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Relationship of Resistant Hypertension and Treatment Outcomes With

Relationship of Resistant Hypertension and Treatment Outcomes With
Relationship of Resistant Hypertension and Treatment Outcomes With

ORIGINAL PAPER

Relationship of Resistant Hypertension and Treatment Outcomes With Total Arterial Compliance in a Predominantly African American

Hypertensive Cohort

Omid Bakhtar,DO;1Brian A.Ference,MD,MPhil,MSc;1,2Lowell A.Hedquist,BS;1,2Phillip D.Levy,MD,MPH;3

John M.Flack,MD,MPH1,2

From the Department of Internal Medicine;1the Division of Translational Research and Clinical Epidemiology,Department of Internal Medicine;2 and the Department of Emergency Medicine and Cardiovascular Research Institute,Wayne State University School of Medicine,Detroit,MI3

Resistant hypertension(RH)affects8%to30%of hyper-tensive patients.Blood pressure(BP)re?ects the interac-tion between vascular compliance,resistance to?ow, intravascular volume,and cardiac contractility.The rela-tionship of RH with total arterial compliance index(TACI) has not been adequately explored.The RH period preva-lence(RH at baseline or follow-up)was determined in a hypertensive cohort(N=156)and compared across quar-tiles of TACI.Age-and sex-adjusted systolic BP,diastolic BP,and antihypertensive therapeutic intensity score(TIS) were also determined at the time of?rst BP control.The cohort was85.3%African American and67.3%female. Median follow-up was7months.The prevalence of RH at baseline was14.7%while the period prevalence was 43.6%.The period prevalence of RH by ascending quar-tile for TACI was66%,36.8%,40%,and30.8% (P=.008).The average BP and antihypertensive TIS at ?rst BP control across TACI quartiles was122.3?73.4 mm Hg(2.26),120.7?72.5mm Hg(1.88),122.4?75.3mm Hg(1.71),and120.0?79.4mm Hg(1.64)(P=.62,P=.03, P=.13).Low TACI was linked to higher RH prevalence and antihypertensive TIS at?rst attainment of goal BP according to the Joint National Committee on Prevention, Detection,Evaluation and Treatment of High Blood Pres-sure.TACI provides prognostic information that is clini-cally and perhaps pathophysiologically relevant in RH. J Clin Hypertens(Greenwich).2012;14:618–622.ó2012 Wiley Periodicals,Inc.

Resistant hypertension(RH)affects a substantive pro-portion of the hypertensive population.1,2Detecting RH is important,in part,because approximately20% of patients have primary aldosteronism(PA)or other forms of secondary hypertension.3,4Despite signi?cant polypharmacy,a subset of individuals with RH exhibit persistently poor blood pressure(BP)control resulting in a high risk of cardiovascular morbidity.5–8 Measured BP represents an interaction between vascular compliance,resistance to?ow,intravascular volume,and ventricular contractility.Impedance cardi-ography(ICG;BioZ,Cardiodynamics,Davis Medical Electronics,Inc,Vista,CA)is a validated modality for obtaining various noninvasive hemodynamic measures.9–11

The existing understanding of the ICG-derived he-modynamic parameters in individuals with persistently elevated BP,particularly in those with RH,is limited. Accordingly,we sought to determine whether noninva-sive measures of vascular function were re?ective of BP control rates as well as the intensity of antihyper-tensive drug therapy needed to achieve BP target levels as de?ned by the Seventh Report of the Joint National Committee on Prevention,Detection,Evaluation,and Treatment of High Blood Pressure(JNC7).12We hypothesized that vascular compliance would relate inversely to the risk of RH as well as directly to the intensity of antihypertensive drug therapy at the time of JNC7BP control.

METHODS

Study Design and Population

We conducted a retrospective cohort study of156hyper-tensive patients seen between January2007and July 2009in the Wayne State University(WSU)Physician Group hypertension clinic after study approval by the WSU Human Investigations Committee.Clinic patients were eligible for inclusion in the study if they had suc-cessful ICG testing(noninvasive vascular measurements) as well as at least two follow-up clinic visits(or at least one follow-up clinic visit if they attained their JNC7BP target goal).The median participant observation period was7months(5clinic visits).

For each patient included in the study,we obtained de-identi?ed information for age,sex,race,body mass index(BMI),BP measurements,prescribed antihyper-tensive medications,ICG hemodynamic measurements, and laboratory values(B-type natriuretic peptide,spot urine albumin:creatinine ratio,and serum creatinine) from an electronic medical record(EMR).

All laboratory analyses were performed in the Detroit Medical Center central laboratory.Random urine specimens were analyzed for albumin by rate

Address for correspondence:John M.Flack,MD,Division of Translational Research and Clinical Epidemiology,Department of Internal Medicine,Wayne State University School of Medicine,4201St.Antoine, 2E-UHC,Detroit,MI48201

E-mail:j?ack@https://www.doczj.com/doc/4e9257650.html,

Manuscript received:February24,2012;revised:March19,2012; accepted:March21,2012

DOI:10.1111/j.1751-7176.2012.00653.x

nephelometry and creatinine content using a modi?ca-tion of the kinetic Jaffe reaction.Serum creatinine was determined by the Vitros Crea Slide method.

At each clinic visit,BP was measured with an oscil-lometric sphygmomanometer using an appropriately sized manually in?atable cuff.At the initial clinic visit, BP measurements were taken in both arms in the seated position.The arm with the highest recorded BP was documented in the EMR and used for compara-tive BP measurement at subsequent visits. Impedance cardiography is a noninvasive procedure that analyzes changes in electrical impedance using4 sensors placed on the patient’s body.These measure-ments were performed,typically at the beginning of a clinic visit,by trained clinic personnel using a BioZ ICG monitor with the patient in a supine position after 5minutes of rest.13The ICG recording date was con-sidered the index clinic visit in our analyses even if the patient had prior clinic visits.A total of147patients (94%)underwent ICG testing during their?rst visit to our clinic;another9patients underwent ICG testing at a subsequent clinic visit.There were no selection crite-ria used for ICG testing.Patients were tested consecu-tively unless the ICG machine?technician was not available during their initial visit.

For patients with diabetes mellitus and?or chronic kidney disease(CKD)(estimated glomerular?ltra-tion rate[eGFR]<60mL?min?1.73m2as calculated by the Modi?cation of Diet in Renal Disease formula and?or spot urine albumin:creatinine ratio>200mg?g), hypertension was de?ned as systolic blood pressure (SBP)!130mm Hg and?or diastolic blood pressure (DBP)!80mm Hg and?or taking antihypertensive medication.In all other patients,hypertension was de?ned as SBP!140mm Hg and?or DBP!90mm Hg and?or taking antihypertensive medication.

RH was de?ned as patients having BP above their JNC7goal level despite the use of!3optimally dosed antihypertensive medications from different classes with at least one of the drug classes being a diuretic or patients with BP less than their JNC7goal who were taking!4optimally dosed antihypertensive medica-tions,one of which was a diuretic.Optimal antihyper-tensive drug dosing was de?ned as each antihypertensive drug class being taken in a daily amount equivalent to at least50%of the maximum Food and Drug Administration(FDA)–approved daily dose for hypertension treatment.There were several important exceptions.First,chlorthalidone and spirono-lactone were both considered adequately dosed at 25mg?d.Second,spironolactone was considered an aldosterone antagonist;thus,its utilization did not sat-isfy the requirement of taking a diuretic.The period prevalence of RH was the number of patients with RH at the index visit or at any time during follow-up divided by the number of total patients meeting study entry cri-teria times100or(RH number?total number)?100. Period prevalence was calculated because a signi?cant number of patients developed RH after their initial visit

because their medication doses and drug classes were optimized,including the prescription of diuretics.

The antihypertensive therapeutic intensity score

(TIS)was based on the antihypertensive drugs pre-scribed at least2weeks prior to a clinic visit.The

class-speci?c antihypertensive TIS was calculated by

dividing the daily dose of a medication by the maxi-mum daily dose of the drug approved by the FDA for

the treatment of hypertension.When multiple antihy-

pertensive drug classes were prescribed,the class-speci?c antihypertensive TIS scores were summed into

an overall antihypertensive drug TIS score.

TACI in mL?m2?mm Hg was calculated by dividing stroke index by pulse pressure(PP):(1)stroke volume (SV)(mL):the volume of blood delivered to the vascu-

lature in one heart beat;(2)stroke index(SI)(mL?m2):

the SV indexed to body surface area(BSA)or SI=SV?BSA;(3)BSA(m2)was estimated by the DuBois

and DuBois formula BSA=weight0.425?height0.725?0.007184;(4)heart rate(HR)(beats per min):the number of heart beats in1minute;(5)cardiac output

(CO)(L?min):the total volume of blood pumped by

the heart in1minute or CO=SV?HR;(6)cardiac index(CI)(L?min?m2):the CO indexed to BSA or CI=CO?BSA;and(7)PP(mm Hg)=SBP)DBP. Analytical Methods

Descriptive statistics were generated using baseline

characteristics of patients,including age,sex,race,and

BP.Continuous variables were summarized as means and standard deviations or as medians and interquar-tile ranges(IQRs).Categorical variables were tabu-lated as frequencies.TACI was divided into quartiles. The period prevalence of RH,JNC7BP control rates, antihypertensive TIS,and attained BP level at the time of JNC7BP control were determined for each TACI quartile.Spearman rank order correlation coef?cients were used to explore the relationships between TACI, systemic vascular resistance index(SVRI),thoracic ?uid content(TFC),and CI.

Logistic regression models were utilized to estimate

odds ratios(ORs)for RH with adjustment for age and

sex.For clarity of presentation,we transformed the log odds of disease within each quartile into a pre-dicted probability.14Age-and sex-adjusted probabili-ties of RH and JNC7BP control rates were calculated for each TACI quartile using the following formula: 1?(1+e-(bo+bx)).The mean antihypertensive drug TIS score as well as the age-and sex-adjusted SBP and DBP averages at the time of attainment of the JNC7 target BP level across TACI quartiles were assessed for heterogeneity with analysis of covariance.Dunnett’s t test was used to contrast these means,respectively,in the lower three quartiles relative to the mean in the reference(highest)quartile4.All mean and frequency contrasts were deemed signi?cant when the two-tail P value was<.05.Statistical analyses were performed using SAS statistical software(SAS version9.2;SAS Institute,Cary,NC).

Resistant Hypertension Risk and Arterial Compliance|Bakhtar et al.

RESULTS

The cohort was largely African American and mostly female with average baseline BP in the JNC stage 1hypertensive range (Table I).The median cohort fol-low-up was 7months.The prevalence of RH at base-line was 14.7%(23of 156).However,the RH period prevalence during a median follow-up of 7months was several-fold higher (43.6%)after optimization of antihypertensive drug therapy regimens.

The period prevalence of RH was approximately twice as great in the lowest compared with the highest TACI quartile (Table II).A total of 113(72.4%)patients achieved their JNC 7BP target during follow-up.Table III displays the age-and sex-adjusted proba-bilities of BP control by TACI quartile.There were no signi?cant differences in BP control across TACI quar-tiles.Furthermore,the average SBP level attained dur-ing treatment among patients who did reach their JNC 7BP goal was not in?uenced by TACI levels (data not shown).However,attained DBP at time of ?rst BP control was directly related to the TACI quartile (Table IV).Similarly,the average antihypertensive TIS at the time of attainment of JNC 7BP goal did not differ signi?cantly across TACI quartiles,although the difference between quartiles 1and 4was statistically different.

All possible correlations between TACI,TFC,SVRI,and CI were explored.TACI was negatively correlated with SVRI ()0.65,P <.0001)but positively correlated with CI (r =0.58,P <.0001).SVRI was negatively related with CI (r =)0.87,P <.001).None of the other correlations were statistically signi?cant.

DISCUSSION

Our analysis demonstrates several new as well as clini-cally signi?cant observations.TACI was related to the period prevalence of RH as well as to the intensity of antihypertensive drug therapy necessary to achieve JNC 7BP control.This observation extends those of Abdelhammed and colleagues 15who showed that TACI was lower in individuals with stage 2compared with stage 1hypertension.The observation that TACI

TABLE I.Patient Characteristics

Characteristic Overall No Resistant

HTN Resistant HTN Patients,No.(%)156(100)88(56.4)68(43.6)Age,y 54.153.654.8Sex

Female,%105(67.3)65(73.9)40(58.8)Male,%51(32.7)23(26.1)28(41.2)Race

African American,%

133(85.3)73(82.9)60(88.2)Non-African American,%23(14.7)15(17.1)8(11.8)BMI,kg ?m 2

32.431.234.0Blood pressure,mm Hg Systolic 153.1147.7160.0Diastolic

91.891.891.9Antihypertensive drugs 2.4 1.8 3.1Antihypertensive TIS 1.40.9 2.0Estimated GFR,

mL ?min ?1.73m 2

80.984.776.0Total arterial compliance index,mL ?m 2

?mm Hg

0.680.740.59Systemic vascular resistance index,dyne s ?cm 5m 2

3352.83067.53722.1Thoracic ?uid content,?kOhm 26.826.427.4BNP,pg ?mL

100.9

100.9

100.8

Abbreviations:BMI,body mass index;BNP,B-type natriuretic pep-tide;GFR,glomerular ?ltration rate;HTN,hypertension;TIS,thera-peutic intensity score.Patient characteristics were determined from the impedance cardiography visit data.Resistant hypertension categories were based on the period prevalence of resistant hypertension.

TABLE II.Prevalence of Resistant Hypertension by

TACI Quartile

TACI Quartile Crude Period Prevalence Adjusted a Period Prevalence 1(0.15–0.44)66.7%67.3%2(0.45–0.66)36.8%38.1%3(0.67–0.85)40.0%42.3%4(0.86–1.84)30.8%44.3%P value

.01

.02

Abbreviation:TACI,total arterial compliance index.a Adjusted for age and sex.

TABLE III.JNC 7BP Control Rates a by TACI

Quartile TACI,mL ?m 2?mm Hg

158.1%279.4%382.0%466.4%P value

.21

Abbreviations:BP,blood pressure;JNC 7,the Seventh Report of the Joint National Committee on Prevention,Detection,Evaluation and Treatment of High Blood Pressure;TACI,total arterial compli-ance index.a Adjusted for age and sex.

TABLE IV.Antihypertensive TIS a and Attained BP a at

Time of BP Control by TACI Quartile

TACI Quartile Attained BP,mm Hg

Systolic Diastolic Antihypertensive TIS

1(0.15–0.44)122.373.4b 2.26b 2(0.45–0.66)120.772.5b 1.883(0.67–0.85)122.475.3b 1.714(0.86–1.84)120.079.4 1.64P value (f test)

0.62

0.03

0.13

Abbreviations:BP,blood pressure;TIS,therapeutic intensity score.a

Adjusted for age and sex.b P <.05relative to total arterial compli-ance index (TACI)quartile 4.

Resistant Hypertension Risk and Arterial Compliance |Bakhtar et al.

was inversely related to RH risk might be explained by data that strongly suggest that RH is exquisitely salt sensitive16and that the vasculature is abnormal in persons manifesting salt sensitivity.Accordingly,the peripheral arterial vasculature appears to be important in the chronic phases of salt sensitivity as salt-sensitive African Americans almost uniformly develop raised peripheral vascular resistance in response to dietary sodium intake.17Indeed,our data showed a strong negative correlation between SVRI and TACI.Given the much higher SVRI in those who had or developed RH as well as the strong inverse relationship between SVRI and TACI,we surmise that reduced arterial com-pliance is a likely vascular perturbation in salt-sensi-tive RH.This observation is consistent with the Bayliss theory of1902,18whereby high BP causes increased muscular tone of the vasculature,?rst on a myogenic then likely on a structural established basis. Nevertheless,we cannot exclude the possibility that reduced total arterial compliance preceded the BP ele-vation and was an important causative factor in such elevations.

An interesting observation in our study was the marked increase in the prevalence of RH over time in our cohort.The marked rise in RH over follow-up, despite incrementally lower BP over time,was almost assuredly the result of our judicious use of diuretics as well as the uptitration of antihypertensive agents that were suboptimally prescribed at baseline.

We are unaware of other studies that have explored the relationships between noninvasive measures of vas-cular function and the risk of RH over an extended period of follow-up.We are also unaware that any noninvasive measure of vascular function has been linked to either the likelihood of BP control or to the intensity of antihypertensive drug therapy utilized at the time of BP control.

STUDY STRENGTHS

Our study had several strengths.First,it was not exclusively cross-sectional as there was longitudinal follow-up of our cohort over an extended period. Therapeutic decisions were also made either directly or overseen by a hypertension specialist as certi?ed by the American Society of Hypertension(ASH).The noninvasive hemodynamic parameters were not uti-lized in any systematic way to select antihypertensive drug therapy.We also utilized a very rigorous de?ni-tion of RH that speci?ed optimal diuretic use and that all other antihypertensive agents(except chlorthali-done and spironolactone)were utilized in doses equiv-alent to at least50%of their FDA-approved maximal daily dose.Finally,there was no conscious selection bias regarding whether patients did or did not undergo noninvasive vascular testing.

LIMITATIONS

Nevertheless,our study does have limitations.It was derived from a largely African American and female

cohort precluding extrapolation to non-African Ameri-cans and men.Additionally,our patient cohort arose largely from a referral population that was speci?cally sent to our clinic for dif?cult to control hypertension. Thus,our?ndings are not directly applicable to pri-mary care or other nonreferral clinical settings.Fur-thermore,we did not differentiate between those who did and did not achieve JNC7BP target levels as long as they met the diagnostic criteria for RH.Finally,our overall sample size was small and therefore probably lacked the statistical power to con?rm some of the numerical trends observed in our data.

Although not standard practice,impedance cardiog-raphy has repeatedly been shown to be a valuable instrument in the management of hypertension.19–21 Smith and coworkers22demonstrated improved BP control with ICG-guided compared with non–ICG-guided https://www.doczj.com/doc/4e9257650.html,ing ICG-derived parameters to achieve BP targets was also veri?ed in a specialty hypertensive clinic23as well as in a community-based clinic.24More recently,a meta-analysis by Ferrario and colleagues25demonstrated optimal BP control with individualized ICG-guided therapy compared with standard care.

CONCLUSIONS

We have shown that TACI,a noninvasive measure of vascular function,is related to the risk of developing RH as well as the intensity of antihypertensive drug therapy required to achieve BP control.Our data fur-ther suggest that cross-sectional reports of RH preva-lence in many settings probably underestimate the true prevalence of RH.Several hemodynamic parameters linked to RH have been shown to be in?uential in the BP response to speci?c antihypertensive treatments.19–26 Thus,it is reasonable to believe that TACI might be useful prognostically or even as a therapeutic target as we move ever so deliberately toward personalized medicine.

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如何写先进个人事迹

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做有偿工作的人 Describe a person you know who is doing a paid job. You should say: Who this person is What job it is; How long the job lasted; And explain why you or this person chose to do this job. 让你笑的小孩 Describe a time that a child did something that made you laugh. You should say: When this happened Who the child was What the child did And explain why it was funny 特殊的旅行 Describe an educational trip you went on when you were in school. You should say: When and where you went; Who you went with; What you did; And explain what you learned on this trip.

Describe an electronic machine you want to buy. You should say: What it is When you know this machine What specific And explain why you want this machine 难忘的广告 Describe an unforgettable advertisement (that you saw or heard liked) You should say: Where you saw or heard it What kind of advertisement it was What the contents of the advertisement were (or, what product or service was advertised) And explain how you felt when you saw or heard this advertisement/why you like it

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