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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

It has become clear that the vasoactive peptide angiotensin II, like other so-called intracrines, can act in the intracellular space. Evidence has accumulated indicating that such angiotensin II activity can be upregulated in disease states and cause pathology. Indeed, other intracrines appear to be involved in disease pathogenesis as well. At the same time, nitric oxide, potentially a cell protective factor, has been shown to be upregulated by intracellular angiotensin II. Recently data have been developed indicating that other potentially protective factors are directly upregulated at neuronal nuclei by angiotensin II. This led to the suggestion that intracellular angiotensin II is cell protective and not pathological. Here, the data on both sides of this issue and a possible resolution are discussed. In summary, there is evidence for both protective and pathological actions of intracellular angiotensin, just as there is abundant evidence derived from whole animal physiology to indicate that angiotensin–driven signaling cascades, including angiotensin II type 2 receptor- and Mas receptor-mediated events, can mitigate the effects of the angiotensin II/angiotensin II type 1 receptor axis (25). This mitigation does not negate the physiological and pathological importance of angiotensin II/angiotensin II type 1 receptor action but does expand our understanding of the workings of both intracellular and extracellular angiotensin II.

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.

Transmissible spongiform encephalopathies have been shown to result from the misfolding of normal cellular prion proteins in neurons caused by a transmissible abnormal form of the protein. in recent years, similar transmission of abnormal proteins capable of inducing abnormal folding of their normal homologues has been reported in other neurological disorders including Alzheimer’s disease, Parkinson’s disease and the so-called tauopathies. Thus, a new paradigm—the notion that some neurodegenerative disorders are protein “foldopathies”—has gained wide support. in addition, over recent years, the notion that some intercellular signaling proteins/peptides are intracrines—that is, they can in some instances act within their cells of synthesis or within target cells—has also gained currency. Tenets of this intracrine physiology/action have been developed. Here, it is argued that the protein functionalities demonstrated by foldopathy-related proteins are similar to intracrine actions and that these disorders could be intracrine in nature. if correct, this proposal would have therapeutic implications.

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.

Several transmembrane receptors are documented to accumulate in nuclei, some as holoreceptors and others as cleaved receptor products. Our prior studies indicate that a population of the 7-transmembrane angiotensin type-1 receptor (AT1R) is cleaved in a ligand-augmented manner after which the cytoplasmic, carboxy-terminal cleavage fragment (CF) traffics to the nucleus. In the present report, we determine the precise cleavage site within the AT1R by mass spectrometry and Edman sequencing. Cleavage occurs between Leu(305) and Gly(306) at the junction of the seventh transmembrane domain and the intracellular cytoplasmic carboxy-terminal domain. To evaluate the function of the CF distinct from the holoreceptor, we generated a construct encoding the CF as an in-frame yellow fluorescent protein fusion. The CF accumulates in nuclei and induces apoptosis in CHO-K1 cells, rat aortic smooth muscle cells (RASMCs), MCF-7 human breast adenocarcinoma cells, and H9c2 rat cardiomyoblasts. All cell types show nuclear fragmentation and disintegration, as well as evidence for phosphotidylserine displacement in the plasma membrane and activated caspases. RASMCs specifically showed a 5.2-fold increase ( P < 0.001) in CF-induced active caspases compared with control and a 7.2-fold increase ( P < 0.001) in cleaved caspase-3 (Asp174). Poly(ADP-ribose)polymerase was upregulated 4.8-fold ( P < 0.001) in CF expressing cardiomyoblasts and colocalized with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). CF expression also induces DNA laddering, the gold-standard for apoptosis in all cell types studied. CF-induced apoptosis, therefore, appears to be a general phenomenon as it is observed in multiple cell types including smooth muscle cells and cardiomyoblasts.

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.

Some extracellular-signaling peptides also at times function within the intracellular space. We have termed these peptides intracrines and have argued that intracrine function is associated with a wide variety of peptides/proteins including hormones, growth factors, cytokines, enzymes, and DNA-binding proteins among others. Here we consider the possibility that intracrines participate in the related phenomena of senescence, apoptosis, and stem cell regulation of tissue biology. Based on this analysis, we also suggest that the concept of intracrine action be expanded to include possible regulatory peptide transfer via exosomes/microvesicles and possibly by nanotubes. Moreover, the process of microvesicular and nanotube transfer of peptides and other biologically relevant molecules, which we inclusively term laterality, is explored. These notions have potentially important therapeutic implications, including implications for the therapy of cardiovascular disease.

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.

Intracrine peptides and proteins participate in the regulation of adult and pleuripotential embryonic-like stem cells. Included among these factors are VEGF, dynorphin, the readthrough form of acetylcholinesterase, Oct3/4, Pdx-1, Pax-6, and high-mobility group protein B1, among others. In some cases, the establishment of intracrine feedback loops can be shown to be relevant to this regulation, consistent with previously proposed principles of intracrine action. Here the role of intracrines in stem cell regulation is reviewed, with particular attention to the intracrine regulation of cardiac stem cells. The reprogramming of cells to restore the pleuripotent phenotype and the possible role of stem/progenitor cells in neoplasia are also discussed.

Proteins that bind to the intracellular expanses, particularly cytoplasmic tail regions, of heptahelical integral membrane receptors are of particular interest in that they can mediate or modulate trafficking or intracellular signaling. In an effort to distinguish new proteins that might promote angiotensin II type 1 (AT 1 ) receptor intracellular events, we screened a yeast 2-hybrid mouse brain library with the rat AT 1A receptor (AT 1 R) carboxyl terminus and identified GABARAP, a protein involved in intracellular trafficking of the GABA A receptor, as a binding partner for the AT 1 R. Interaction of GABARAP with the AT 1 R carboxyl terminus was further substantiated using GST pull-down assays, and binding of the full-length tagged AT 1 R to GABARAP was verified using coimmunoprecipitation. Bioluminescence resonance energy transfer assays further confirmed specific interaction of GABARAP with AT 1 R. Moreover, GABARAP clearly increased the steady-state level of plasma membrane-associated AT 1 R in PC-12 cells. Cotransfection of GABARAP with an AT 1 R fluorescent fusion protein increased PC-12 cell surface expression of the AT 1 R more than 6-fold when standardized to the level of intracellular expression. Furthermore, GABARAP overexpression in CHO-K1 cells engineered to express AT 1 R increased angiotensin II binding sites 3.7-fold and angiotensin II–induced phospho–extracellular signal-regulated kinase 1/2 and cellular proliferation significantly over levels obtained with AT 1 R overexpression alone. In addition, small interfering RNA–mediated knockdown of GABARAP reduced the steady-state levels of the AT 1 R fluorescent fusion protein by 43% and its cell surface expression by 84%. Immunoblot analyses confirmed the quantitative image data. We conclude that GABARAP binds to and promotes trafficking of the AT 1 R to the plasma membrane.

Intracrines are extracellular signaling peptide factors that can act in the intracellular space after either internalization or retention in the cells that synthesize them. They are structurally diverse and include hormones, growth factors, enzymes, DNA-binding proteins, and other peptide moieties. We have suggested principles of intracrine action and have applied those principles to forms of cellular and tissue differentiation, hormonal responsiveness, and memory. Moreover, recent findings make clear that some currently available pharmaceuticals act via the alteration of intracrine function. Thus, the beginnings of an intracrine pharmacology are at hand and we here review principles applicable to the design of such agents. The intracrine pharmacology of the renin-angiotensin system, angiogenesis, and stem cell development is discussed.

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.

The intracellular actions of peptide hormones, growth factors, as well as of extracellular-signaling enzymes and DNA-binding proteins, either within target cells or within their cells of synthesis has been called intracrine action. Although these intracrine moieties are structurally diverse, they share certain characteristics of synthesis and function. This has given rise to the development of a theory of intracrine action which permits testable predictions to be made regarding the functioning of these peptides/proteins. Here the intracrine hypothesis is briefly described and then recent experimental findings which bear on predictions made earlier on the basis of the theory are discussed. These findings provide new support for the intracrine hypothesis.

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.

In recently published studies, we show that angiotensin II (AII) generated from an engineered rat angiotensinogen cDNA, and maintained intracellularly, is growth stimulatory for a rat hepatoma cell line. In the present study, we report that co-expression of AII fused to cyan fluorescent protein (ECFP/AII) and angiotensin type I receptor fused to yellow fluorescent protein (AT1R/EYFP) enhances proliferation of COS-7 and CHO-K1 cells by 59% and 64%, respectively, compared to cells expressing the corresponding independent proteins (P < 0.001 for both). This effect is inhibited by losartan, suggesting (as in our previous published studies) that losartan is internalized by the cells, via receptor-mediated endocytosis, and thus inhibits intracellular receptor-ligand interaction. The growth effect is independent of anti-AII antibodies suggesting that it does not reflect AII secretion into the culture media; AII is also undetectable in the media. Expression of AT1R/EYFP with ECFP/AIIC (control scrambled sequence AII fused to ECFP) has no effect upon cell proliferation. ECFP/AII also alters the cellular localization of AT1R/EYFP. ECFP/AII is concentrated in the nucleus, but shows diffuse cytoplasmic fluorescence as well. AT1R/EYFP, expressed independently, is visible in the endoplasmic reticulum and Golgi apparatus of COS-7 and CHO-K1 cells as early as 24-h post-transfection. At 72 h, it is visibly associated with the plasma membrane. By 144 h, 85% of the cells show detectable circumferential fluorescence. In contrast, in cells that express AT1R/EYFP and ECFP/AII, both proteins accumulate in the nucleus and only 13% of the cells show visible plasma membrane-associated yellow fluorescence at 144 h (P < 0.001). Furthermore, co-expression of ECFP/AII with AT1R/EYFP stimulates cAMP response element-binding protein (CREB) activity in CHO-K1 and COS-7 cells. Exogenous AII similarly significantly increases CREB activation in AT1R/EYFP-stably transfected CHO-K1 and COS-7 cells.

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

J. L. Cook, J. F. Giardina, Z. Zhang and R. N. Re. Intracellular Angiotensin II Increases the Long Isoform of PDGF mRNA in Rat Hepatoma Cells. Journal of Molecular and Cellular Cardiology (2002) 34, 1525–1537. Our recent published studies suggest that angiotensin II (AII), generated and retained intracellularly, enhances growth of H4-II-E-C3 rat hepatoma cells, an average of 33%. Proliferation conferred by introduction of a plasmid [ Ang(-S)Exp/pSVL ] encoding a signal sequence-depleted angiotensinogen [Ang(-S)Exp] into these cells (which we have shown possess ACE and renin mRNAs) is mediated, at least in part, by enhanced PDGF-A chain mRNA production and protein secretion. The mitogenic effect is inhibited by losartan suggesting that it involves AII interaction with an AT1-like receptor. Introduction of anti-AII antibodies into the medium of these transfected cells has no effect upon growth of the cells, suggesting that AII is retained by the cells and that intracellular AII is growth stimulatory. In the present study, we sought to further characterize the intracellular localization and mode of action of Ang(-S)Exp. Consistent with our expectations, we now show that a fusion product of Ang(-S)Exp with green fluorescent protein [Ang(-S)Exp/EGFP], generated from an expression plasmid, is abundant and primarily cytoplasmic. Wild-type angiotensinogen/EGFP, in contrast, is only detectable following a cold-block (which acts to enhance folding-kinetics and slow secretion) and is largely restricted to the secretory pathway. We further show, using semi-quantitative RT/PCR that the long isoform of PDGF mRNA is elevated in Ang(-S)Exp transfected cells and in AII-treated naive cells but not in losartan-treated Ang(-S)Exp transfected cells. We identify C-terminal amidation recognition sites within the long-form protein (that are not present in the short-form) and show that these cells possess PAM (amidating enzyme precursor) and carboxypeptidase E mRNAs (the corresponding proteins of which are sufficient for amidation). Inhibitors of amidation inhibit growth of naive and Ang(-S)Cntr/ pSVL -transfected cells (2.6-fold for phenylbutenoic acid and 3.5-fold for disulfiram treatment) but more profoundly inhibit growth of Ang(-S)Exp/pSVL -transfected cells (6.7-fold for phenylbutenoic acid and 13-fold for disulfiram). In conclusion, these data confirm that signal sequence-depleted Ang(-S)Exp is retained within cells and is largely cytoplasmic. Because C-terminal amidation is absolutely required for full biological potency of a number of peptide hormones (including oxytocin, gastrin and calcitonin), we postulate that growth effects of both intracellular AII and exogenous AII can be conferred by PDGF long-form, possibly through an amidation-dependent mechanism.

Many extracellular signaling proteins act within their cells of synthesis and/or in target cells after internalization. This type of action is called intracrine and it plays a role in diverse biological processes. The mechanisms of intracrine intracellular action are becoming clear thanks to the application of modern techniques of molecular biology. Here, progress in this area is reviewed. In particular the intracrine biology of angiotensin II is discussed.

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.

Assessing the impact of new technologies on health care costs is an important research area. This paper evaluates two technologies used to treat coronary artery disease. We estimate two separate stochastic frontier models - one for balloon angioplasty patients and one for cardiac bypass surgery patient - using data taken from detailed chart and cost files of a large urban hospital. Cost estimates for the two technologies are purged of inefficiency so that forecasts of the cost consequences of technology shift can be based on "best-practice" production techniques. Learning behavior, physician effects, and patient clinical characteristics are also taken into account. We find that there are potential cost savings associated with making angioplasty a more perfect substitute for bypass surgery, as well as current inefficiency in production. © 2001 by the President and Fellows of Harvard College and the Massachusetts Institute of Technology

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 …

Abstract —Current theory holds that peptide hormone action results from hormone binding to cell-surface receptors, with the generation of intracellular second messengers. However, a growing body of evidence suggests that intracellular peptide hormone, either internalized or synthesized in situ, can exert physiologically relevant effects. These effects are diverse and poorly understood. I propose that such intracrine action can serve to modulate cellular function over time and thereby play a role in biological memory of various sorts, in the maintenance of hormonal responsiveness, and in cellular differentiation.

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

We previously identified the binding of the chaperone protein gamma-aminobutyric acid receptor-associated protein (GABARAP) to a sequence on the carboxy-terminus of the angiotensin II AT1 receptor (AT1R) and showed that this binding enhances AT1R trafficking to the cell surface as well as angiotensin signaling.In this study, we treated sodium-depleted mice with decoy peptides consisting either of a fusion of the cell-penetrating peptide penetratin and the GABARAP/AT1R binding sequence or penetratin fused to a mutated AT1R sequence. We used telemetry to measure blood pressure.Systolic and diastolic pressure fell during the 24 hours following decoy peptide injection but not after control peptide injection. Active cell-penetrating decoy peptide decreased 24-hour average systolic blood pressure from 129.8 ± 4.7 mmHg to 125.0 ± 6.0 mmHg (mean ± standard deviation). Diastolic blood pressure fell from 99.0 ± 7.1 mmHg to 95.0 ± 9.2 mmHg (n=5). Administration of the control peptide raised systolic blood pressure from 128.7 ± 1.3 mmHg to 131.7 ± 2.9 mmHg and diastolic pressure from 93.9 ± 4.5 mmHg to 95.9 ± 4.2 mmHg (n=5). The decreases in both systolic and diastolic blood pressure after active peptide administration were statistically significant compared to control peptide administration (P0.05, two-tailed Wilcoxon rank-sum test).These results indicate the physiological and potentially therapeutic relevance of inhibitors of GABARAP/AT1R binding.