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Background: Potassium-induced natriuresis may contribute to the beneficial effects of potassium on blood pressure but has not been well-characterized in human postmenopausal hypertension. We determined the time course and magnitude of potassium-induced natriuresis and kaliuresis compared with hydrochlorothiazide in 19 hypertensive Hispanic postmenopausal women. We also determined the modulating effects of sodium intake, sodium-sensitivity, and activity of the thiazide-sensitive NCC (sodium-chloride cotransporter). Methods: Sixteen-day inpatient confinement: 8 days low sodium followed by 8 days high sodium intake. During both periods, we determined sodium and potassium excretion following 35 mmol oral KCl versus 50 mg hydrochlorothiazide. We determined sodium-sensitivity as change in 24-hour systolic pressure from low to high sodium. We determined NCC activity by standard thiazide-sensitivity test. Results: Steady-state sodium intake was the key determinant of potassium-induced natriuresis. During low sodium intake, sodium excretion was low and did not increase following 35 mmol KCl indicating continued sodium conservation. Conversely, during high sodium intake, sodium excretion increased sharply following 35 mmol KCl to ≈37% of that produced by hydrochlorothiazide. Under both low and high sodium intake, 35 mmol potassium was mostly excreted within 5 hours, accompanied by a sodium load reflecting the steady-state sodium intake, consistent with independent regulation of sodium/potassium excretion in the human distal nephron. Conclusions: Potassium-induced natriuresis was not greater in sodium-sensitive versus sodium-resistant hypertensives or hypertensives with higher versus lower basal NCC activity. We studied an acute KCl challenge. It remains to further characterize potassium-induced natriuresis during chronic potassium increase and when potassium is administered a complex potassium-containing meal.

The thiazide-sensitive sodium-chloride cotransporter (NCC;SLC12A3) is central to sodium and blood pressure regulation. Metabolic syndrome induces NCC upregulation generating sodium-sensitive hypertension in experimental animal models. We tested the role of NCC in sodium sensitivity in hypertensive humans with metabolic syndrome. Conversely, oral potassium induces NCC downregulation producing potassium-induced natriuresis. We determined the time course and magnitude of potassium-induced natriuresis compared with the natriuresis following hydrochlorothiazide (HCTZ) as a reference standard. We studied 19 obese hypertensive humans with metabolic syndrome during 13-day inpatient confinement. We determined sodium sensitivity by change in 24-hour mean systolic pressure by automated monitor from days 5 (low sodium) to 10 (high sodium). We determined NCC activity by standard 50 mg HCTZ sensitivity test (day 11). We determined potassium-induced natriuresis following 35 mmol KCl (day 13). We determined (1) whether NCC activity was greater in sodium-sensitive versus sodium-resistant participants and correlated with sodium sensitivity and (2) time course and magnitude of potassium-induced natriuresis following 35 mmol KCl directly compared with 50 mg HCTZ. NCC activity was not greater in sodium-sensitive versus sodium-resistant humans and did not correlate with sodium sensitivity. Thirty-five-millimoles KCl produced a rapid natriuresis approximately half that of 50 mg HCTZ with a greater kaliuresis. Our investigation tested a key hypothesis regarding NCC activity in human hypertension and characterized potassium-induced natriuresis following 35 mmol KCl compared with 50 mg HCTZ. In obese hypertensive adults with metabolic syndrome ingesting a high-sodium diet, 35 mmol KCl had a net natriuretic effect approximately half that of 50 mg HCTZ.

Acute severe hypertension is a common problem among inner-city ethnic minority populations. Nevertheless, the effects of currently employed treatment regimens on blood pressure have not been determined in a clinical practice setting. We determined the SBP responses to acute antihypertensive drug protocols and the 2-year natural history of patients presenting with severe hypertension.Retrospective cohort investigation in consecutive patients with SBP at least 220 mmHg and/or DBP at least 120 mmHg during 3-month enrollment in 2014 with 2-year follow-up. Primary outcomes were SBP versus time for the first 5 h of emergency treatment and 2-year follow-up including repeat visits, target organ events, and hospitalizations.One hundred and fifty-six unique patients met criteria with 69% Black; 34% Hispanic; 56% had previous visits for severe hypertension; 31% had preexisting target injury. Acute management: Acute antihypertensive regimens resulted in grossly unpredictable and often exaggerated effects on SBP. Treatment acutely reduced SBP to less than 140 mmHg in 30 of 159 patients. Clonidine reduced SBP to less than 140 mmHg in 19/61. Two-year follow-up: We observed 389 repeat visits for severe hypertension, 99 new target events, and 76 hospitalizations accounting for 620 hospital days.Acute treatment of severe hypertension produced unpredictable and potentially dangerous responses in SBP. Two-year follow-up demonstrated extraordinary rates of recurrent visits, target organ events, and hospitalizations. Our findings indicate a need to develop effective management strategies to lower blood pressure safely and to prevent long-term consequences. Our findings may apply to other hospitals caring for ethnic minority populations.

Prehypertension (systolic blood pressure 120–139 or diastolic blood pressure 80–89 mm Hg) confers a risk of progression to hypertension, impairment of cognitive function, increased left ventricular mass, risk of end-stage renal disease, and an association with arteriosclerosis. Recent studies provide data that could support the rationale for treating prehypertensives subjects with antihypertensive medications in addition to lifestyle modification, especially if they have concomitant cardiovascular risk factors.

STATEMENTOF PURPOSE: These guidelines have been written to provide a straightforward approach to managing hypertension in the community. We have intended that this brief curriculum and set of recommendations be useful not only for primary care physicians and medical students, but for all professionals who work as hands-on practitioners. We are aware that there is a great variability in access to medical care among communities. Even in so-called wealthy countries, there are sizable communities in which economic, logistic, and geographic issues put constraints on medical care. And, at the same time, we are been reminded that even in countries with highly limited resources, medical leaders have assigned the highest priority to supporting their colleagues in confronting the growing toll of devastating strokes, cardiovascular events, and kidney failure caused by hypertension. Our goal has been to give sufficient information to enable healthcare practitioners, wherever they are located, to provide professional care for people with hypertension. All the same, we recognize that it will often not be possible to carry out all of our suggestions for clinical evaluation, tests, and therapies. Indeed, there are situations in which the most simple and empirical care for hypertension-simply distributing whatever antihypertensive drugs might be available to people with high blood pressure-is better than doing nothing at all. We hope that we have allowed sufficient flexibility in this statement to enable responsible clinicians to devise workable plans for providing the best possible care of hypertension in their communities. We have divided this brief document into the following sections: 1. General introduction, 2. Epidemiology, 3. Special issues with black patients (African ancestry), 4. How is hypertension defined?, 5. How is hypertension classified?, 6. Causes of hypertension, 7. Making the diagnosis of hypertension, 8. Evaluating the patient, 9. Physical examination, 10. Tests, 11. Goals of treating hypertension, 12. Nonpharmacologic treatment of hypertension, 13. Drug treatment of hypertension, 14. Brief comments on drug classes, 15. Treatment-resistant hypertension. Fil: Weber, Michael A.. State University of New York; Estados Unidos Fil: Schiffrin, Ernesto L.. McGill University; Canadá Fil: White, William B.. University of Connecticut; Estados Unidos Fil: Mann, Samuel. Weil Cornell College of Medicine; Estados Unidos Fil: Lindholm, Lars H.. Universidad de Umea; Suecia Fil: Kenerson, John G.. Cardiovascular Associates; Estados Unidos Fil: Flack, John M.. Wayne State University; Estados Unidos Fil: Carter, Barry L.. University of Iowa; Estados Unidos Fil: Materson, Barry J.. University of Miami; Estados Unidos Fil: Ram, C. Venkata S.. MediCiti Institutions; India Fil: Cohen, Debbie L.. University of Pennsylvania; Estados Unidos Fil: Cadet, Jean Claude. State University School of Medicine; Estados Unidos Fil: Jean Charles, Roger R.. Hypertension Center of Haiti; Haití Fil: Taler, Sandra. Mayo Clinic. Department of Medicine; Estados Unidos Fil: Kountz, David. Jersey Shore University Medical Center; Estados Unidos Fil: Townsend, Raymond. University of Pennsylvania; Estados Unidos Fil: Chalmers, John. University of Sydney; Australia Fil: Ramírez, Agustín José. Fundación Favaloro; Argentina. Universidad Favaloro; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Bakris, George L.. University of Chicago; Estados Unidos Fil: Wang, Jiguang. Shanghai Jiaotong University; China Fil: Schutte, Aletta E.. North West University; Sudáfrica Fil: Bisognano, John D.. University of Rochester; Estados Unidos Fil: Touyz, Rhian M.. University of Glasgow; Reino Unido Fil: Sica, Dominic. Virginia Commonwealth University; Estados Unidos Fil: Harrap, Stephen B.. University of Melbourne; Australia

We provide a review of recent additions to the antihypertensive armamentarium in the form of combination therapy. These include two-drug and three-drug combinations in a single pill. There is evidence that such combinations are more efficacious than the individual components and that patient adherence to therapy is improved.

Extant data indicate that treating to lower systolic pressure confers significant advantage to younger people in general good health and to relatively healthy octogenarians. Few data exist to guide practitioners on the treatment of frail elderly hypertensives. Chronological age alone does not suffice to make useful judgments regarding therapy. The definition of frailty remains controversial. One method, use of a simple questionnaire or a test of walking speed is practical but not universally accepted. Frail subjects, while at higher risk for cardiovascular complications, seem to benefit less or not at all from antihypertensive drug treatment. Clinicians should treat robust older patients as they would younger patients because the benefits far outweigh the low risk of adverse effects. Successful antihypertensive therapy in those younger than 80 years should not be discontinued simply because that age milestone has been crossed. Treatment of frail older patients must be individualized. Some frail survivors age 80 years or older may actually fare better with elevated systolic pressures. Pending the cognitive function substudy of Systolic Blood Pressure Intervention Trial, there is little evidence that antihypertensive treatment benefits established cognitive dysfunction. Because hypertension in middle age is a good predictor of later cognitive dysfunction, the clinical approach should be one of early prevention.

Hypertension is prevalent in an estimated 29% to 80% of patients treated with peritoneal dialysis (PD). Cardiovascular disease represents the most common cause of mortality in this population, and hypertension (HTN) plays an important role. Volume overload is prevalent in PD patients because of liberal intake of fluids and loss of residual renal function (RRF). Noncompliance with salt restriction causes weight gain and makes HTN more difficult to manage. Physiology of the peritoneal membrane and its transport characteristics governs the ultrafiltration rate and consequently both volume and HTN. Therapeutic options for blood pressure control are ultrafiltration through the osmotic or colloid osmotic effects of dialysis solutions, salt restriction, and the use of antihypertensive medications such as diuretics, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Loop diuretics are used to maintain urine output in nonoliguric patients. Doses may exceed 250 mg of furosemide; ototoxicity is not problematic if blood levels are monitored carefully. Preservation of RRF is important for maintaining volume control and, thereby, control of HTN.

The practice of quality clinical medicine is predicated by evaluating accurate historical, physical, laboratory and imaging data, and making decisions based thereon. Intra-arterial pressure estimation has evolved over millennia from detailed analysis of the pulse to sophisticated instruments that determine pressure indirectly and display it as numerical data. Such data are only as accurate as the device permits. No matter how accurate the device, if the subject is not properly prepared and positioned, the data may be inaccurate. Those who take blood pressure in the clinic should be well trained in the correct technique and be aware of the factors that cause variation in the readings. Accurate estimation of intra-arterial pressure is even more challenging in pediatric patients. The correct cuff size must be used and motion artifacts minimized. Oscillometric readings are good for screening, but auscultation remains the gold standard.

Nonadherence and poor or no persistence with taking antihypertensive medications results in uncontrolled high blood pressure, poor clinical outcomes and preventable health care costs. Factors associated with nonadherence are multilevel and relate not only to the patient, but also to the provider, health care system, health care organization, and community. National guideline committees have called for more aggressive approaches to implement strategies known to improve adherence and technologies known to enable changes at the systems level including improved communication among providers and patients. Improvements in adherence and persistence are likely to be achieved by supporting patient self-management, a team approach to patient care, technology-supported office practice systems, better methods to measure adherence, and less clinical inertia. Integrating high blood pressure control into health care policies that emphasize and improve prevention and management of chronic illness remains a challenge. Four strategies are proposed: focusing on clinical outcomes; empowering informed, activated patients; developing prepared proactive practice teams; and advocating for health care policy reform. With hypertension remaining the most common reason for office visits, the time is now.

versy was generated by the JNC 8 panel that suggested that elevated blood pressure up to 150 mm Hg systolic need not be treated in patients over 60 years of age. This has generated considerable heated discussion among those who write guidelines, practitioners, and even members of the JNC 8 panel who chose to write a dissenting minority report. 2,3 This issue of JASH contains two papers that address the issue of the point at which BP should be treated in patients over 60 years of age. One paper presented the results of a large 10-year follow-up study that showed that there was a risk over 140 mm Hg. The other paper presented data that appears to support the JNC 8 recommendation. We shall examine each of these papers in greater detail. The study by Mohebi et al 4 was of 1845 subjects over age 60 years of age who were identified in 1999‐2001 as part of a larger study of 15,005 subjects in Tehran, Iran. They were followed for a median of 10 years. They were divided into four groups: Optimal (systolic blood pressure [SBP] 90 mm Hg); Hypertensive (SBP � 150 mm Hg or DBP � 90 mm Hg or taking antihypertensive medications). They were followed closely and outcomes events were carefully defined and analyzed. During the 10 years, 380 cases of cardiovascular disease (CVD) and 305 cases of incident coronary heart disease (CHD) were identified. The prehypertensive group was not different for incident CVD, CHD, or cardiovascular mortality from the Optimal group. Group 3, the one generating the most controversy by the JNC 8 report, was at a significantly higher risk of incident CVD and CHD but not total mortality or CVD mortality. The hypertensive group did have a higher risk for incident CVD, CHD and CVD mortality, and a marginally increased risk of total mortality events. The study was limited in several ways. First, BP was measured twice on the initial visit, and the results were averaged. Second, the study population was derived from a defined area of Tehran that may not even be representative of all of Tehran, let alone Iran or areas outside of the Middle East. For example, only 5.4%‐10.1% of groups 2, 3, and 4 smoked, and they were, in general, not obese or diabetic. The study by Rock et al 5 followed a smaller group of subjects (317) with an average age of 59.2 years who were 81% men and who were followed for a median of 6 years. Over this period, 19 patients had a new coronary artery event, and three had a cerebrovascular event. BP was determined by 24-hour ambulatory BP monitoring. There were 195 patients with SBP

This American Society of Hypertension position paper focuses on the importance of out-of-office blood pressure (BP) measurement for the clinical management of patients with hypertension and its complications. Studies have supported direct and independent associations of cardiovascular risk with ambulatory BP and inverse associations with the degree of BP reduction from day to night. Self-monitoring of the BP (or home BP monitoring) also has advantages in evaluating patients with hypertension, especially those already on drug treatment, but less is known about its relation to future cardiovascular events. Data derived from ambulatory BP monitoring (ABPM) allow the identification of high-risk patients, independent from the BP obtained in the clinic or office setting. While neither ABPM nor self-BP monitoring are mandatory for the routine diagnosis of hypertension, these modalities can enhance the ability for identification of white-coat and masked hypertension and evaluate the extent of BP control in patients on drug therapy.

Editor’s Note: The American Society of Hypertension is publishing a series of Position Papers in their official journals throughout the 2008–2011 years. The following Position Paper originally appeared: JASH. 2010;4:42–50. The goal of antihypertensive therapy is to abolish the risks associated with blood pressure (BP) elevation without adversely affecting quality of life. Drug selection is based on efficacy in lowering BP and in reducing cardiovascular (CV) end points, including stroke, myocardial infarction, and heart failure. Although the choice of initial drug therapy exerts some effect on long‐term outcomes, it is evident that BP reduction per se is the primary determinant of CV risk reduction. Available data suggest that at least 75% of patients will require combination therapy to achieve contemporary BP targets, and increasing emphasis is being placed on the practical tasks involved in consistently achieving and maintaining goal BP in clinical practice. It is within this context that the American Society of Hypertension presents this Position Paper on Combination Therapy for Hypertension. It will address the scientific basis of combination therapy, present the pharmacologic rationale for choosing specific drug combinations, and review patient selection criteria for initial and secondary use. The advantages and disadvantages of single‐pill (fixed) drug combinations and the implications of recent clinical trials involving specific combination strategies will also be discussed. J Clin Hypertens (Greenwich). 2011;13:146–154. © 2010 Wiley Periodicals, Inc.

Since the publication of a paper by the American Society of Hypertension, Inc. Writing Group in 2003, some refinements have occurred in the definition of hypertension. Blood pressure is now recognized as a biomarker for hypertension, and a distinction is made between the various stages of hypertension and global cardiovascular risk. This paper discusses the logic underlying the refinements in the definition of hypertension.

Heterogeneity of treatment effects (HTE) is a measure of the variations in individual treatment response to the same agent across a population. Hypertension affords an appropriate model for investigators of HTE. Use of blood pressure measurement guidelines and consistent techniques help to reduce the potential variability associated with clinician measurements. Patient characteristics such as age and race/ethnicity can affect blood pressure, including patient response and adverse events observed with antihypertensive medication. Through pharmacogenetic advances, potential underlying causes for such variation are emerging. The growing number of clinical examples of mutations that affect antihypertensive response includes multiple polymorphisms within the components of the renin-angiotensin-aldosterone system. The most prominent examples of these polymorphisms exist in the genes coding for angiotensinogen, angiotensin-converting enzyme, and the angiotensin II type 1 receptor. An understanding of the components of blood pressure variability and sources of HTE in antihypertensive therapy is important for analyzing published reports on this topic. It is also helpful when designing treatment protocols for individual patients with hypertension and in assessing their response to therapy.

Elevated blood pressure (BP) is a common problem in patients hospitalized for reasons other than hypertension. Unexpected elevations commonly result in calls to physicians who too often prescribe medication to reduce the numbers without evaluating the patient or determining the cause of the elevation. This may result in unnecessary and sometimes harmful treatment. Such BP elevation has many potential causes. These include anxiety, post-operative salt and volume overload, failure to administer the patient's known antihypertensive medication, inability to give oral antihypertensive medication to patients who cannot take pills by mouth, incipient heart failure, previously unrecognized renal failure, obstructive uropathy and other causes. These must be identified and treated prior to addressing only the elevated BP numbers. We present an algorithm for evaluating hospitalized patients with elevated BP in order to assist physicians in identifying the true cause of the elevation, treating the identified cause, and giving appropriate drug treatment. We also note that this is a golden opportunity for communication with the outpatient providers who will follow the patient.

Nondrug therapy of hypertension really does work but requires strong motivation by both patient and physician. In addition to global health benefits, prescription of weight loss, exercise, moderation of salt and alcohol intake, Dietary Approach to Stop Hypertension (DASH) eating plan, and tobacco avoidance can decrease the risk for normotensive and prehypertensive patients of developing fixed hypertension. Initiating and maintaining a healthy lifestyle may be sufficient to avoid pharmacologic therapy for some patients and is a valuable adjunct to drug therapy for most. Blood pressure lowering can be achieved by weight reduction (5-20 mm Hg/10 kg), DASH eating plan (8-14 mm Hg), dietary sodium reduction (2-8 mm Hg), increased physical activity (4-9 mm Hg), and moderation of alcohol consumption (2-4 mm Hg). Combination of two or more modalities may have an additive benefit. Cessation of tobacco abuse not only has global health benefits, but may reduce blood pressure.

The prevalence of hypertension increases with advancing age, due primarily to increases in systolic blood pressure. Systolic hypertension is the most common form of hypertension in individuals over 50 years of age and reflects pathologic decreases in arterial compliance. Systolic blood pressure elevation is a more important risk factor for cardiovascular disease than is diastolic blood pressure elevation. Stage 2 hypertension, defined as blood pressureor =160/100 mm Hg, is often found in older persons, who are at highest risk for cardiovascular events. In this clinical review, hypertension experts utilize a case study to provide a paradigm for treating older patients with stage 2 hypertension.

Dr. David Ayman (1901–1986) was an astute clinician and observer who challenged medical dogma by performing placebo‐controlled studies and by meticulous measurement of blood pressure under standardized conditions. He demonstrated that almost all drugs reported to have an antihypertensive effect in the early 20th century had achieved nothing more than placebo response. He noted the marked variability of blood pressure and devised methods to reduce that variability. These observations led to his publications concerning what is now known as “white coat” or office hypertension. He determined blood pressure personally in 1524 members of 277 families over three generations and made observations on the hereditary nature of hypertension that countered the single‐gene thinking of the day. His work is proof that clinical inquisitiveness, hard work, and the courage to challenge conventional wisdom can result in significant contributions to medicine and science.

Blood pressure increases with increasing body mass index (BMI) and BMI is linearly related to blood pressure in population studies. Obesity has been said to cause resistance to antihypertensive medications. We compared short‐term and 1‐year blood pressure response by BMI category and weight change with hydrochlorothiazide, atenolol, diltiazem‐SR, captopril, clonidine, prazosin, or placebo in 1292 male veterans. Drug doses were titrated to achieve goal diastolic blood pressure 30) were 2.5 times more likely to have diastolic blood pressure controlled by atenolol than normal weight (BMI

Several consistent lines of evidence indicate an association between sodium sensitivity and impaired nitric oxide bioactivity. Nevertheless, whether restoring nitric oxide in humans by pharmacological means can ameliorate sodium sensitivity has not been investigated. Because nebivolol has been demonstrated to increase nitric oxide bioactivity in both laboratory and clinical investigations, we hypothesized that nebivolol might ameliorate sodium sensitivity and improve renal sodium handling in comparison to metoprolol. We therefore conducted a randomized, 2-treatment-period crossover trial in 19 Hispanic postmenopausal women with hypertension to determine the comparative effects of nebivolol versus metoprolol on (1) 24-hour ambulatory blood pressure response to an increase in dietary sodium from 5 days of low sodium to 5 days of high sodium, (2) renal natriuretic response to a 1-L saline challenge, and (3) asymmetrical dimethylarginine. Clinic blood pressure and heart rate were significantly reduced after 4 weeks of treatment with both nebivolol and metoprolol. Twenty-four–hour mean systolic blood pressure increased sharply from low sodium to high sodium for both nebivolol and metoprolol. Nevertheless, the increases in blood pressure did not differ between the 2 drugs: 7.7 (3.1, 12.3) mm Hg with metoprolol and 9.3 (4.6, 13.9) mm Hg with nebivolol ( P =0.63). Furthermore, we observed no differences between the drugs in natriuretic response to saline challenge or asymmetrical dimethylarginine. In a sodium-sensitive population, at doses sufficient to produce reductions in blood pressure and heart rate, nebivolol did not demonstrate a significant effect on sodium sensitivity or sodium handling compared with metoprolol.

Pulse pressure has been more strongly associated with cardiovascular outcomes, especially myocardial infarction and heart failure, than has systolic, diastolic, or mean arterial pressure in a variety of populations. Little is known, however, of the comparative effects of various classes of antihypertensive agents on pulse pressure. In retrospective analyses of the Veterans Affairs Single-Drug Therapy for Hypertension Study, we compared changes in pulse pressure with 6 classes of antihypertensive agents: 1292 men with diastolic blood pressure of 95 to 109 mm Hg on placebo were randomized to receive hydrochlorothiazide, atenolol, captopril, clonidine, diltiazem, prazosin, or placebo. Drug doses were titrated to achieve a goal diastolic blood pressure of P P

This study assesses and evaluates left ventricular (LV) contractile function after treatment of hypertension, with an emphasis on LV midwall mechanics. Although prior studies have assessed cardiac function after hypertension treatment, none has performed an analysis of LV midwall mechanics. The Veterans Affairs Study of monotherapy in hypertension was a study large enough to permit analysis of midwall mechanics across a wide spectrum of mass changes accompanying hypertension treatment. LV chamber function was assessed by computing fractional shortening at the endocardial surface; LV midwall shortening was used to define myocardial function. Both shortening indexes were related to end-systolic circumferential stress in the entire population by partitioning values of mass and relative wall thickness changes. Two hundred sixty-eight patients were studied at baseline and again after a 1- or 2-year period. In the entire group, there was no significant change in circumferential shortening either at the endocardium (38 ± 8% at baseline vs 37 ± 7% at follow up, p = 0.29) or in shortening at the midwall (20 ± 3% vs 20 ± 3%, p = 0.53). However, 83 patients had a reduction in relative wall thickness and an increase in midwall shortening. The change in midwall shortening was significantly related to changes in relative wall thickness (r = −0.53, p = 0.0001). Thus, reductions in LV mass associated with antihypertensive therapy are generally not accompanied by a decrement in LV chamber or myocardial function. Improvement in midwall shortening is more closely related to normalization of LV geometry than to reduction in LV mass.

Many physicians will be sued for malpractice at some time during their careers. Risk of litigation can be reduced by adopting practices that include keeping thorough medical records, educating office personnel, and fostering good patient-physician relationships. The last is important because patients who view their physicians as caring tend not to sue even if an adverse outcome occurs.

After the data collection phase of a clinical trial has been completed, new hypotheses may surface which require additional data before they can be tested. In the Veterans Affairs Cooperative Study on Single Drug Therapy of Hypertension, we investigated the relationship between location of the participating center, race and ability to control blood pressure. The analysis indicated poorer blood pressure control among sites located in the “stroke belt” (southeastern United States), especially among African-Americans. We sought to determine whether the effect was attributable to socioeconomic patternss however, income data were not collected as part of the original study. Therefore, we accessed centralized data bases to obtain zipcode-level income information for the randomized study patients. This approach yielded estimates of income data for 94.3% of the patients and compared favorably to data acquisition rates for variables which were collected prospectively in the study.

Baseline heart rate is becoming recognized as a predictor of cardiovascular risk. Various antihypertensive drugs have differing effects on heart rate. A randomized controlled clinical trial of 1292 ambulatory men with stage 1 or 2 hypertension was conducted in 15 Veterans Affairs medical centers. Patients were treated with hydrochlorothiazide, atenolol, captopril, clonidine, diltiazem, prazosin, or placebo for up to 2 years. Heart rates were measured at baseline, the end of titration, 1 year, and 2 years. Data were also stratified by baseline heart rate. A subset of patients had heart rate also determined by electrocardiogram. All drugs except prazosin reduced heart rate from baseline; additional small decreases were obtained over time with hydrochlorothiazide and placebo. The decrease initially achieved with clonidine was attenuated over time. The overall reduction in heart rate was greatest for atenolol (-12.2 beats/min) and least for prazosin (+3.8 beats/min). Only atenolol effected a further reduction of heart rate for patients whose baseline rate was or =85 beats/min. Data derived by electrocardiogram yielded similar results. The drugs used in this study differ in their ability to reduce heart rate, sustain that reduction over time, and to change heart rate in groups with high or low rates at baseline. The importance of these comparative changes as independent cardiac risk factor variables remains to be determined.

Background Antihypertensive drugs may differ in their ability to reduce LV mass. Covariates other than drug selection, such as pretreatment LV mass, body weight, the magnitude of blood pressure reduction, race, and age may modify the response of LV mass to therapy. Methods and Results Patients with mild to moderate hypertension (diastolic blood pressure, 95 to 109 mm Hg) were randomly allocated to treatment with atenolol, captopril, clonidine, diltiazem, hydrochlorothiazide, or prazosin in a double-masked trial. Patients achieving the goal diastolic blood pressure of Conclusions Antihypertensive drugs have disparate effects on LV mass independent of the magnitude of blood pressure reduction. Patients with adequate blood pressure control on captopril, hydrochlorothiazide, and atenolol show a reduction of LV mass after 1 year of treatment, whereas patients on diltiazem, clonidine, or prazosin do not.

Objectives. We sought to determine the relations of left atrial (LA) size to blood pressure, obesity, race, age and left ventricular (LV) mass in hypertension. Background. Although obesity, race and age may influence LV mass, their effects on LA size have not been defined in hypertension. Methods. Left atrial size was measured in 690 men (58% African-Americans) with mild to moderate hypertension (mean [±SD] blood pressure 152 ± 15/98 ± 6 mm Hg) and a high prevalence of LV hypertrophy. Effects of LV mass, adiposity, race, age, physical activity, height, weight, sodium excretion, plasma renin activity and heart rate were examined. Results. Left atrial size was greater (p ≤ 0.0001) in obese (44.2 ± 5.7 mm) than in overweight (41.6 ± 5.9 mm) or normal weight (38.9 ± 6.2 mm) patients. Left atrial enlargement (≥43 mm) was present in 56% of obese patients compared with 42% of overweight and 25% of normal weight hypertensive men. As age increased, white patients had a greater LA size than African-American patients. Although there was no relation between LV mass and LA size in normal weight patients, there was a significant positive relation in obese patients. On multiple regression analysis, obesity was the strongest independent predictor of increased LA size. Conclusions. Obesity is the strongest predictor of LA size in patients with hypertension and amplifies the relation between LA size and LV mass. Race influences effects of age and hypertension on LA size. Because increased LA size and LV mass (also influenced by obesity) are associated with an adverse outcome, these findings underscore the importance of obesity, race and age with regard to the cardiac effects of hypertension. (J Am Coll Cardiol 1997;29:651–8)

A subset of 102 patients of an original cohort of 1292 with stage 1 to 2 hypertension was characterized by having failed to achieve goal blood pressure (< 90 mm Hg diastolic) after treatment with two single antihypertensive drugs. These patients were given a combination of the two drugs on which they had failed to achieve blood pressure goal when they were administered as single-drug therapy. The drugs were hydrochlorothiazide, atenolol, captopril, diltiazem-SR, clonidine, and prazosin. We examined the responses in each of the drug combination categories by the order that the drugs were administered, by estimated total response rates for the combinations, and by age and race. The order of drug administration did have an effect for some of the drug pairs. This was of two types: 1) different results for each member of the pair, but the same combination result; and 2) different end result of the combination. An example of the first type is that prazosin had only a 6% response rate in patients who had failed on diltiazem, while diltiazem had a 22% response rate in patients who had failed on prazosin. Nevertheless, the combinations yielded the same total responses (86% and 84%) regardless of order. An example of the second type is that captopril-diltiazem was less effective in total response than diltiazem-captopril (88% v 97%). Differences were seen in the response to combinations in the race and age groups. There were ordering differences of type similar to those described above. We conclude that combination drug therapy is highly effective even when the individual components have failed and that some differences in response by order of drug administration may occur.

BACKGROUND: An important issue in clinical practice is how to treat patients whose blood pressure does not respond to the first antihypertensive drug selected. OBJECTIVE: To analyze the antihypertensive response of patients who had failed to achieve their diastolic blood pressure goal (< 90 mm Hg at the end of 8 to 12 weeks of titration) with one of six randomly allocated drugs or placebo to the random allocation of an alternate drug. METHODS: We initially randomized 1292 men with diastolic blood pressure of 95 to 109 mm Hg to treatment with hydrochlorothiazide, atenolol, captopril, clonidine hydrochloride, diltiazem hydrochloride (sustained release), prazosin hydrochloride, or placebo. Of 410 men in whom initial treatment failed, 352 qualified for randomization to the alternate drug. RESULTS: Of the 352 patients, 173 (49.1%) achieved their goal diastolic blood pressure, in 133 (37.8%) the alternate drug failed, and 46 (13.1%) left the study for various reasons. Overall response rates were as follows: diltiazem, 63%; clonidine, 59%; prazosin, 47%; hydrochlorothiazide, 46%; atenolol, 41%; and captopril, 37%. The best response rate for patients in whom hydrochlorothiazide failed was achieved with diltiazem (70%); after atenolol failure, clonidine (86%); after captopril failure, prazosin (54%); after clonidine failure, diltiazem (100%); after diltiazem failure, captopril (67%); and after prazosin failure, clonidine (53%). The combined response rate for patients initially randomized to an active treatment was 76.0%, which is similar to that achieved by the combination of two drugs in previous studies. CONCLUSIONS: We conclude that sequential single-drug therapy is a rational approach for treatment of hypertension in patients in whom initial drug therapy has failed.

The antihypertensive efficacy of six drugs and placebo was compared in 1292 men with untreated diastolic blood pressure of 95 to 109 mm Hg. The primary end point "success" was defined as the patient having achieved a diastolic blood pressure of < 90 mm Hg at the end of the drug titration period and having maintained a diastolic blood pressure of < 95 mm Hg for 1 year without drug intolerance. The original published success rate data (N Engl J Med 1993;328:914-921) were discovered to be in error due to a computer programming code omission (N Engl J Med 1994;330:1689). This paper presents corrected graphic figures. The corrected success rates were generally higher than originally published. Overall, diltiazem (72%) was significantly higher than hydrochlorothiazide (55%), prazosin (54%), captopril (50%), and placebo (31%); clonidine (62%) and atenolol (60%) were intermediate. There were some changes in the hierarchy of drug response, but important differences in success rates according to age by race subgroups remained. Whites responded well to all drug classes, except for lower efficacy of hydrochlorothiazide in younger whites. Blacks responded better to diltiazem than other agents. In addition, we have analyzed the data using a definition of success based on < 90 mm Hg for 1 year. Use of the

Objectives. The purpose of this study was to determine the effects of obesity and its interaction with age, race and the magnitude of blood pressure elevation in a large cohort of patients with mild to moderate hypertension and a high prevalence of left ventricular hypertrophy. Background. Obesity, race and age each have important effects on the incidence and severity of hypertension and may contribute to the effects of blood pressure elevation on the cardiac manifestations of hypertension. Methods. Left ventricular structure and function were assessed with two-dimensional targeted M-mode echocardiography in 692 men with mild to moderate hypertension (average blood pressure 153/100 mm Hg), and the data were compared in relation to obesity (determined from body mass index), age, race, blood pressure, physical activity, plasma renin activity, urinary sodium excretion, hematocrit, heart rate and serum lipids. Results. Left ventricular hypertrophy was common (630% with increased left ventricular mass, 22% with left ventricular hypertrophy on the electrocardiogram [ECG]). On multivariable regression analysis, body mass index was the strongest predictor of left ventricular mass and magnified the slope relation of blood pressure to left ventricular mass. Despite a greater prevalence of ECG left ventricular hypertrophy in blacks (31%) than in whites (10%), left ventricular mass and echocardiographic prevalence of left ventricular hypertrophy did not differ by race. However, septal, posterior left ventricular and relative wall thickness were greater in black than in white men. Conclusions. Obesity is the strongest clinical predictor of left ventricular mass and left ventricular hypertrophy la men, even in those with mild to moderate hypertension of sufficient severity to be associated with a high prevalence of left ventricular hypertrophy. Moreover, independent effects of systolic blood pressure on left ventricular mass an amplified by obesity. Although race does not affect left ventricular mass or the prevalence of left ventricular hypertrophy, black race is associated with greater relative wall thickness, itself a predictor of unfavorable cardiovascular outcome.

Heart rate variability (HRV) and its circadian rhythm were evaluated in 22 patients with treated hypertension and left ventricular hypertrophy in whom coronary artery disease was excluded by stress thallium or angiography. By using 24-hour Holter monitoring, HRV and its spectral components were measured. Findings were compared with 11 age-matched normal controls. The difference between mean R-R intervals during sleep (11 PM to 7 AM) and while awake (9 AM to 9 PM) (73 +/- 33 vs 263 +/- 63 msec, p0.0001) and the mean 24-hour SD of the R-R intervals (55 +/- 6.3 vs 93 +/- 11, p0.0001) were lower among the hypertensive patients compared with controls. The percentage of difference between successive R-R intervals that exceeded 50 msec, a measure of parasympathetic tone, was also lower among the hypertensive patients (6.8 +/- 7.1 vs 13.6 +/- 8.9, p0.002); it increased at night and decreased during the day among the controls, and this circadian rhythm was blunted among the patients. Spectral analysis showed that power in the high-frequency range (0.15 to 0.40 Hz) was lower among the hypertensive patients during 21 of 24 hours but that the difference was statistically significant only during 9 hours (p ranging from0.05 to 0.009). Power in the low-frequency range (0.04 to 015 Hz) was lower at night, increased in the morning, and higher during the day among controls; this circadian rhythm was absent among hypertensive patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Background Characteristics such as age and race are often cited as determinants of the response of blood pressure to specific antihypertensive agents, but this clinically important issue has not been examined in sufficiently large trials, involving all standard treatments, to determine the effect of such factors. Methods In a randomized, double-blind study at 15 clinics, we assigned 1292 men with diastolic blood pressures of 95 to 109 mm Hg, after a placebo washout period, to receive placebo or one of six drugs: hydrochlorothiazide (12.5 to 50 mg per day), atenolol (25 to 100 mg per day), captopril (25 to 100 mg per day), clonidine (0.2 to 0.6 mg per day), a sustained-release preparation of diltiazem (120 to 360 mg per day), or prazosin (4 to 20 mg per day). The drug doses were titrated to a goal of less than 90 mm Hg for maximal diastolic pressure, and the patients continued to receive therapy for at least one year. Results The mean (±SD) age of the randomized patients was 59 ±10 years, and 48 percent we...