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There is a need for a brief, open access, self-report medication adherence scale that overcomes challenges of existing adherence tools, is associated with incident cardiovascular disease (CVD), and identifies low 'implementation' adherers to antihypertensive medications to facilitate blood pressure management.Antihypertensive medication adherence was assessed in a cohort of 1532 older hypertensive adults without prior CVD using the self-report 4-item Krousel-Wood Medication Adherence Scale (K-Wood-MAS-4), a hybrid tool developed to predict pharmacy refill and which captures four domains of adherence behavior: self-efficacy, physical function, intentional medication-taking, and forgetfulness. The 4-item scale categorized participants as low and high adherers using scores at least 1 and less than 1, respectively. Participants were followed after K-Wood-MAS-4 assessment to identify incident CVD events (stroke, myocardial infarction, congestive heart failure, or CVD death). The prevalence of low adherence was 38.7%. During a median follow-up of 2.8 years (maximum 3.8 years), 136 (8.9%) participants had an incident CVD event; 12.8 and 6.4% in low and high adherers, respectively. The adjusted hazard ratio (aHR) for incident CVD associated with low versus high adherence was 2.29 [95% confidence interval (CI): 1.61, 3.26]. Results were similar when stratified by age [75 years - aHR 3.53 (95% CI: 1.65, 7.56); ≥75 years - aHR 1.98 (95% CI: 1.32, 2.97)], sex [women - aHR 1.90 (95% CI: 1.16, 3.12); men - aHR 2.80 (95% CI: 1.68, 4.65)], and race [black - aHR 2.22 (95% CI: 0.93, 5.31); white - aHR 2.26 (95% CI: 1.54, 3.34)].Low medication adherence using the 'hybrid' K-Wood-MAS-4 predicts incident CVD in a cohort of older adults with established hypertension.

BACKGROUND: The appropriate dose of aspirin to lower the risk of death, myocardial infarction, and stroke and to minimize major bleeding in patients with established atherosclerotic cardiovascular disease is a subject of controversy. METHODS: Using an open-label, pragmatic design, we randomly assigned patients with established atherosclerotic cardiovascular disease to a strategy of 81 mg or 325 mg of aspirin per day. The primary effectiveness outcome was a composite of death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke, assessed in a time-to-event analysis. The primary safety outcome was hospitalization for major bleeding, also assessed in a time-to-event analysis. RESULTS: A total of 15,076 patients were followed for a median of 26.2 months (interquartile range [IQR], 19.0 to 34.9). Before randomization, 13,537 (96.0% of those with available information on previous aspirin use) were already taking aspirin, and 85.3% of these patients were previously taking 81 mg of daily aspirin. Death, hospitalization for myocardial infarction, or hospitalization for stroke occurred in 590 patients (estimated percentage, 7.28%) in the 81-mg group and 569 patients (estimated percentage, 7.51%) in the 325-mg group (hazard ratio, 1.02; 95% confidence interval [CI], 0.91 to 1.14). Hospitalization for major bleeding occurred in 53 patients (estimated percentage, 0.63%) in the 81-mg group and 44 patients (estimated percentage, 0.60%) in the 325-mg group (hazard ratio, 1.18; 95% CI, 0.79 to 1.77). Patients assigned to 325 mg had a higher incidence of dose switching than those assigned to 81 mg (41.6% vs. 7.1%) and fewer median days of exposure to the assigned dose (434 days [IQR, 139 to 737] vs. 650 days [IQR, 415 to 922]). CONCLUSIONS: In this pragmatic trial involving patients with established cardiovascular disease, there was substantial dose switching to 81 mg of daily aspirin and no significant differences in cardiovascular events or major bleeding between patients assigned to 81 mg and those assigned to 325 mg of aspirin daily. (Funded by the Patient-Centered Outcomes Research Institute; ADAPTABLE ClinicalTrials.gov number, NCT02697916.).

BACKGROUND: Sex-race stratification may lead to identification of risk factors for low antihypertensive medication adherence that are not apparent when assessing risk factors in women and men without race stratification. We examined risk factors associated with low pharmacy refill adherence across sex-race subgroups (white women, black women, white men, black men) within the Cohort Study of Medication Adherence among Older Adults (n=2,122). METHODS: Pharmacy refill adherence was calculated as proportion of days covered (PDC) using all antihypertensive prescriptions filled in the year prior to a baseline risk factor survey. Sex- and sex-race-stratified multivariable Poisson regression models with robust standard errors were used to estimate adjusted prevalence ratios and 95% confidence intervals for associations between participant characteristics and low adherence. RESULTS: Prevalence of low adherence was 22.9% versus 40.7% in white versus black women (p

Heart failure and chronic renal diseases are usually progressive and only partially amenable to therapy. These disorders can be the sequelae of hypertension or worsened by hypertension. They are associated with the tissue up-regulation of multiple peptides, many of which are capable of acting within the cell interior. This article proposes that these peptides, intracrines, can form self-sustaining regulatory loops that can spread through heart or kidney, producing progressive disease. Moreover, mineralocorticoid activation seems capable of amplifying some of these peptide networks. This view suggests an expanded explanation of the pathogenesis of progressive cardiorenal disease and suggests new approaches to treatment.

Objective To determine the association of post-traumatic stress disorder (PTSD) symptoms following Hurricane Katrina with incident cardiovascular disease (CVD) events in older, hypertensive, community-dwelling adults both overall and stratified by age, sex, and race. Methods This was a prospective cohort study performed in Southeastern Louisiana 12–24 months following Hurricane Katrina through February 2011. Participants were community-dwelling older adults (n = 2,073) enrolled in the Cohort Study of Medication Adherence Among Older Adults with no known history of CVD events. PTSD symptoms were assessed via telephone interview 12–24 months following Hurricane Katrina using the PTSD CheckList-Specific Version. The presence of PTSD symptoms was defined by scores greater than or equal to 37. Incident CVD events (stroke, myocardial infarction, hospitalization for congestive heart failure, or CVD death) were identified and adjudicated over a median 3.8-year follow-up period. Results Overall, 8.6% of participants screened positive for PTSD symptoms, and 11.6% had an incident CVD event during follow-up. PTSD symptoms were associated with an adjusted hazard ratio (aHR) for CVD events of 1.7 (95% confidence interval [CI], 1.1, 2.6). The association was present among blacks (aHR, 3.3, 95% CI, 1.7, 6.3) but not whites (aHR, 0.9, 95% CI, 0.4, 1.9); the interaction of PTSD symptoms and race on CVD events was statistically significant. Conclusion PTSD symptoms following Hurricane Katrina were associated with a higher risk of incident CVD in older adults with hypertension, with a stronger association in blacks compared with whites.

Berecek et al reported in the 1990s that when spontaneously hypertensive rat (SHR) mating pairs were treated with captopril and the resulting pups were continued on the drug for 2 months followed by drug discontinuation, the pups did not develop full blown hypertension, and the cardiovascular structural changes associated with hypertension in SHR were mitigated. The offspring of the pups also displayed diminished hypertension and structural changes, suggesting that the drug therapy produced a heritable amelioration of the SHR phenotype. This observation is reviewed. The link between cellular renin angiotensin systems and epigenetic histone modification is explored, and a mechanism responsible for the observation is proposed. In any case, the observations of Berecek are sufficiently intriguing and biologically important to merit re-exploration and definitive explanation. Equally important is determining the role of renin angiotensin systems in epigenetic modification.

Various forms of chronic renal disease as well as congestive heart failure progress irrespective of currently available supportive care. Clinical evidence indicates that blockade of the renin–angiotensin system and/or mineralocorticoid inhibition are partially effective. Recently, it was suggested that the initiation of feed–forward intracrine loops such as renin–angiotensin system up–regulation can explain the progression of disease in the face of the control of initiating factors such as high glucose or hypertension. Here, these notions are expanded to include a potential interaction of mineralocorticoid activity with intracrine renin–angiotensin system up–regulation. In addition to suggesting therapeutic interventions, these observations lead to an expanded view of intracrine physiology.

A variety of peptide signaling moieties that we have termed intracrines can act in the interiors of their cells of synthesis or of target cells after internalization. These intracrine factors are known to be upregulated in such disorders as diabetic nephropathy, systolic heart failure, and age-related macular degeneration. Indeed, a similar set of intracrines is upregulated in each of these disorders, suggesting a commonality of mechanism. In addition, several chronic neurodegenerative disorders such as Alzheimer disease and Parkinson disease involve intercellular trafficking of intracellular disease-causing proteins. These disorders can be considered intracrine-like. Here the mechanistic and therapeutic implications of these observations, and of the relevant modes of intracrine action, are discussed, including the possibility that similar therapeutic approaches could be effective in multiple progressive disorders and the implications of these observations for intracrine pharmacology in general.

In the classical renin-angiotensin system, circulating ANG II mediates growth stimulatory and hemodynamic effects through the plasma membrane ANG II type I receptor, AT1. ANG II also exists in the intracellular space in some native cells, and tissues and can be upregulated in diseases, including hypertension and diabetes. Moreover, intracellular AT1receptors can be found associated with endosomes, nuclei, and mitochondria. Intracellular ANG II can function in a canonical fashion through the native receptor and also in a noncanonical fashion through interaction with alternative proteins. Likewise, the receptor and proteolytic fragments of the receptor can function independently of ANG II. Participation of the receptor and ligand in alternative intracellular pathways may serve to amplify events that are initiated at the plasma membrane. We review historical and current literature relevant to ANG II, compared with other intracrines, in tissue culture and transgenic models. In particular, we describe a new transgenic mouse model, which demonstrates that intracellular ANG II is linked to high blood pressure. Appreciation of the diverse, pleiotropic intracellular effects of components of the renin-angiotensin system should lead to alternative disease treatment targets and new therapies.

Objectives: Secondary analysis of clinical trial data suggests visit-to-visit variability (VVV) of blood pressure is strongly associated with the incidence of cardiovascular disease. Measurement of blood pressure in usual practice settings may be subject to substantial error, calling into question the value of VVV in real-world settings. Methods: We analyzed data on adults of at least 65 years of age with diagnosed hypertension who were taking antihypertensive medication from the Cohort Study of Medication Adherence among Older Adults (n = 772 with 14 or more blood pressure measurements). All blood pressure measurements, taken as part of routine outpatient care over a median of 2.8 years, were abstracted from patients’ medical charts. Results: Using each participant's first seven SBP measurements, the mean intraindividual standard deviation was 13.5 mmHg. The intraclass correlation coefficient for the standard deviation based on the first seven and second seven SBP measurements was 0.28 [95% confidence interval (CI) 0.20–0.34]. Individuals in the highest quintile of standard deviation of SBP based on their first seven measurements were more likely to be in the highest quintile of VVV using their second seven measurements (observed/expected ratio = 1.71, 95% CI 1.29–2.22). Results were similar for other metrics of VVV. The intraclass correlation coefficient was lower for DBP than SBP. Conclusion: These data suggest VVV of SBP measured in a real-world setting is not random. Future studies are needed to assess the prognostic value of VVV of SBP assessed in routine clinical practice.visit-to-visit variability

Few data are available on the predictors of decline in antihypertensive medication adherence and the association of decline in adherence with subsequent blood pressure (BP) control. The current analysis included 1965 adults from the Cohort Study of Medication Adherence Among Older Adults recruited between August 2006 and September 2007. Decline in antihypertensive medication adherence was defined as a ≥2-point decrease on the 8-item Morisky Medication Adherence Scale assessed during telephone surveys 1 and 2 years after baseline. Risk factors for decline in adherence were collected using telephone surveys and administrative databases. BP was abstracted from outpatient records. The annual rate for a decline in adherence was 4.3% (159 participants experienced a decline). After multivariable adjustment, a decline in adherence was associated with an odds ratio (OR) for uncontrolled BP (≥140/90 mm Hg) at follow-up of 1.68 (95% CI: 1.01–2.80). Depressive symptoms (OR: 1.84 [95% CI: 1.20–2.82]) and a high stressful life events score (OR: 1.68 [95% CI: 1.19–2.38]) were associated with higher ORs for a decline in adherence. Female sex (OR: 0.61 [95% CI: 0.42–0.88]), being married (OR: 0.68 [95% CI: 0.47–0.98]), and calcium channel blocker use (OR: 0.68 [95% CI: 0.48–0.97]) were associated with lower ORs for decline. In summary, a decline in antihypertensive medication adherence was associated with uncontrolled BP. Modifiable factors associated with decline were identified. Further research is warranted to determine whether interventions can prevent the decline in antihypertensive medication adherence and improve BP control.

In recent years the actions of intracellular-acting, extracellular signaling proteins/peptides (intracrines) have become increasingly defined. General principles of intracrine action have been proposed. Mitochondria represent one locus of intracrine action, and thus far, angiotensin II, transforming growth factor-β, growth hormone, atrial natriuretic peptide, Wnt 13, stanniocalcin, other renin-angiotensin system components, and vascular endothelial-derived growth factor, among others, have been shown to be mitochondria-localizing intracrines. The implications of this mitochondrial intracrine biology are discussed.

Hypertension and its sequelae are complex processes. Optimization of the care of the hypertensive patient requires not only attention to the regulation of arterial pressure but also attention to blunting the hypertension-related processes that lead to vascular disease. It is clear that the regulation of these processes is much more complex than previously understood. Here several new insights into the pathogenesis of hypertension-related vascular disease have been explored. While this review is not exhaustive, it does serve to point out the varied nature of the biologic processes that must be taken into account and it points to new avenues for the development of therapeutic agents.

Hormones, growth factors, DNA-binding proteins and enzymes can all display intracrine functionality. Here Richard Re and Julia Cook examine the role intracrines have in the heart and vasculature, and argue that understanding the principles of intracrine physiology could help the development of more-effective therapeutic interventions in cardiovascular disease. The field of intracrine physiology attempts to codify the biological actions of intracrines—extracellular signaling proteins or peptides that also operate in the intracellular space, either because they are retained in their cells of synthesis or because they have been internalized by a target cell. Intracrines are structurally diverse; hormones, growth factors, DNA-binding proteins and enzymes can all display intracrine functionality. Here, we review the role of intracrines in the heart and vasculature, including the intracrine actions of renin–angiotensin-system components in cardiac pathology, dynorphin B in cardiac development, and a variety of factors in pathologic and therapeutic angiogenesis. We argue that principles of intracrine physiology can inform our understanding of important pathologic processes such as left ventricular hypertrophy, diabetic cardiomyopathy and arrythmogenesis, and can aid the development of more-effective therapeutic interventions in cardiovascular disease.

Angiogenesis, in most cases, is a requirement for tumor growth beyond a diameter of a few millimeters and is, therefore, a major target for cancer therapy. The intracellular actions of certain extracellular signaling proteins (intracrines) have been reported, and it is clear that intracrines such as vascular endothelial growth factor, basic fibroblast growth factor, angiogenin, angiotensin, and endothelin, among others, are involved in angiogenesis. We have proposed that intracrine networks play an important role in angiogenesis, and have suggested that very similar intracrine networks exist in some tumor cells. These notions have implications for the development of anti-angiogenesis therapies because they suggest that the inhibition of intracellular intracrine trafficking pathways may be an effective therapeutic target. Here the participation and regulation of intracrines in angiogenesis is explored, as are the actions of various anti-angiogenic factors.

Chronic renal diseases and congestive heart failure are progressive disorders, which cannot be completely controlled by established therapies. It has been argued that intracrine biology involving the formation of self-sustaining intracrine regulatory loops accounts for the progression of these disorders and for the inability of standard therapies to stop disease spread. The renin-angiotensin system is a prime candidate to be involved in any such process, and an amplifying role for mineralocorticoid activation is also consistent with this view. Here, the notion of intracrine participation in congestive heart failure and chronic renal disease is expanded to include consideration of the participation of other intracrines including transforming growth factor beta 1, parathyroid hormone-related protein and vascular endothelial growth factor among others. The possibility that intracrine expression patterns account for disease phenotypes is explored. The therapeutic implications of this view are discussed.

Background Reliable approaches for measuring antihypertensive medication compliance in the outpatient setting are not readily available. The objective of the current study was to determine the reliability of the Hill-Bone Compliance Scale among elderly hypertensive patients. Methods We conducted a cross-sectional survey of community-dwelling patients attending the hypertension section of the Internal Medicine Clinic in a large multispecialty group practice. Participants (n = 239) completed a self-administered questionnaire consisting of demographic questions and the Hill-Bone Compliance to High Blood Pressure Therapy Scale, which includes a nine-item medication compliance subscale. Results The mean age of respondents was 69 years; 51% of patients were men, 73% were white, 86% had at least a high school education, and 61% were married. The Cronbach alpha was 0.68 for the medication compliance subscale. All nine items of the medication compliance subscale maintained higher correlations with their own subscale total than with the salt intake and appointment keeping subscale totals. After adjusting for other demographic variables, the odds ratio (95% confidence interval) of perfect medication compliance as reported on the medication compliance subscale was 1.71 (0.95–3.07) for participants 65 years of age and older versus those younger than 65 years of age, 2.53 (1.37–4.66) for whites versus non-whites, 1.27 (0.73–2.20) for males versus females, 1.30 (0.73–2.29) for married versus unmarried participants, and 1.63 (0.74–3.62) for those with at least a high school education versus those with less education. Conclusion The medication compliance subscale of the Hill-Bone Compliance Scale appears reliable and may be a useful tool for detecting noncompliant patients in outpatient settings.

Accumulating evidence has made it clear that not only does the renin-angiotensin-aldosterone system (RAAS) exist in the circulation where it is driven by renal renin, but it is also active in many tissues-and likely within cells as well. These systems might not be completely independent of each other, but rather interact. These local RAASs affect tissue and cellular angiotensin II concentrations and appear to be associated with clinically relevant physiologic and pathophysiologic actions in the cardiovascular system and elsewhere. Evidence in support of this possibility is reviewed here. In addition, direct (pro)renin action after binding to its specific receptor, the existence of renin transcripts, which apparently encode an intracellular renin, the discovery of an angiotensin-converting-enzyme homologue (ACE2), which leads to enhanced generation of angiotensin-(1-7) and the newly appreciated role of angiotensin-receptor dimerization in the regulation of angiotensin activity, all point to the conclusion that the RAASs are complexly regulated, multifunctional systems with important roles both within and outside the cardiovascular system.

The RAAS is a powerful regulator of vascular tone and intravascular volume and of tissue architecture and a variety of other functions. The recent appreciation of the immunoregulatory role of angiotensin II and its possible involvement in the genesis of atherosclerosis and in plaque rupture all speak to the wide-ranging physiologic and pathophysiologic activities of the peptide. So do its actions in fat cell differentiation and in neuromodulation. The system exists in the circulation, and RAASs, whole or partial, exist in many tissues. These systems are regulated at many levels ranging from the synthesis of renin to the dimerization of angiotensin receptors. Regulation occurs in multiple tissues and, as a result, tissue concentrations of angiotensin II and the concentration of other RAS components and their active metabolites can vary independently of the circulating system in these tissues. An RAS seems also to function within certain cells. Therapeutic interventions involving ACEIs and ARBs seem likely to provide benefit at least in part through the interruption of local systems. It is to be expected that with enhanced understanding of the biology of the multiple RASs, new suggestions for therapeutic interventions will be forthcoming.

BACKGROUND Pharmacy refill adherence assesses the medication-filling behaviors, whereas self-report adherence assesses the medication-taking behaviors. We contrasted the association of pharmacy refill and self-reported antihypertensive medication adherence with blood pressure (BP) control and cardiovascular disease (CVD) incidence. METHODS AND RESULTS Adults (n = 2075) from the prospective Cohort Study of Medication Adherence among Older Adults recruited between August 2006 and September 2007 were included. Antihypertensive medication adherence was determined using a pharmacy refill measure, medication possession ratio (MPR; low, medium, and high MPR

Chronic neurologic diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as various forms of chronic renal disease and systolic congestive heart failure, are among the most common progressive degenerative disorders encountered in medicine. Each disease follows a nearly relentless course, albeit at varying rates, driven by progressive cell dysfunction and drop–out. The neurologic diseases are characterized by the progressive spread of disease–causing proteins (prion–like proteins) from cell to cell. Recent evidence indicates that cell autonomous renin angiotensin systems operate in heart and kidney, and it is known that functional intracrine proteins can also spread between cells. This then suggests that certain progressive degenerative cardiovascular disorders such as forms of chronic renal insufficiency and systolic congestive heart failure result from dysfunctional renin angiotensin system intracrine action spreading in kidney or myocardium.

The presence, and in many cases the regulated synthesis, of components of the renin-angiotensin system have been demonstrated in multiple tissues, indicating the existence of tissue angiotensin-generating systems. These vary with respect to which renin-angiotensin system components are synthesized locally and which are taken up from plasma. Enzymes unrelated to the classical renin-angiotensin system may also contribute to tissue angiotensin synthesis. However, based on the available data, the prevailing opinion that kidney-derived renin is in all cases the only physiologically relevant renin in tissues must be revised. Also there is evidence indicating a role for tissue angiotensin systems in the pathogenesis of cardiovascular disease and in cardiovascular structural remodeling. The angiotensin-regulated synthesis of aldosterone in cardiac tissue has been described, suggesting the possibility that a renin-angiotensin-aldosterone system exists in the heart. In addition, intracellular (intracrine) sites of angiotensin action have been reported. Some of these findings have implications for therapeutics and, in particular, for the use of angiotensin converting-enzyme inhibitors and angiotensin receptor blockers. Finally, tissue angiotensin systems outside the cardiovascular system also appear to be physiologically relevant.

Article-at-a-Glance Introduction It has been proposed that a ratio of the discordant cells from a McNemar's Chi-square table be used as a measure of quality improvement, and that this measure be called the Quality Improvement Ratio (QuIR). As proposed, patients enrolled in only one year of a two-year study are excluded from the McNemar's table of the QuIR. Since the original proposal of the McNemar's Chi-square in 1947 included application to matched pair data, a more comprehensive analysis would be possible if the single-year enrollees were matched into pairs. Methods Patients enrolled in only the first study year are matched and paired with patients enrolled in only the second study year. The pairs are matched on variables important to the disease or process being evaluated. The matched pairs are combined with the repeatedly measured subjects to increase the statistical power of the analysis. The Combined Quality Improvement Ratio (CQuIR) is demonstrated with parameters from the original articles, in a–Markov chain Monte-Carlo simulation, so a direct comparison can be made. Results CQuIR improved statistical power, especially in simulations of small populations. In some simulations the statistical power was double that of the QuIR alone. Discussion Although the QuIR provides important information, the CQuIR allows more of the data to be used to evaluate the effect of interventions in policy, delivery, and practice. The increase in statistical power of the CQuIR over the QuIR can facilitate successful evaluation of health care services.

Detection controlled estimation (DCE) is a powerful new econometric estimator in the family of missing data estimators. By collecting measures from a variety of inspectors or inspection technologies, DCE is able to make inferences about the entire population, even when that population is not directly observed. Using this innovative method, we were able to assess whether telemedicine technology could be substituted for in-person visits when providing maintenance care for patients with hypertension. Our findings indicate that there is no support for the proposition that telemedicine is less effective than in-person visits for determining whether patients have high blood pressure. Indeed, our results imply that telemedicine misses 7% fewer cases of high blood pressure than in-person visits do. The results of this study indicate that DCE may be an effective tool for use in cost-effectiveness or cost-benefit analysis in health care. Copyright © 2001 John Wiley & Sons, Ltd.

Dear Colleagues: This is the sixth annual report to you, our readers, who are the major raison d’etre of Hypertension. We continue to be most heartened by your words of encouragement; many of you have also supported our journal by submitting and reviewing the best manuscripts in the field of hypertension and blood pressure regulation and control. With respect to our most recent publication statistics, we are proud and pleased to tell you that the impact factor of our journal remains the highest of all hypertension journals. The number of manuscripts submitted to us continues to increase. Last year, 1054 manuscripts were submitted to the journal; and, as of November 1, we have received 1090 papers and we conservatively anticipate receiving 1250 submissions by year’s end. We continue to maintain a very speedy initial review time of 3.9 weeks from submission to first decision and 13.7 weeks from submission to final acceptance. As you know, the first figure is probably the most pertinent for the author to assess the promptness of journal review. The latter figure reflects many other factors including the speediness of the authors to respond to the reviewers’ comments and suggestions (including the performance of additional experiments). Special note should be made that over the past six years, we have increased the number of clinical research papers published in Hypertension so that now they comprise over one half of the manuscripts published. They are of the very best work in clinical investigation and, clearly, are on par with those papers published in our journal from the various fundamental laboratory sciences. We are also pleased that over one half of the papers submitted to Hypertension emanate from the best laboratories of countries other than the United States. The top five countries submitting papers in the past year to …

With this issue, we begin our renewed tenure as Editors of our journal, and we are pleased to advise our readers of the journal’s progress during our first five-year stint. As we communicated to you last year, the editors are truly pleased and honored with the confidence of the American Heart Association and its Scientific Publishing Committee who have awarded our team, for the first time with Hypertension , another three years to continue our editorial responsibilities. We are delighted to accept this vote of confidence. Clearly, the successes of our initial five years would not have been possible without the support that we have received from: the authors and readers of our journal; the tremendous number of reviewers of the submitted manuscripts (now exceeding 1800 scientists); and the hard-working members of our Editorial Board. Without such broad support, we would not have had this tremendous success that we all enjoy. We publicly extend to each of you our deep gratitude. Much of your hard work can be translated into very real and hard data. Thus, in 1998 our journal received almost 1100 manuscripts (and we did not have an Inter-American Society of Hypertension meeting this year). We are most grateful to William B. Campbell, PhD, Guest Editor for the publication of the proceedings of the annual Fall meeting of the Council for High Blood Pressure Research, and to Joey P. Granger, PhD, Guest Editor for the biennial publication of the Inter-American Society of Hypertension proceedings. The review process by their respective peer-review committees resulted in rapid publication of these two important issues in Hypertension . We must emphasize the giant task of these two review processes, which may be summarized by the fact that these proceedings were published within four months of these two important scientific meetings. Support of …

Angiotensin II, a major effector protein of the renin-angiotensin, system plays important roles in the regulation of arterial pressure and intravascular volume. In addition, operating at the systemic, tissue, and cellular levels it modifies vascular structure and inflammation, thereby participating in the pathogenesis of hypertension, atherosclerosis, and vascular stiffening. Here recent findings regarding angiotensin II biology and their potential relevance for vascular biology and disease are discussed

OBJECTIVE: We investigated and compared the effects of three different comorbid indices on selection of procedure and outcome variation to determine which, if any, could be used for interpreting outcomes data. DESIGN: Retrospective cohort study. SETTING: Large multispecialty group practice. PATIENTS: Patients (aged 55–85 years) with residence in the United States who underwent a first-time prostatectomy for benign prostatic hyperplasia: 302 total; 253 transurethral procedures (TURP) versus 49 open procedures (OP). MEASUREMENTS AND MAIN RESULTS: The following indices were used to assess comorbid disease: Charlson index (CI), index of coexistent disease (ICED), and Kaplan-Feinstein index (KFI). The main outcome measure was the five-year mortality rate. The unadjusted five-year mortality rates were 16% (40/ 253) for TURP and 4% (2/49) for OP; survival analysis revealed this difference to be marginally significant at thep=.05 level. In an effort to control for the effect of comorbidity, CI, ICED, and KFI were independently assessed; together with age, they each had similar effects in rendering the risk of death associated with procedure type insignificant. However, comorbidity, as derived with ICED (not CI or KFI), was identified as a confounding variable when assessing the five-year mortality rate after prostatectomy as ICED was associated with the procedure type (predictor variable) and the five-year mortality (outcome variable). CONCLUSION: Differences in the composition and scoring of comorbid indices may have important implications for interpreting outcomes data. Nevertheless, these results, together with those of previous studies, suggest that the reported increased mortality for patients undergoing TURP is probably due to case-mix differences.

We have previously shown that oligonucleotides designed to bind in triplex fashion to a specific p53 binding site homology inhibit the proliferation of colon cancer cells in vitro. The present study was designed to extend these observations in an in vivo model. HCT 116 human colon carcinoma cells were injected subcutaneously into Ncr nude mice and tumors formed at one to two weeks. Tumors were injected daily for 14 days with either triplex forming oligonucleotide (Hoog 1), a scrambled Hoog 1 oligonucleotide (Hoog3) as control, or vehicle. Tumor size was measured twice weekly. Active triplex forming oligonucleotide (Hoog1) reduced tumor size in comparison to either control oligonucleotide (Hoog3) or vehicle. Tumor sizes in the three groups were significantly different (P < 0.001). Student Newman Keuls test shows statistically significant differences between the experimental group and each of the control and vehicle groups (P < 0.05). A triplex forming oligonucleotide directed at a p53 consensus binding site reduces tumor growth suggesting a novel method of tumor inhibition.

Cardiac myocytes (AT-1 cells) derived from heart tumors of mice transgenic for an atrial natriuretic factor promoter, SV40 large T-antigen DNA transgene, demonstrate properties consistent with normal cardiac myocytes but retain the capacity to proliferate in culture. We studied the renin-angiotensin system (RAS) and related growth regulation of these cells because AT-1 cells (or transgenically similar cells) may be useful to repair injured myocardium. This study reveals two separate and distinct findings: 1) AT-1 cells proliferate or hypertrophy in response to angiotensin II (ANG II), depending on their competence to proceed through the cell cycle; and 2) AT-1 cells possess components of a RAS, and angiotensinogen antisense experiments suggest that the RAS is functional in these cells. Specifically, AT-1 cells proliferate in response to ANG II in low-serum medium but hypertrophy in response to ANG II when first treated with mitomycin C (at a concentration that inhibits DNA replication but is not cytotoxic). The ANG II-mediated proliferative and hypertrophic responses are inhibited by DuP 753. In addition, there is a significant increase in the protein-to-DNA ratio of cells, which are proliferation-inhibited in the absence of ANG II treatment (20%, P < 0.05). DuP 753 also inhibits this hypertrophy, suggesting that these cells possess a functional RAS. AT-1 cells contain mRNAs for angiotensin-converting enzyme, renin, angiotensinogen, and the AT1 receptor as determined by sequence analysis of polymerase chain reaction amplification products. Antisense oligonucleotides complementary to the angiotensinogen mRNA specifically inhibit angiotensinogen mRNA accumulation and proliferation of AT-1 cells. In summary, these cells contain a growth-regulating RAS, suggesting that such a system may play a significant role in left ventricular hypertrophy.

The circulatory effects associated with lifelong plasma atrial natriuretic factor (ANF) elevation were examined by generating transgenic mice, which constitutively express a fusion gene consisting of the transthyretin promoter and the ANF structural gene. These mice have chronically elevated ANF levels as compared with their nontransgenic siblings. Transgenic animals exhibited immunoreactive ANF levels that were nearly fivefold higher than those measured in nontransgenic littermates. Systemic and regional hemodynamics and blood volumes were explored by using modifications of the reference microsphere and dilution techniques. Mean arterial pressure was reduced by 24 mm Hg, associated with a 27% reduction in total heart weight. This chronic reduction in blood pressure was due to a 21% reduction in total peripheral resistance, whereas cardiac output, stroke volume, and heart rate were not significantly altered, despite a 15% elevation in plasma volume. Transgenic mice displayed reductions of 35%, 33%, 32%, and 19% in muscle, skin, brain, and renal vascular resistance, respectively, whereas coronary and splanchnic resistances were not significantly altered. The findings complement earlier data from chronically infused normotensive mammals and suggest that these mice are an excellent model for investigating the effects of lifelong ANF elevation.

OBJECTIVE: To determine the ability of patient-reported health status information to predict physician-determined fit-for-work status for patients reporting complaints of low back pain. DESIGN: Cross-sectional study using survey methods. SETTING: Occupational medicine section of a large multispecialty private clinic. PATIENTS: Four hundred sixty-two questionnaire packets were distributed to patients who were seen for work-related conditions or disorders over a 13-week period; 235 questionnaires were returned (51% response rate). One hundred seven responders reported low back pain and completed the Low Back Pain TyPE (Technology of Patient Experience) Tool. The mean (+/- SD) age of respondents was 39 (+/- 12) years; 67% of respondents were male, 70% were white, 87% were receiving worker's compensation, 58% were married, and 55% had a high school education or less. INTERVENTIONS: Questionnaire packets for self-administration containing health/functional status questions (short form [SF]-36, COOP Charts) and the Low Back Pain TyPE Tool were distributed to the patients. Other variables were abstracted from the medical records and administrative databases. MAIN OUTCOME MEASURES: The primary study outcome measured was fitness for work; patients were examined and categorized as fit or not fit for work by physicians who were unaware of the questionnaire results. RESULTS: Logistic regression analysis consisted of variables from 107 patients who reported low back pain. The final model contained the physical functioning scale (SF-36), employment status, smoking status, and physical functioning (SF-36) by gender interaction. Seventy-seven percent of the fit-for-work cases and 90% of the not-fit-for-work cases were correctly classified. CONCLUSION: Patient-reported physical function (as modified by gender), smoking status, and employment status predicted physician-determined work status for patients reporting low back pain in this study. Larger studies will be required to confirm this finding.

Angiotensin II is a modulator of myometrial activity; both AT1 and AT2 receptors are expressed in myometrium. Since in other tissues angiotensin II has been reported to activate intracellular receptors, we assessed the effects of intracellular administration of angiotensin II via microinjection on myometrium, using calcium imaging. Intracellular injection of angiotensin II increased cytosolic Ca2+ concentration ([Ca2+]i) in myometrial cells in a dose-dependent manner. The effect was abolished by the AT1 receptor antagonist losartan but not by the AT2 receptor antagonist PD-123319. Disruption of the endo-lysosomal system, but not that of Golgi apparatus, prevented the angiotensin II-induced increase in [Ca2+]i. Blockade of AT1 receptor internalization had no effect, whereas blockade of microautophagy abolished the increase in [Ca2+]i produced by intracellular injection of angiotensin II; this indicates that microautophagy is a critical step in transporting the peptide into the endo-lysosomes lumenum. The response to angiotensin II was slightly reduced in Ca2+-free saline, indicating a major involvement of Ca2+ release from internal stores. Blockade of inositol 1,4,5-trisphosphate (IP3) receptors with heparin and xestospongin C or inhibition of phospholipase C (PLC) with U-73122 abolished the response to angiotensin II, supporting the involvement of PLC-IP3 pathway. Angiotensin II-induced increase in [Ca2+]i was slightly reduced by antagonism of ryanodine receptors. Taken together, our results indicate for the first time that in myometrial cells, intracellular angiotensin II activates AT1-like receptors on lysosomes and activates PLC-IP3-dependent Ca2+ release from endoplasmic reticulum; the response is further augmented by a Ca2+-induced Ca2+ release mechanism via ryanodine receptors activation.

Over the past 3 decades it has become clear that a large number of extracellular signaling proteins/peptides also act in the intracellular space. These factors are termed intracrines and, although diverse in structure, they share a variety of functional features. In recent years, attention has increasingly turned to identifying the intracellular mechanisms of intracrine action and their implications for human disorders, such as cancer and cardiovascular disease. Perhaps not surprisingly, some intracrines have been shown to bind to and activate their cognate receptors located on intracellular membranes, such as the nuclear envelope. Here we discuss known intracrine actions and argue that mechanisms distinct from membrane receptor activation (that is, "noncanonical" actions) are often operative and physiologically relevant. These actions, we argue, expand our understanding of peptide signaling in important ways. Moreover, an appreciation of noncanonical intracrine functionality informs our understanding of the major effector protein of the renin-angiotensin system, angiotensin II, as well as other hormones operative in cardiovascular biology.

The renin-angiotensin system has long been known as a potent determinant of cardiovascular homeostasis and a powerful regulator of vascular hemody namics. Over the last twenty years, it has become clear that components of the renin-angiotensin system are present in and, in many instances, synthesized in local tissues. The role of some of these local renin systems is now becoming clear, but the role, if any, of local production of angiotensin II in the heart and vasculature remains unknown. Recent evidence indicates that angiotensin II can serve as a growth factor for a variety of cell types including those in the cardio vascular system, and it thus appears possible that systemically or locally pro duced angiotensin II could subserve important functions in the determination of heart and vasculature structure. Clinical studies tend to corroborate this possi bility. The potent effects of converting enzyme inhibition on the regression of left ventricular hypertrophy, the demonstration that the administration of these agents following myocardial infarction reduces detrimental cardiac remodeling, and the finding that converting enzyme inhibition prolongs survival in conges tive heart failure patients all point to an important role of angiotensin II on cardiovascular function and raise the distinct possibility that angiotensin II growth effects are involved in these beneficial responses. Additionally, recent data demonstrate conclusively that under certain circumstances and in certain cell types locally produced angiotensin II can serve as an autocrine growth regu latory factor, further adding support to the idea that local renin systems may play an important role in the determination of cardiovascular structure.

We have generated transgenic mice that express angiotensin II (ANG II) fused downstream of enhanced cyan fluorescent protein, expression of which is regulated by the mouse metallothionein promoter. The fusion protein, which lacks a secretory signal, is retained intracellularly. In the present study, RT-PCR, immunoblot analyses, whole-animal fluorescent imaging, and fluorescent microscopy of murine embryonic fibroblasts confirm expression of the fusion protein in vivo and in vitro. The transgene is expressed in all tissues tested (including brain, heart, kidney, liver, lung, and testes), and radioimmunoassay of plasma samples obtained from transgenic mice indicate no increase in circulating ANG II over wild-type levels, consistent with intracellular retention of the transgene product. Kidneys from transgenic and corresponding wild-type littermates were histologically evaluated, and abnormalities in transgenic mice consistent with thrombotic microangiopathy were observed; microthrombosis was frequently observed within the glomerular capillaries and small vessels. In addition, systolic and diastolic blood pressures, measured by telemetry ( n = 8 for each group), were significantly higher in transgenic mice compared with wild-type littermates. Blood pressure of line A male transgenic mice was 125 ± 1.7 over 97 ± 1.6 compared with 109 ± 1.7 over 83 ± 1.4 mmHg in wild-type littermates (systolic over diastolic). In summary, overexpression of an intracellular fluorescent fusion protein of ANG II correlates with elevated blood pressure and kidney pathology. This transgenic model may be useful to further explore the intracellular renin-angiotensin system and its implication in abnormal kidney function and hypertension.

HYPERTENSIVE heart disease can be defined as the response of the heart to the afterload imposed on the left ventricle by the progressively increasing arterial pressure and total peripheral resistance produced by hypertensive vascular disease. Although the response sometimes appears to be out of proportion to the level of the arterial pressure, it is primarily the result of the hemodynamic overload. Hypertension can cause or is related to various cardiac manifestations, among them left ventricular hypertrophy, congestive heart failure, cardiac dysrhythmias, and ischemic heart disease. Although the risk of atherosclerotic coronary heart disease is related to the systolic and diastolic . . .

Innovation is intrinsic to medicine and to medical progress. As American medicine enters the twenty-first century, it is confronted with enormous opportunities to innovate both in the science and practice of medicine. Indeed, medicine is challenged to do so by society. Cellular and molecular medicine, along with new insights derived from health care research, offer the opportunity to improve the health of the American people without unduly taxing the economy. Research and innovation in these areas are within the grasp of many clinics, and it would seem important that, because they are major providers of health care, as many clinics as possible aggressively enter these fields in preparation for delivering health care in the next century.

The concept of local renin angiotensin systems in the cardiovascular system is discussed, and evidence is presented that these systems work independently of the systemic one.

Are Local Renin-Angiotensin Systems the Focal Points for Understanding Salt Sensitivity in Hypertension?.- Newer Insights into the Biochemical Physiology of the Renin-Angiotensin System: Role of Angiotensin-(1-7), Angiotensin Converting Enzyme 2, and Angiotensin-(1-12).- Renin, Prorenin, and the (Pro)renin Receptor.- Intracellular Accumulation and Nuclear Trafficking of Angiotensin II and the Angiotensin II Type 1 Receptor.- Pathophysiologic Implications of Cell Swelling in the Failing Heart: Influence of Intracrine and Extracellular Renin-Angiotensin Systems.- Exploiting Rat Genetics to Investigate Hypertensive End-Organ Damage.- Alternative Renin Transcripts and Functions of Cytoplasmatic Renin.- Novel Aspects of the Cardiac Renin-Angiotensin System.- Intracrine Function from Angiotensin to Stem Cells.- Renin Cell Identity and Homeostasis.- Role of Renal Aminopeptidases and Angiotensin Type-2 (AT2) Receptors in Sodium Excretion and Hypertension.- Intrarenal Angiotensin II Augmentation in Hypertension.- Collecting Duct Renin: A Critical Linkin Angiotensin II-Dependent Hypertension.- Renin-Angiotensin-Aldosterone System and Cardiomyocyte Apoptosis in Hypertensive Heart Disease.- Upregulation of Angiotensin II Type 2 Receptor (agtr2) Attenuates Atherosclerotic Lesion Formation and Enhances Apoptosis in the LDL Receptor Knockout Mice Fed High Cholesterol Diet.- Salt and Heart: RAAS Involvement.- Cardiac Effects of Aldosterone, the Bad, but Is There Also a Good?.

The renin angiotensin system (RAS) is an established regulator of intravascular volume and arterial pressure. It is now clear that complete and partial RASs exist in multiple tissues, including the cardiovascular system, with the result that local regulation of angiotensin can occur. In addition, newly identified factors such as ACE 2 and the (pro)renin receptor expand the potential physiological actions of these tissue RASs. Here evidence for the existence and functional relevance of local RASs in cardiovascular tissues is reviewed.

Abnormalities of cellular growth regulation are integral to the development of cardiovascular disorders such as atherogenesis, ventricular hypertrophy, and diabetic glomerulopathy. Moreover, cellular growth is in large measure controlled by peptide and nonpeptide growth factors that mediate their actions, in part, through the transcriptional regulation of normal cellular genes called protooncogenes. Because angiotensin II is one such growth regulatory factor and because changes in intracellular calcium are intimately involved in the action of angiotensin and other growth factors, it is likely that inhibitors of angiotensin action and calcium-channel-blocking agents will be found to have useful growth regulatory properties.

In post-disaster situations, additional barriers may reduce antihypertensive medication adherence.Between November 2005 and August 2006, 210 hypertensive patients receiving care at a multispecialty group practice in New Orleans completed a structured questionnaire. Antihypertensive medication adherence was measured with the Hill-Bone medication compliance subscale. In a subset of patients, data on difficulties patients encountered with blood pressure medications in the aftermath of Hurricane Katrina were collected.: Seventy-six percent of patients reported damage to their residence and 46% of patients had less-than-perfect medication adherence. After multivariate adjustment, less than perfect medication adherence postdisaster was more common among people aged65 years (prevalence ratio = 1.37; 95% confidence interval: 1.03-1.82) and non-whites (1.32; 95% confidence interval: 1.02-1.71). Uncontrolled blood pressure (systolic/diastolicor =140/or =90 mm Hg) was more common in those with less-than-perfect adherence than their counterparts with perfect adherence (51% versus 42%, respectively). In addition, 7% of patients reported not bringing their blood pressure medications when they evacuated, 28% ran out of blood pressure medications, 16% reported difficulties getting medications filled, and 28% reported a blood pressure medication change postdisaster.Opportunities exist to improve disaster planning and prescription refill processes and increase medication adherence and hypertension control postdisasters.

Angiogenesis, the generation of new blood vessels from pre-existing vessels, is an integral component of wound healing, responses to inflammation and other physiologic processes. It is also an essential part of tumor growth; in the absence of new vessel formation, tumors cannot expand beyond a small volume. Although much is known about angiogenesis and its regulation, there is no overall theory that describes or explains this process. It is here suggested that the intracrine hypothesis, which ascribes to certain extracellular signaling peptides (whether hormones, growth factors, DNA-binding proteins or enzymes) a role in both intracellular biology and extracellular signaling, can contribute to a more general understanding of angiogenesis. Intracrine factors participate in angiogenesis in the following ways: (1) they can act within the cells that synthesized them (type I intracrine action), (2) they can be secreted and then taken up by their cell of synthesis to act intracellularly (type II intracrine action ), or (3) they can be secreted and internalized by a distant target cell (type III intracrine action). The parallels between the intracrine growth factor mechanisms cancer cells employ in stimulating their own growth and the mechanisms operative in endothelial cell proliferation during angiogenesis ("intracrine reciprocity") are discussed. Collectively, these explorations lead to testable hypotheses regarding the regulation of normal and pathological angiogenesis, and point to similarities between tumor-induced angiogenesis and tissue differentiation.