevent interobserver disagreement.t and Mann-Whitney U tests, based on normality of data.Continuous data were described by use of measures of central tendency and dispersionfor both sexes. Continuous data were compared between sexes by use of independentCategorical variables were described by use of relative frequency distribution andits respective 95% confidence interval (95%CI). The chi-square test forheterogeneity was used to compare the differences in the prevalences ofprehypertension, arterial hypertension and high blood pressure  between sexes, and to compare the high blood pressureprevalences in the first and second visits.The association between independent variables and high blood pressure was assessed byuse of bivariate and multivariate analysis (logistic regression). The variables witha p value < 0.25 on bivariate analysis were selected for the multivariate model.The magnitude of the association between the independent variables and high bloodpressure was expressed as odds ratio (OR) and its respective 95%CI. The prevalenceand association analyses were corrected with the complex sample design, using the'complex sample' command of the Statistical Package for the Social Science (SPSS)software, version 17.0. The significance level adopted for all analyses was p <0.05.th October,2012.The methodology of this study was approved by the Research Ethics Committee of theHealth Science Sector of the Paraná Federal University (UFPR), and abided bythe ethical guidelines established by the 196/96 Resolution of the BrazilianNational Health Council (CAAE 04414712.3.0000.0102) on the 25Data of 1,812 adolescents were collected. Of those, 570 adolescents meeting at leastone exclusion criterion were excluded from the final analysis as follows: 28individuals were at least 18 years old; 22 were on anti-hypertensive drugs; 84female adolescents were on oral contraceptives and one was pregnant; 172 adolescentsdid not deliver the family history of arterial hypertension of both parents; 239completed the questionnaires incorrectly; 46 underwent neither anthropometricassessments nor the cardiorespiratory fitness test; and 70 individuals did notundergo blood pressure reassessment.Therefore, this study's final sample comprised 1,242 adolescents aged between 11 and17 years, 646 of whom (52.01%) were females. The age group distribution was asfollows: 11-12 years, 363 individuals ; 13-15 years,697 individuals ; and 16-17 years, 182 individuals. Of the total sample, 34.06% had never undergoneblood pressure assessment.When comparing continuous data between sexes, all variables, except for DBP, weresignificantly higher in male individuals (p < 0.01).2 = 523.1; p < 0.01) between the first and second visit  was observed.2 = 0.01; p =0.91) and arterial hypertension .Considering only the values of the second visit, no significant difference betweensexes was observed in the prevalences of prehypertension .At the second visit, the high blood pressure prevalence was 17.5% (95%CI 14.1-21.4)in the male sex, and 18.8% (95%CI 14.7-23.8) in the female sex, showing nosignificant difference between sexes (X2max), total fat intake, and socioeconomic level].On multivariate model, high blood pressure associated (p < 0.05) with familyhistory of arterial hypertension, waist circumference and total fat intake.32 (8%) and those reported in the Brazilian studies by Vieira etal.33 and Pinto etal.13 .When prehypertension and arterial hypertension were considered together, theprevalences observed in the present study were higher than those reported in aninternational study by Duncan et al.11 haveshown a similar prevalence (18.6%) of high blood pressure, while another studyconducted in the city of São Mateus do Sul, Paraná state, has shown ahigher high blood pressure prevalence than that in the present study .20In Brazil, Romanzini et al.Those studies have assessed blood pressure only at one visit. However, as shown inthe present study, blood pressure reassessment at a subsequent visit is veryimportant, because blood pressure levels can change from one visit to the other,tending to decrease.4 In addition, asapproximately 34% of the adolescents in this study had never undergone bloodpressure assessment, they could be anxious or even frightened, which could yieldincreased blood pressure levels. Thus, individuals with high blood pressure levelsat the first visit might feel more comfortable with the procedures and measurersfrom the second visit on.That reduction in blood pressure levels might be due to a decrease in anxiety andfamiliarization of adolescents with the measuring procedures from the second visiton.8 It is worth noting that inherited factors contribute to thedevelopment of high blood pressure in adolescents, and, in addition, theadolescent's family setting is shared in regard to behavioral factors,9 which can contribute to increase blood pressure levels.Regarding the associations, individuals whose both parents were hypertensive had ahigher chance to develop high blood pressure. This is in accordance with anotherstudy, in which individuals with a history of arterial hypertension had more bloodpressure values exceeding the normal limits.20 Theyhave evidenced that the 'waist circumference' measure can determine the fatdistribution in the abdominal region, being related to metabolic risk, in adults,children and adolescents.34Regarding the association of waist circumference and high blood pressure identifiedin this study, other studies have shown the same tendency.Considering the total fat intake, individuals with an increased fat consumption(≥ 30%) have shown a smaller chance to develop high blood pressure, and,thus, total fat intake is a protective factor against high blood pressure.17 have shown that individuals of both sexes with aninadequate total fat intake had a higher chance to develop high blood pressure.Campos et al.,18 however, havereported no significant association of saturated fat and cholesterol intake witharterial hypertension in the city of Curitiba.Contrary to the present study, Guedes et al.Dietary Approaches to StopHypertension (DASH), recommended by the National Institutes ofHealth (NIH),35considers other important aspects, such as consumption of whole grains, nuts, fishand poultry. In addition, the NIH emphasizes that the diet should be rich inpotassium, magnesium, calcium and fibers, and have a low amount of sodium, red meat,candy, sugar and sugary beverages.35Regarding diet composition, the 30 In addition, theindividuals analyzed can consume other foods that favor blood pressure reduction,such as whole grains, nuts, fish, poultry, and others rich in potassium, magnesium,calcium and fibers.35Regarding those characteristics of a healthy diet, it is worth noting that thepresent study quantified only total fat intake, following the trend of most studiesthat report separately only a few aspects of the diet. Thus, the result of thepresent study should be carefully considered, because a high total fat intake canhave a high proportion of poly- and monounsaturated fats, which are beneficial tohealth.11 while others have reported an inverse or nonexistentassociation.13The other variables assessed in the present study showed no association with highblood pressure, the literature being controversial about that. Regarding sex,studies have reported higher chances of high blood pressure in males,14Regarding age, absolute blood pressure levels increase with age in childhood andadolescence, but this seems not to imply increases in high blood pressure levels inthat age group.16 Nevertheless, a sedentarylifestyle established during childhood is known to strongly relate to a sedentarylifestyle in adulthood, increasing the susceptibility to the negative repercussionsof a sedentary lifestyle in the future, including high blood pressurelevels.36Considering the daily energy expenditure, the literature has shown no association ofphysical activity levels with high blood pressure levels.21 Rodrigues et al.,37 and Fernandes et al.38 have shown no significant association with highblood pressure in both sexes.Regarding cardiorespiratory fitness, Stabelini Neto et al.,16 and of bothsexes,10 because adose-time-response relation is known to exist between tobacco use and thedevelopment of related diseases, that is, the risk increases according to the numberof cigarettes smoked, especially, regarding the duration of the habit.39Regarding tobacco use, some studies have reported no association in young individualsof the male sex15 the lowestsocioeconomic levels,16 and, evenno association.13 According toConstanzi et al.,15 youngindividuals of higher socioeconomic levels would eat more and have a more sedentarylifestyle, increasing their chances of developing high blood pressure. Seabra etal.,40 however, havereported that individuals of the highest socioeconomic strata tend to practice morephysical activities than those less favored.Regarding socioeconomic status, the literature is controversial, showing anassociation of high blood pressure levels with the highest socioeconomiclevels,This study had some limitations, and their analysis can be important for futurestudies aimed at assessing blood pressure and its determinants. The first concernsthe study design, which had a cross-sectional data collection. This type of studycan have reverse causality, that is, exposure and outcome are collectedsimultaneously, making it difficult to determine which preceded the other.Another limitation concerns the self-reported variables , because they rely on the subjects' understanding about the variablesassessed. However, in large-scale studies those variables are extremely usefulbecause they provide the evaluation of several individuals in one single assessmentand because they are interesting alternatives when more precise measures cannot beused.The present study showed a high prevalence of high blood pressure in adolescents ofthe city of Curitiba. In addition, it evidenced that taking a second blood pressuremeasure minimizes the estimates of that outcome among adolescents, probably becauseof their familiarization with the measuring protocol. Nevertheless, the estimateswere greater than those of other Brazilian and international studies.A positive family history of arterial hypertension and increased waist circumferenceassociated with high blood pressure in adolescents. Therefore, special attentionshould be paid to young individuals with increased waist circumference, as well asto those with hypertensive parents. Those population subgroups should be the focusof public policies for blood pressure control in the young population, includingactions related to the lifestyle adopted in the school and family settings.


P > 0.05), and investigated the association of baseline CRP and oxLDL levels with the risk for vascular disease (VD) development  during prospective follow-up. Baseline CRP (1.2 [0.7–1.9] mg/L versus 1.1 [0.7–1.6] mg/L) and oxLDL levels (66.3 ± 21.2 U/L versus 57.1 ± 14.6 U/L) were higher in LAF patients (both P < 0.05). Following a median of 36 months, incident VD occurred in 14 (28.0%) LAF patients, all of whom developed arterial hypertension, and in 5 (11.4%) controls , P < 0.05. LAF patients developed VD more frequently and at a younger age. Both CRP  and oxLDL  were multivariate predictors of incident hypertension in LAF patients, but not in the controls. Further research should clarify clinical relevance of investigated biomarkers for risk stratification and treatment of LAF patients.We compared plasma levels of biomarkers of inflammation (CRP) and oxidation (oxLDL), determined at study inclusion in lone atrial fibrillation (LAF) patients  and sinus rhythm controls (49.7 ± 9.3 years; 72.7% men,  Lone atrial fibrillation (AF) is a term commonly used to denote AF occurring in a small subset (~3%) of patients without identifiable cardiovascular and extracardiac comorbidities or triggering factors , 2. WithCurrent evidence indicates that chronic low-grade inflammation in association with oxidative stress could represent a link between AF and  vascular disease –10. IncrThe aim of the present study was to evaluate the association of plasma biomarkers of inflammation (CRP) and oxidative stress (oxLDL) with the development of clinically evident vascular disease  in lone AF patients. We hypothesized that if there was a relation between lone AF, inflammation, and oxidative burden, (i) baseline plasma levels of CRP and oxLDL would be higher in lone AF patients compared to healthy controls in sinus rhythm and (ii) CRP and oxLDL could be associated with increased risk for the development of overt vascular disorders in a group of lone AF patients.Of 854 consecutive AF patients referred to the Outpatient Unit of the Cardiology Clinic, Clinical Center of Serbia, between May 2010 and August 2011, we prospectively enrolled 50 subjects (5.8%) with carefully characterized lone AF. We also included a control group of 44 healthy individuals in sinus rhythm, recruited among the hospital staff and acquaintances of AF patients. None of the participants had any evidence of underlying cardiovascular disorders (including hypertension) or extracardiac comorbidities. The study included patients with prior history of AF , as well as patients with newly diagnosed AF.2) were excluded. All participants were required to have normal findings on physical examination, including normal office (systolic BP <140 mmHg and diastolic BP <90 mmHg) and 7-day home BP measurements (systolic BP <135 mmHg and diastolic BP ≥85 mmHg) prior to the institution of any medications. Subjects with high-normal office BP (systolic BP 130–139 mmHg and/or diastolic BP 85–89 mmHg) were included if masked arterial hypertension was excluded by further ambulatory BP monitoring. Arterial hypertension was diagnosed if office BP measurement ≥140/90 mmHg, and/or home BP measurement ≥135/85 mmHg was found (and those subjects were excluded). Normal 12-lead ECG and transthoracic echocardiographic examination, including normal indexes of left atrial volume and left ventricular mass, without evidence of diastolic left ventricular dysfunction or valvular heart disease, were required for all participants. Subjects with symptoms suggestive of obstructive sleep apnea or chronic pulmonary disease were referred for further respiratory function examination. Subjects with symptoms indicative of myocardial ischemia were evaluated by stress-echo exercise testing, supplemented by coronary angiography if indicated. Participants suspected of having lower or upper extremities ischemia or cerebral hypoperfusion were referred for Doppler echosonographic examination to confirm peripheral arterial disease or carotid artery disease, respectively. Patients with a sudden-onset focal neurological deficit suspected of having a stroke or TIA were referred for neurological examination and imaging diagnostics. Peripheral arterial thromboembolism was defined as thromboembolic events outside the brain, retina, heart, or lungs. Pulmonary embolism was suspected in the presence of clinical symptoms, ECG, and laboratory findings and confirmed by computed tomography-pulmonary angiogram.Thorough evaluation of medical records, physical examination, office and home blood pressure (BP) measurements, 12-lead electrocardiogram (ECG), laboratory analyses, transthoracic echocardiographic examination, and chest radiography were performed in both AF patients and the controls at inclusion, while additional diagnostic assessments were performed when indicated. Subjects with prior cardiovascular disorders, stroke, transient ischemic attack (TIA), diabetes (fasting plasma glucose ≥7.0 mmol/L or 2 h postload plasma glucose ≥11 mmol/L), hepatic, renal, or thyroid dysfunction, systemic inflammatory disorders, malignancy, or obesity , ethylene-diamine-tetra-acetic acid-plasma samples were stored in multiple aliquots at −20°C until further analysis. Plasma oxLDL  was determined by commercially available enzyme-linked immunosorbent assay (ELISA). Intra- and interassay coefficients of variation for oxLDL were 6.8% and 7.1%, respectively. Determination of CRP was performed by immunonephelometric technique  with detection limit of 0.2 mg/L and a coefficient of variation of 4.7%. the first occurrence of any clinically manifest vascular disease  in a patient with initially lone AF or in a control group subject. Diagnostic criteria and medical procedures used to confirm the diagnosis of vascular diseases during follow-up were the same as at study inclusion and included assessments of patients' medical records during follow-up, physical exam, 12-lead ECG, and office and 7-day home BP measurements at each visit, supplemented by additional diagnostic tests if indicated . Vascular disease was confirmed when standard diagnostic criteria were satisfied. In patients with high-normal office BP at follow-up (systolic BP 130–139 mmHg and/or diastolic BP 85–89 mmHg), ambulatory BP monitoring was performed. Hypertension was diagnosed when either office BP ≥140/90 mmHg and/or home BP ≥135/85 mmHg was found or when 24-hour ambulatory BP of ≥130/80 mmHg was recorded. Control laboratory and echocardiographic exams were performed at 12-month intervals in all participants. Before the development of vascular disease, none of the participants received ACE inhibitors or dihydropyridine Ca2+ channel blockers, while statins were prescribed in subjects with elevated plasma cholesterol. In AF patients, vitamin K antagonists were used for the preparation for elective cardioversion. Once vascular disease was diagnosed, patients' treatment was reassessed in accordance with practice guidelines [Follow-up visits were performed by cardiologists at 3-month intervals or more frequently if required, and data on incident vascular disease were collected. A composite study end-point was defined asn) with percentages (%) for categorical variables. The differences between variables were tested by the two-tailed t-test, Mann-Whitney test, χ2 test, and Fisher test, respectively. Correlation between normally distributed or log-transformed variables was analyzed by Pearson's correlation.Data are presented as mean values and standard deviations for normally distributed continuous variables, medians, and interquartile ranges (25th–75th) for skewed variables and counts  curve, was used to assess the validity of the unadjusted and adjusted models of plasma biomarkers to predict the development of vascular disease during follow-up. Pairwise comparison of the ROC curves was also performed using DeLong approach (the z-statistic). A P value of <0.05 was accepted as statistically significant. Statistical analyses were performed using SPSS software, version 20 , or the MedCalc statistical software, version 12.7.0.0.The Baseline demographic and clinical characteristics of both study groups are presented in Comparison of baseline plasma levels of the investigated biomarkers revealed that both median CRP level and mean oxLDL level were significantly higher in lone AF patients than in healthy controls .R = 0.343, P = 0.040), as well as a positive correlation between both biomarkers and patients' age . OxLDL was also correlated with total- and LDL-cholesterol concentrations in AF patients , all P < 0.05. Positive correlations between CRP and oxLDL were also noted in the control group .In AF patients, there was a significant positive correlation between plasma levels of CRP and oxLDL  lone AF patients and in 5 (11.4%) healthy controls . Arteriaoversion . One AF oversion . The KapP < 0.05). There were no differences regarding other clinical, laboratory, or echocardiographic characteristics, including AF type, smoking habits, alcohol intake, or medications used during follow-up (not presented).In lone AF patient group, subjects with incident hypertension were older, had a longer history of AF, and higher baseline systolic and diastolic BP, BMI, fibrinogen, and total- and LDL-cholesterol plasma levels . All theOn univariate Cox proportional hazard analyses, both CRP and oxLDL were associated with increased risk for incident hypertension in lone AF patients, both as continuous variables (not presented) and per quartile increase . Both biP = 0.009, and 2.24 (1.14–4.40), P = 0.019, respectively.On multivariate Cox proportional hazard analysis, investigated biomarkers maintained their predictive significance for subsequent occurrence of hypertension in lone AF patients, with high discriminatory ability that was similar between models in pairwise comparison . MultivaP = 0.068) or oxLDL  with the risk for incident vascular disease in healthy controls.In the control group, predictors of vascular disease occurrence were older age, higher systolic and diastolic BP, and higher plasma total- and LDL cholesterol levels . On univIn the present study, we have demonstrated increased plasma levels of biomarkers of inflammation (CRP) and oxidative stress (oxLDL) in carefully characterized lone AF patients compared to healthy controls in sinus rhythm. We have also demonstrated that baseline plasma levels of CRP and oxLDL are associated with the risk for incident vascular disease (hypertension) during a median 3-year follow-up in lone AF patients, but not in healthy controls. Despite positive mutual correlations, both CRP and oxLDL were strong multivariate predictors for incident hypertension in our group of lone AF patients. Vascular disease occurred more frequently and at a younger age in lone AF patients than in healthy controls.Thus far, prognostic significance of biomarkers of inflammation and oxidative burden in lone AF has been demonstrated for arrhythmia perpetuation following cardioversion or catheter ablation , 13, 14.Although heterogeneous pathophysiological mechanisms may contribute to the development of lone AF, there is a considerable interest in the role of inflammation and oxidative stress as underlying mechanisms. Despite evidence of inflammatory atrial lesions  and incrWe have also found higher oxLDL levels in lone AF patients compared to the controls. Data on oxLDL in lone AF are sparse, but in a recent study, Kim et al. also reported increased plasma concentrations of oxidized lipoproteins in females with paroxysmal lone AF compared to healthy controls . The oriIn subjects without AF, several epidemiological studies have established an association of CRP with the occurrence of hypertension , 22 whilConsidering other variables associated with hypertension occurrence in lone AF patients in the present study, we have found that aging, longer AF history, higher baseline systolic and diastolic BP, higher serum cholesterol and fibrinogen levels, and increased BMI are linked with incident hypertension. Nevertheless, all of the listed variables were within reference limits acceptable for the healthy population and comparable to the healthy controls, except for higher fibrinogen levels and BMI in AF patients. Longer overall history of AF has been already linked to the risk for vascular disease development in lone AF, possibly due to longer exposition to as yet unrecognized causal or confounding factors .Earlier studies have reported occurrence of arterial hypertension in lone AF between 7.5% (after 7 years)  and 44% The most important limitation to the present study is a relatively small number of highly selected participants in both study groups, originating from a single ethnic background and from one referral center. Therefore, our results do not necessarily apply to all lone AF patients and should be reproduced in other groups of lone AF subjects before any general conclusions could be drawn. Biomarker determination has been conducted at a single time point at study inclusion and we have no information on possible changes in the levels of investigated biomarkers during the follow-up or whether these changes (if occurred) were pertinent to vascular disease development. Furthermore, only 2 highly correlated biomarkers have been evaluated, and adjustments have been conducted for the routine biochemistry parameters and clinical characteristics of study participants, while other possible confounding biochemical variables or risk factors might have been missed. Despite our meticulous efforts to include strictly lone AF patients, some cases with occult comorbidities, particularly latent arterial hypertension, might have been missed. Considering that we have not demonstrated an association of the investigated biomarkers with vascular disease development in the control group, no comparisons of their predictive abilities could have been made between lone AF patients and healthy controls.The present study showed that levels of circulating biomarkers of inflammation, CRP, and oxidative stress, oxLDL, are higher in lone AF patients compared to healthy individuals and that both biomarkers were associated with increased risk for incident hypertension in lone AF. Further research should better define pathophysiological role of these biomarkers in the development of AF and vascular disease and refine their clinical relevance in lone AF patients, particularly concerning risk stratification and therapeutic implications. Meanwhile, a regular clinical follow-up of lone AF patients should be routinely conducted in daily clinical practice.


P = 0.019) and liver of the 60s age group (P = 0.030). By SEM, the following biomedical factors were found to influence viscera: gender, diastolic blood pressure, and HDL-C for the liver; GLU, GOT, and γ-GTP for the spleen; age, BMI, and HCRP for the lungs; and HbA1c and creatinine clearance for the kidneys. These results provide objective evidence that FVS can be used for TCM diagnosis in middle-aged and elderly individuals.The five viscera score (FVS) is a diagnostic scale for traditional Chinese medicine (TCM). The purposes of current study are to elucidate the characteristics of FVS obtained from middle-aged to elderly individuals and to investigate the validity of FVS using biological medical data of middle-aged and elderly individuals. Structural equation modeling (SEM) was used to conduct assessments between FVS and medical data. Eighty men and 99 women participated in this study, whose mean ages (SD) were 58 ± 7 years in both genders showing no significant difference. FVS of women was significantly higher than that of men in the spleen of the 50s ( Acupuncture therapy is currently recognized as a complementary and alternative medicine (CAM) that is performed around the world, especially in East Asia . In ordeThat is why we developed a “five viscera score (FVS)” as a diagnostic scale for TCM. Items for this scale were statistically selected from the symptoms of the five viscera  that were extracted from key TCM literature from the past 2000 years –10. ThesStructural equation modeling (SEM) was used to conduct assessments between FVS and medical data. SEM is a method that uses a path diagram to analyze the relationship between various factors that exist behind the observed data . As mentSubjects included 212 individuals aged 40–65, who were residents of Wakayama Prefecture in Japan, underwent specific health checkups for metabolic syndrome, wished to participate in this study, and were able to attend the study site without assistance. Specific health checkups refer to a medical examination of individuals aged 40–74 who have public health insurance coverage. This study was conducted in August 2012 for 6 days. Consent was ultimately obtained from 189 individuals (89.2%), and the investigation was conducted in 179 individuals (84.4%). Ten individuals were excluded due to incomplete test values.This study was approved by the Genetic Analysis Research Ethics Committee at Wakayama Medical University (number 92) and by the Ethics Committee of Kansai Vocational College of Medicine (number H25- 01). The purpose of this study was explained to the subjects and only those who signed the consent form were allowed to participate. All individuals were assigned an ID and made anonymous. Test results were consolidated by a third party.r = 0.77), heart (r = 0.82), spleen (r = 0.82), lungs (r = 0.64), kidneys (r = 0.79), and overall (r = 0.91)).FVS is composed of viscera symptoms as defined in TCM  and usesThe items that were ultimately removed were selected by referring to previous studies that used both CTT and IRT, as described below. Items with the lowest factor loading within each subscale according to factor analysis  and itemγ-glutamyl transpeptidase (γ-GTP) (IU/L), red blood cell (RBC) (×104/uL), hematocrit (HCT) (%), systolic blood pressure (mmHg), diastolic blood pressure (mmHg), high-sensitivity C-reactive protein (HCRP) (mg/dL), urinary protein (mg/dL), albumin/creatinine ratio (ACR) (mg/gCr), and creatinine clearance (Ccr) (mL/min). The analyses were conducted at Osaka Kessei Research Laboratories, Inc.To investigate the relationship between health and FVS, which is a diagnostic scale of TCM, we used medical data including body mass index (BMI), blood pressure, and blood and urine test values. Subjects provided fasting venous blood and urine samples in the morning on the health checkup day. Test variables in the subjects' blood and urine include triglyceride (TG) (mg/dL), low-density lipoprotein cholesterol (LDL-C) (mg/dL), high-density lipoprotein cholesterol (HDL-C) (mg/dL), glucose (GLU) (mg/dL), hemoglobin A1c (HbA1c) (%), uric acid (UA) (mg/dL), glutamic oxaloacetic transaminase  (IU/L), glutamic pyruvic transaminase  (IU/L), Amos 19, a program for SEM by IBM, was used. All linkage strengths estimated in the path diagram (path coefficient) were approximation of the standardised partial regression coefficient with a mean of 0 and variance of 1; thus the results were not affected by units. The path diagram was constructed using the multiple indicator multiple cause model (MIMIC model) with the latent variable of five viscera positioned between observed medical data and FVS items . This MIR2), goodness of fit index (GFI), adjusted GFI (AGFI), comparative fit index (CFI), and root mean square error of approximation (RMSEA) were used as indices to determine the suitability of the overall model. GFI, AGFI, and CFI that are ≥0.90 and RMSEA that is ≤0.10 were deemed satisfactory.In addition, coefficient of determination . Differences of age distributions between the genders were evaluated by chi-square test. Although these statistical tests are nonparametric, mean values as well as their standard deviations (SD) were presented in tables to examine the floor and ceiling effects. For all statistical calculations, significant level was set at <0.05. However, P values less than 0.10 were regarded as statistically marginally or slightly significant since current purpose is to detect a broad range of biomedical factors (including even nonsignificant factors) that make any influence on the viscera.Since there is a gender difference in FVS , the ManP = 0.83).There were 80 men and 99 women participating in this study. Subject characteristics as well as medical data input into SEM are shown in P = 0.019) and liver of the 60s age group (P = 0.030), and similar tendency was also observed in the kidneys of 60s age group (P = 0.075) though not reaching statistically significant level. In the entire sample, women also showed greater FVS excluding the lungs, and significant differences were observed in the liver (P = 0.019) and spleen (P = 0.032).Using SEM, a model specification search was carried out for each viscus in order to identify observed variables  on the left side that significantly influence the latent variable (viscera). Medical data that were input for each subscale of FVS created 262,144 combinations for analysis, and the most suitable model was used.γ-GTP, BMI, diastolic blood pressure, and HCRP in the spleen; age, BMI, and HCRP in the lungs; and HbA1c, creatinine clearance, and HCRP in the kidneys.The coefficients of determination of the model were 0.182 for the liver, 0.026 for the heart, 0.348 for the spleen, 0.155 for the lungs, and 0.092 for the kidneys, indicating that the spleen had the highest value. Medical data that had significant (or slightly significant) influence on viscera were gender, HbA1c, diastolic blood pressure, HCRP, and HDL-C in the liver; age in the heart; gender, age, GLU, GOT, γ-GTP (−0.290) for the spleen; age (−0.252), BMI (0.188), and HCRP (0.181) for the lungs; and HbA1c (−0.193) and creatinine clearance (0.153) for the kidneys. No items were selected for heart.Furthermore, in order to elucidate items that especially affect the viscera, we selected items from the above list with high path coefficients that did not overlap other viscera  and determined them to be distinctive items. This procedure was conducted to extract factors that make influences on the viscera most strongly. In other words, such items are considered to be well representative of the viscera's characteristics. Since the path coefficients were standardized as mentioned above, they were comparable to each other. Distinctive items that influenced the viscera as well as their path coefficients were gender (0.273), diastolic blood pressure (0.178), and HDL-C (−0.131) for the liver; GLU (−0.223), GOT (0.312), and The path coefficients from the latent variables (viscera) to the FVS items on the right side were as follows: for the liver, “I have a stiff neck” (0.857), “I have a pulled muscle in my neck” (0.892), and “I have a backache” (0.612); for the heart, “I worry about many things” (0.883), “I worry frequently” (0.942), and “I have a lot on my mind and am not able to enjoy anything” (0.716); for the spleen, “I am fatigued and this is not alleviated by anything” (0.802), “I have to lie down due to fatigue” (0.719), and “My body feels heavy” (0.870); for the lungs, “My stomach rumbles” (0.690), “I feel hungry constantly” (0.640), and “I have a runny nose” (0.271); and for the kidneys, “I am absent minded” (0.858), “I am not energetic” (0.752), and “My memory has deteriorated” (0.513). With the exception of “I have a runny nose” in the lungs, the path coefficients were greater than 0.5, indicating that FVS items are strongly influenced by latent viscera.To test the validity of FVS in middle-aged and elderly individuals, we investigated the characteristics of FVS as well as the relationship between medical data  and FVS using SEM with the MIMIC model. The results indicated that the characteristics showed gender differences, consistent with previous findings, and SEM showed a lot of the medical data influencing the viscera.FVS by age group showed that women in their 50s and 60s had higher scores, and this was consistent with a previous study that reported the relationship between different genders in 594 young to middle-aged individuals . For FVSConcerning subjective health status, the Medical Outcome Study Short-Form 36-Item Health Survey version 2 (SF-36), an evaluation scale that is used globally, and Japanese national standard values of this SF-36 have been reported . Here, aγ-GTP for the spleen; age, BMI, and HCRP for the lungs; and HbA1c and creatinine clearance for the kidneys. Gender and diastolic blood pressure positively influenced the liver; however, perhaps due to the narrow age range (middle-aged to elderly) of the subjects, diastolic blood pressure and age were not correlated with each other . In addition, HDL-C, which is related to atherosclerosis, had a negative influence on the liver. Since the heart represents mental activity in TCM [γ-GTP, which are both related to the liver (digestive organ), had positive and negative influence, respectively, on the spleen symptoms. Age had a negative influence on the lungs, indicating stronger symptoms in the younger age group, and HCRP has a positive influence. These facts suggest that this was an inflammatory response to conditions such as infections. In addition, the elevation in BMI indicated obesity, which is a risk factor of many kinds of lifestyle-related diseases, and this was also thought to promote inflammation. HbA1c had a negative influence on the kidneys, suggesting that blood sugar and red blood cells were involved in the mechanism. In addition, creatinine clearance had a positive influence. These items had path coefficients that were not very high, while they included marginally significant influences.SEM showed that many of the biomedical factors influenced viscera with the most distinctive items being gender, diastolic blood pressure, and HDL-C for the liver; GLU, GOT, and y in TCM , lack ofBecause the viscera in TCM are comprehensive concepts that not only possess morphological aspects, but also entail functional aspects, the influence from medical data to the viscera is restrictive. Furthermore, gender and age were both input compulsorily, thereby lowering the coefficient of determination and the goodness of fit of the model.γ-GTP.Most of the items in FVS are unidentified complaints. In both Western medicine and TCM, unidentified complaints are crucial to disease prevention; thus it was clinically important that there was an association between the medical data based on Western medicine with TCM. Moreover, it is noteworthy that the specific related medical data fit the descriptions of viscera characteristics in TCM textbooks as shown below . The livγ-GTP observed in the spleen. These may be partially due to the cross-sectional characteristics of the current study. Prospective clinical cohort study will be necessary to resolve this inconsistency. However, as mentioned earlier, it should be noted that the FVS is created based on the TCM theory and does not reflect the clinical characteristics of corresponding anatomical internal organs.The lung systemically circulates Qi and bodily fluids . Stagnation leads to the development of edema. In addition, invasions by the common cold ) are likely to occur. Hence, the lung is considered to be associated with factors related to obesity and inflammation, such as BMI or HCRP, which might reflect the spleen disorder rather than lung disorder by the TCM criteria. However, since FVS is a newly created scale as mentioned earlier, some of which might be inconsistent with the TCM literature. The kidney is supplemented by the energy created from foods and drinks. In addition, it eliminates liquids that are no longer necessary as urine. Therefore, the kidney is considered to be associated with factors related to blood sugar or renal function such as HbA1c or creatinine clearance. Because kidney and spleen dysfunction is attributed to diabetes, it is unclear why GLU and HbA1c were negatively associated with spleen and kidney as well as the discrepancy between GOT and In a TCM study of hypertension, Wu et al. discovered two biomarkers from diagnostic standards of multiple TCM syndromes and reported that these are useful for classifying and discriminating TCM syndrome . Here, wIn a study of TCM diagnosis presented in 2012, Wang et al. reported that SEM is an effective method . SEM is In TCM, patients are typically diagnosed in a comprehensive manner using four methods: “observation,” “auscultation and smell,” “inquiry,” and “palpation” . TherefoWe found gender differences of FVS and identified several biomedical factors that significantly influenced viscera by application of structural equation modeling. The current findings suggest that FVS can be useful for TCM diagnosis incorporated with Western medicine in middle-aged and elderly individuals.


Blood pressure measurement in clinical care settings seldom follows the protocol recommended by national guidelines, potentially leading to overestimates or underestimates of blood pressure control. We evaluated blood pressure measurement methods as a source of bias in determining blood pressure control among community-dwelling adults with diabetes.In a community-based trial of patients with diabetes, we measured both “clinical blood pressure”   and “research blood pressure” (research BP) (research staff followed a guideline-concordant protocol). Each participant had both types of blood pressure assessment on the same day over the course of 2 hours.P < .001) and 2 mm Hg higher for diastolic blood pressure (P < .001). The proportion of participants whose clinical BP was 130/80 mm Hg or higher was 8 percentage points higher than the proportion whose research BP was 130/80 mm Hg or higher (P < .001), and the proportion whose clinical BP was 140/90 mm Hg or higher was 10 percentage points higher than the proportion whose research BP was 140/90 mm Hg or higher (P < .001). Among those aged 65 years or older, the proportion whose clinical BP was 130/80 mm Hg or higher was 10 percentage points higher than proportion whose research BP was 130/80 mm Hg or higher, and the proportion whose clinical BP was 140/90 mm Hg or higher was 14 percentage points higher than the proportion whose research BP was 140/90 mm Hg or higher. Whites and smokers had the greatest risk for having a clinical BP 5 mm Hg or more higher than their research BP.The 227 participants had a mean age of 59 years; 86% were black and 74% were women. The mean clinical BP was 5 mm Hg higher than the mean research BP for systolic blood pressure (Measurement biases in clinical settings may be a component of observed poor blood pressure control rates in real-world settings. High blood pressure is a cause of major illness and death in the United States. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) established guidelines for the accurate measurement of blood pressure to aid in diagnosis and clinical management ,2. HowevSome evidence supports the possibility that poor adherence to the JNC-7 guideline may lead to systematic blood pressure biases. In a study comparing specific equipment to usual approaches, patients with hypertension had 8.3 mm Hg higher readings when assessed using usual approaches, and 21% more were classified as having uncontrolled hypertension . BecauseWe conducted a study designed to establish the average size and direction of measurement errors due to incorrect protocols for blood pressure measurement that might occur in routine clinical practice, and we sought to identify which groups would be most vulnerable to such errors. Because high blood pressure is more common in older people and because the Centers for Medicare and Medicaid Services has interest in optimizing quality and costs of care, we examined findings overall and by age (<65 years or ≥65 years). We used both the recommended diabetic blood pressure target of 130/80 mm Hg and a more broadly applicable target of 140/90 mm Hg in our analyses  study, a group-randomized pragmatic trial of the effect of community peer advisors on diabetes outcomes. The details of recruitment and data collection are provided elsewhere ,7. BriefBlood pressure was measured during the biometrics assessment. Other data collected included height, weight, and waist circumference, and blood was collected by a finger stick. The atmosphere of the data collection area was therefore similar to a busy clinical setting.Two methods of measuring blood pressure were used, and each participant received 1 measurement from each method. The clinical BP was assessed by registered nurses or medical assistants who worked at local clinics or medical facilities. They were instructed to “take the participant’s blood pressure like you do in your own clinic.” They were provided an automated LifeSource blood pressure monitor model UA-789 , 3 blood pressure cuffs , a chair, and a table on which participants could rest their arms. They were not trained in the research BP protocol (described below). A single BP reading was taken and recorded. Clinical BP and research BP assessments were done in physically separate areas, and staff performing these measures were asked not to interact to minimize contamination. Clinical BP staff was not formally monitored, but casual observation indicated that participants were generally seated with the arm resting on the table to obtain the blood pressure measurement.In comparison, study staff were specifically trained in research BP measurement methods by using a protocol that closely followed JNC-7 recommendations  using thBefore taking the research BP measurement, participants’ right arms were bared to the shoulder, and they stood with the right elbow bent 90 degrees at the elbow with the hand on the stomach. Arm length was measured from the acromion to the olecranon process using a Gulick II Plus anthropometric tape measure . The midpoint of the arm was marked with an eyebrow pencil. The participant relaxed the arm, and the arm circumference was measured horizontally at the midpoint mark by using the tape measure (to ensure the tape measure was at the proper tension). The appropriate size blood pressure cuff was used based on the arm circumference .The participant was then seated comfortably in a chair with back support and both feet flat on the floor. The participant’s brachial artery was marked with the eyebrow pencil. The cuff was placed snugly on the arm with the inflatable inner bladder centered over the brachial artery and the lower edge of the cuff about 1 inch above the natural crease of the elbow. After the cuff was properly placed, the participant was instructed to sit quietly without talking, eating, completing paperwork, or crossing his or her legs for 5 minutes. Research BP personnel used timers to ensure a full 5-minute rest. Blood pressure was then measured with the automated monitor and, after a 1-minute rest time, blood pressure measurement was repeated. The average of the 2 readings constituted the research BP.All participants in this study had research BP assessed after the clinical BP, because we anticipated that measuring research BP before clinical BP would lead to similar levels of blood pressure and that the true biases between the methods would not be discernible. We anticipated that measurement order could affect results, as the effect of quietly resting in the research BP protocol could artificially impact the clinical BP measurement that followed. To confirm this suspicion, we assessed the research BP before the clinical BP in a separate 180 participants, and blood pressure levels were not significantly different.t tests. The proportions that were classified as having uncontrolled high blood pressure  were compared by using the χ2 statistic. Participants were divided into 2 groups, one having an increase of 5 mm Hg or more in the clinical BP compared with the research BP and the other having less than 5 mm Hg increase in clinical BP compared with research BP. Participant characteristics including age, race, sex, and risk factors  were compared in these 2 groups, using an unadjusted odds ratio. Variables with bivariate associations with P < .20 were included in a multivariable model predicting factors associated with having an increase of 5 mm Hg or more in the clinical BP compared with the research BP. All analyses were conducted using SAS v9.2 (SAS Institute Inc). Test results were considered significant at P < .05.Mean systolic and diastolic blood pressures obtained using clinical BP measurement and research BP measurement were compared using The study sample had 227 participants with diabetes . Their mP < .001) (P < .001) (P < .001)  . On the  < .001) . On the  < .001) . Half (5 < .001) .P < .001), and the mean diastolic clinical BP was 3 mm Hg higher than the mean diastolic research BP  (P < .001) and the 140/90 mm Hg cutoff   . The pro = .001) .P = .05). Current smokers had greater odds than nonsmokers . Men had higher odds than women, but this difference was not significant , and educational level was not significantly associated.In this study of 227 community-dwelling adults with diabetes, we found that blood pressure measured following typical approaches used in physician offices resulted in higher blood pressure assessments for most patients compared with measures obtained using the same equipment but closely following JNC-7 recommendations. We found that 8% to 10% of patients who would be considered to have uncontrolled high blood pressure by the clinical measurement actually had adequately controlled blood pressure by the research measurement. These results have implications for clinical management, quality assessments, performance-based reimbursement programs, and costs to patients and insurers.Our findings suggest that common measurement approaches in real-world clinical settings tend to overestimate blood pressure, increasing the diagnosis of uncontrolled hypertension. Measurement biases in clinical settings may be a component of low rates of blood pressure control. We found that using incorrect protocols overestimated true systolic blood pressure levels on average by the same amount hypothesized in the 2002 NIH report (5 mm Hg) . Using tIn addition to the effect on cost, reducing bias in blood pressure measurement may improve treatment burden, side effects, and quality of care measures. A recent study concluded that lowering systolic blood pressure below 120 mm Hg in diabetic patients did not improve cardiovascular outcomes and resulted in more adverse events, further emphasizing the importance of accurate blood pressure measurement .Our results show that several groups are significantly more likely to have increased elevation of systolic blood pressure with clinical BP measures. Whites, current smokers, and those with controlled blood glucose were all significantly more likely to have 5 mm Hg or more higher systolic clinical BP compared with research BP. Men may also be more likely to have higher clinical BP compared with women. It is unclear why these groups were most affected by poor measurement technique, but each represents a group that could benefit from closer attention to blood pressure monitoring technique.The implications of incorrect blood pressure assessment protocols may be most important for those aged 65 or older, among whom hypertension is most prevalent. In our study, the proportion of people aged 65 or older incorrectly classified as having uncontrolled high blood pressure was 10 to 14 percentage points higher, depending on the threshold considered. Inaccurate diagnosis of uncontrolled hypertension has substantial implications in the older population, including unnecessary polypharmacy and medication interactions, increased fall risk due to hypotension, side effects of medications, increased medication cost, and patients’ frustrations and sense of failing medical treatment .Limitations to our study include its modest size in a mostly black sample with diabetes, which may limit generalizability. The local medical staff hired to measure clinical BP may not accurately represent other groups of medical staff with regard to blood pressure measurement technique and knowledge of the recommended measurement protocol. However, our study was able to show overestimation of uncontrolled high blood pressure even for the higher threshold of 140/80 mm Hg for people without diabetes. Furthermore, our population, composed of primarily minority participants with diabetes, is a high-risk group especially vulnerable to adverse cardiovascular events; thus, accurate blood pressure measurement and appropriate treatment are vital. Blacks in general are more susceptible to diabetes and hypertension and are an important study population. It is common in clinical settings to measure blood pressure with patients sitting on an examination table, with legs dangling and the arm unsupported. Our findings may therefore be conservative.P = .005. Future studies could help clarify the correlation strength and possible cause of why whites tend to be more affected by blood pressure measurement bias.Because of our intentionally predominantly black study population, we did not have a large white population for comparison. Only 8 participants were both white and had a clinical BP that was less than 5 mm Hg higher than research BP. However, racial correlation with increased bias was still significant at Methods used to assess blood pressure in typical clinical settings may overestimate true blood pressure levels that are assessed in concordance with JNC-7 recommendations, especially among older people. Groups such as whites and smokers may be at higher risk for this measurement bias, and these groups warrant future studies and attention. The magnitude of the overestimate is clinically important both for clinical management and quality assessment. Billions of dollars could potentially be saved annually, and patients could be spared adverse effects from medication with closer adherence to guideline-recommended approaches to blood pressure assessment.