Endosperm-based incompatibilities in hybrid monkeyflowers.

Endosperm is an angiosperm innovation central to their reproduction whose development, and thus seed viability, is controlled by genomic imprinting, where expression from certain genes is parent-specific. Unsuccessful imprinting has been linked to failed inter-specific and inter-ploidy hybridization. Despite their importance in plant speciation, the underlying mechanisms behind these endosperm-based barriers remain poorly understood. Here, we describe one such barrier between diploid Mimulus guttatus and tetraploid Mimulus luteus. The two parents differ in endosperm DNA methylation, expression dynamics, and imprinted genes. Hybrid seeds suffer from underdeveloped endosperm, reducing viability, or arrested endosperm and seed abortion when M. guttatus or M. luteus is seed parent, respectively, and transgressive methylation and expression patterns emerge. The two inherited M. luteus subgenomes, genetically distinct but epigenetically similar, are expressionally dominant over the M. guttatus genome in hybrid embryos and especially their endosperm, where paternal imprints are perturbed. In aborted seeds, de novo methylation is inhibited, potentially owing to incompatible paternal instructions of imbalanced dosage from M. guttatus imprints. We suggest that diverged epigenetic/regulatory landscapes between parental genomes induce epigenetic repatterning and global shifts in expression, which, in endosperm, may uniquely facilitate incompatible interactions between divergent imprinting schemes, potentially driving rapid barriers.

A likelihood ratio test for changes in homeolog expression bias.

BACKGROUND: Gene duplications are a major source of raw material for evolution and a likely contributor to the diversity of life on earth. Duplicate genes (i.e., homeologs, in the case of a whole genome duplication) may retain their ancestral function, sub- or neofunctionalize, or be lost entirely. A primary way that duplicate genes evolve new functions is by altering their expression patterns. Comparing the expression patterns of duplicate genes gives clues as to whether any of these evolutionary processes have occurred. RESULTS: We develop a likelihood ratio test for the analysis of the expression ratios of duplicate genes across two conditions (e.g., tissues). We demonstrate an application of this test by comparing homeolog expression patterns of 1448 homeologous gene pairs using RNA-seq data generated from leaves and petals of an allotetraploid monkeyflower (Mimulus luteus). We assess the sensitivity of this test to different levels of homeolog expression bias and compare the method to several alternatives. CONCLUSIONS: The likelihood ratio test derived here is a direct, transparent, and easily implemented method for detecting changes in homeolog expression bias that outperforms alternative approaches. While our method was derived with homeolog analysis in mind, this method can be used to analyze changes in the ratio of expression levels between any two genes in any two conditions.

A complementary transposon tool kit for Drosophila melanogaster using P and piggyBac.

With the availability of complete genome sequence for Drosophila melanogaster, one of the next strategic goals for fly researchers is a complete gene knockout collection. The P-element transposon, the workhorse of D. melanogaster molecular genetics, has a pronounced nonrandom insertion spectrum. It has been estimated that 87% saturation of the approximately 13,500-gene complement of D. melanogaster might require generating and analyzing up to 150,000 insertions. We describe specific improvements to the lepidopteran transposon piggyBac and the P element that enabled us to tag and disrupt genes in D. melanogaster more efficiently. We generated over 29,000 inserts resulting in 53% gene saturation and a more diverse collection of phenotypically stronger insertional alleles. We found that piggyBac has distinct global and local gene-tagging behavior from that of P elements. Notably, piggyBac excisions from the germ line are nearly always precise, piggyBac does not share chromosomal hotspots associated with P and piggyBac is more effective at gene disruption because it lacks the P bias for insertion in 5' regulatory sequences.

Population genetics of transposable element load: A mechanistic account of observed overdispersion.

In an empirical analysis of transposable element (TE) abundance within natural populations of Mimulus guttatus and Drosophila melanogaster, we found a surprisingly high variance of TE count (e.g., variance-to-mean ratio on the order of 10 to 300). To obtain insight regarding the evolutionary genetic mechanisms that underlie the overdispersed population distributions of TE abundance, we developed a mathematical model of TE population genetics that includes the dynamics of element proliferation and purifying selection on TE load. The modeling approach begins with a master equation for a birth-death process and extends the predictions of the classical theory of TE dynamics in several ways. In particular, moment-based analyses of population distributions of TE load reveal that overdispersion is likely to arise via copy-and-paste proliferation dynamics, especially when the elementary processes of proliferation and excision are approximately balanced. Parameter studies and analytic work confirm this result and further suggest that overdispersed population distributions of TE abundance are probably not a consequence of purifying selection on total element load.

Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.

BACKGROUND: Angiotensin-receptor blockers (ARBs) are effective treatments for patients with heart failure, but the relation between dose and clinical outcomes has not been explored. We compared the effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure. METHODS: This double-blind trial was undertaken in 255 sites in 30 countries. 3846 patients with heart failure of New York Heart Association class II-IV, left-ventricular ejection fraction 40% or less, and intolerance to angiotensin-converting-enzyme (ACE) inhibitors were randomly assigned to losartan 150 mg (n=1927) or 50 mg daily (n=1919). Allocation was by block randomisation stratified by centre and presence or absence of beta-blocker therapy, and all patients and investigators were masked to assignment. The primary endpoint was death or admission for heart failure. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00090259. FINDINGS: Six patients in each group were excluded because of poor data quality. With 4.7-year median follow-up in each group (IQR 3.7-5.5 for losartan 150 mg; 3.4-5.5 for losartan 50 mg), 828 (43%) patients in the 150 mg group versus 889 (46%) in the 50 mg group died or were admitted for heart failure (hazard ratio [HR] 0.90, 95% CI 0.82-0.99; p=0.027). For the two primary endpoint components, 635 patients in the 150 mg group versus 665 in the 50 mg group died (HR 0.94, 95% CI 0.84-1.04; p=0.24), and 450 versus 503 patients were admitted for heart failure (0.87, 0.76-0.98; p=0.025). Renal impairment (n=454 vs 317), hypotension (203 vs 145), and hyperkalaemia (195 vs 131) were more common in the 150 mg group than in the 50 mg group, but these adverse events did not lead to significantly more treatment discontinuations in the 150 mg group. INTERPRETATION: Losartan 150 mg daily reduced the rate of death or admission for heart failure in patients with heart failure, reduced left-ventricular ejection fraction, and intolerance to ACE inhibitors compared with losartan 50 mg daily. These findings show the value of up-titrating ARB doses to confer clinical benefit. FUNDING: Merck (USA).

Author Correction: Origin and evolution of the octoploid strawberry genome.

In the version of this article originally published, author Joshua R. Puzey was incorrectly listed as having affiliation 7 (School of Plant Sciences, University of Arizona, Tucson, AZ, USA); affiliation 6 (Department of Biology, College of William and Mary, Williamsburg, VA, USA) is the correct affiliation. The error has been corrected in the HTML and PDF versions of the article.

Origin and evolution of the octoploid strawberry genome.

Cultivated strawberry emerged from the hybridization of two wild octoploid species, both descendants from the merger of four diploid progenitor species into a single nucleus more than 1 million years ago. Here we report a near-complete chromosome-scale assembly for cultivated octoploid strawberry (Fragaria × ananassa) and uncovered the origin and evolutionary processes that shaped this complex allopolyploid. We identified the extant relatives of each diploid progenitor species and provide support for the North American origin of octoploid strawberry. We examined the dynamics among the four subgenomes in octoploid strawberry and uncovered the presence of a single dominant subgenome with significantly greater gene content, gene expression abundance, and biased exchanges between homoeologous chromosomes, as compared with the other subgenomes. Pathway analysis showed that certain metabolomic and disease-resistance traits are largely controlled by the dominant subgenome. These findings and the reference genome should serve as a powerful platform for future evolutionary studies and enable molecular breeding in strawberry.

Transcriptome of neonatal preBötzinger complex neurones in Dbx1 reporter mice.

We sequenced the transcriptome of brainstem interneurons in the specialized respiratory rhythmogenic site dubbed preBötzinger Complex (preBötC) from newborn mice. To distinguish molecular characteristics of the core oscillator we compared preBötC neurons derived from Dbx1-expressing progenitors that are respiratory rhythmogenic to neighbouring non-Dbx1-derived neurons, which support other respiratory and non-respiratory functions. Results in three categories are particularly salient. First, Dbx1 preBötC neurons express κ-opioid receptors in addition to µ-opioid receptors that heretofore have been associated with opiate respiratory depression, which may have clinical applications. Second, Dbx1 preBötC neurons express the hypoxia-inducible transcription factor Hif1a at levels three-times higher than non-Dbx1 neurons, which links core rhythmogenic microcircuits to O2-related chemosensation for the first time. Third, we detected a suite of transcription factors including Hoxa4 whose expression pattern may define the rostral preBötC border, Pbx3 that may influence ipsilateral connectivity, and Pax8 that may pertain to a ventrally-derived subset of Dbx1 preBötC neurons. These data establish the transcriptomic signature of the core respiratory oscillator at a perinatal stage of development.

The protective effects of angiotensin II blockade with olmesartan medoxomil on resistance vessel remodeling (The VIOS study): rationale and baseline characteristics.

BACKGROUND: The VIOS (Vascular Improvement with Olmesartan medoxomil Study) study is a randomized, parallel study to determine the relative effects of suppressing the renin-angiotensin system (RAS) with the angiotensin receptor antagonist olmesartan medoxomil versus suppressing sympathetic drive with the beta-adrenoceptor antagonist atenolol on remodeling of the subcutaneous small resistance vessel. Remodeling of small resistance vessels may be the earliest pathologic finding associated with hypertension. It may predate the onset of clinically apparent hypertension. METHODS: In this study, 100 patients with stage I hypertension are characterized at baseline before being treated for 1 year to obtain a goal BP of less than 140/90 mm Hg as defined by Joint National Committee (JNC)-7. Resistance vessel remodeling is determined using the gluteal fat biopsy technique in the hypertensive patients and a group of normotensive healthy volunteers. Additionally, efforts will be made to define whether noninvasive hemodynamic parameters, retinal vessel measurement changes, or biologic markers may predict and track the underlying vascular morphologic and physiologic changes induced by either regimen during the 12-month treatment period. RESULTS: The primary endpoint will be the degree of vascular remodeling as obtained from percutaneous biopsy of gluteal subcutaneous resistance vessels in each of two treatment arms compared with the normal volunteers. The design of the study and the pertinent baseline characteristics of these patients with uncomplicated essential hypertension are presented. CONCLUSION: The suppression of the RAS by the blockade of angiotensin II type 1 (AT(1)) receptors may demonstrate remodeling effects on the ubiquitous small resistance vessels similar to that seen in the myocardium and renal glomeruli, thus affording more complete end-organ protection.

Different effects of antihypertensive therapies based on losartan or atenolol on ultrasound and biochemical markers of myocardial fibrosis: results of a randomized trial.

BACKGROUND: In hypertensive left ventricular hypertrophy (LVH), myocardial texture is altered by a disproportionate increase in fibrosis, but there is insufficient clinical evidence whether antihypertensive therapy or individual agents can induce regression of myocardial fibrosis. METHODS AND RESULTS: We compared the effects of an angiotensin II receptor antagonist with a beta-blocker on myocardial collagen volume (assessed by echoreflectivity and serum collagen markers) in 219 hypertensive patients with echocardiographically documented LVH. Patients were allocated randomly to receive losartan 50 to 100 mg/d (n=111) or atenolol 50 to 100 mg/d (n=99) with or without hydrochlorothiazide 12.5 to 25 mg/d for 36 weeks. Echoreflectivity analysis was conducted on ultrasound tracings of the midapex septum with specifically designed and validated software. A color histogram of reflecting echoes was obtained, and its spread (broadband [BB], previously shown to correlate directly with collagen volume fraction on endomyocardial biopsies) was used as the primary outcome measure. Mean color scale and serum markers of collagen synthesis (PIP, PIIIP) or degradation (CITP) were secondary outcome variables. Echoreflectivity analysis proved feasible in 106 patients (losartan 52, atenolol 54). Losartan reduced BB over 36 weeks (from 114.5 to 104.3 color levels, P<0.02), whereas atenolol treatment was associated with an increase in BB (from 109.0 to 113.6 color levels, P=NS), the difference between treatments being -12.8 color levels (95% CI -23.6 to -2.0, P=0.02). Secondary end points (mean color scale and collagen markers) also changed in the direction of decreased collagen in patients receiving losartan, but differences between groups were not statistically significant. CONCLUSIONS: In hypertensive patients with LVH, losartan decreases myocardial collagen content, whereas atenolol does not. The difference between the 2 treatments is statistically significant.

Role of blood pressure reduction in prevention of cardiac and vascular hypertrophy.

We investigated whether prevention of cardiac and vascular remodeling associated with inhibition of angiotensin II is independent of the blood pressure (BP)-lowering action of angiotensin II type 1 (AT1) receptor blockade. Spontaneously hypertensive rats, 8 weeks old, were treated with olmesartan, atenolol, or vehicle in their drinking water for 56 days. At the end of each treatment, arterial pressure and heart rate were measured, the ratio of heart weight to body weight was calculated, collagen deposition in the heart was determined histochemically using picrosirius red staining, and wall-to-lumen ratio in isolated mesenteric arteries was measured by a videographic approach. At 3 weeks after the initiation of treatment, rats medicated with olmesartan showed lower values of systolic BP compared with rats given atenolol or vehicle, whereas no difference in directly measured BP were observed at the end of study in anesthetized rats given olmesartan or atenolol. Rats given atenolol showed sustained bradycardia, whereas cardiac hypertrophy and collagen deposition was prevented only in spontaneously hypertensive rats given olmesartan. Olmesartan or atenolol reduced arteriolar wall-to-lumen ratio (olmesartan: 11.5+/-0.4%; atenolol: 13.3+/-0.6%; vehicle: 18.4%+/-1.1); however, this effect was greatest in rats medicated with the angiotensin II type 1 antagonist. Although control of BP is a factor in the prevention of cardiac and vascular hypertrophy, our studies suggest that blockade of angiotensin II receptors may attenuate the structural changes in the heart and blood vessels of hypertensive animals independent of a reduction in BP.

Noninvasive hemodynamic profiles in hypertensive subjects.

BACKGROUND: Hypertension is a disease state characterized by increased blood pressure (BP) associated with hemodynamic abnormalities, including elevated systemic vascular resistance index (SVRI); and altered cardiac index (CI). The objective of this study was to use noninvasive impedance cardiography (ICG) to evaluate hemodynamic characteristics of subjects with and without hypertension. METHODS: A total of 19 healthy nonhypertensive and 136 hypertensive subjects were retrospectively evaluated. Hemodynamic parameters were measured with ICG and included CI, SVRI, total arterial compliance index (TACI), and thoracic fluid content (TFC); these were compared with subject type, blood pressure value, demographics, and medications. RESULTS: The BP levels of healthy and hypertensive subjects were 117/71 and 154/90 mm Hg, respectively (P < .0001). Subjects with prehypertension had a lower TACI (0.97 v 1.21, P < .05) compared with those with a normal BP, ie, <120/80 mm Hg. Hypertensive subjects had significantly lower SI, CI, TACI, and TFC and significantly higher SVRI. Subjects with stage 2 hypertension had higher SVRI (4149 v 3418 dyne.sec(2).cm(-5).m(2), P < .01) and lower TACI (0.61 v 0.53 mm Hg/mL/m(2), P < .05) than those with stage 1 hypertension. Compared with subjects with controlled hypertension, normal subjects had significantly lower SVRI (1996 v 2746 dyne.sec(2).cm(-5).m(2), P < .0001) and significantly higher CI (3.23 v 2.63 L/min/m(2), P < .001), SI (48.2 v 37.4 mL/m(2), P < .0001), TACI (1.08 v 0.85 mm Hg/mL/m(2), P < .01), and TFC (29.1 v 24.1/kOhm, P < .0001). The parameters of TACI, SVRI, and CI demonstrated modest correlation (-0.75, 0.62, and -0.30), respectively, with SBP. In the 54 subjects with BP <140/90 mm Hg, SVRI values varied significantly, with 32 subjects (39.2%) with SVRI values in the high range (>2483 dyne.sec(2).cm(-5).m(2)). CONCLUSIONS: Hemodynamic parameters from ICG displayed significantly different hemodynamic profiles between hypertensive and nonhypertensive subjects. However, significant individual variation of hemodynamic status exists. Hemodynamic measurements with ICG characterize hemodynamic status and may be helpful in diagnostic, prognostic, and therapeutic decision making in hypertensive subjects.

Effects of losartan and atenolol on left ventricular mass and neurohormonal profile in patients with essential hypertension and left ventricular hypertrophy.

OBJECTIVE: To compare the effects of the angiotensin II antagonist, losartan, with those of atenolol on left ventricular hypertrophy (LVH), blood pressure and neurohormone concentrations in hypertensive patients with LVH. DESIGN: A multinational, randomized, double-blind trial. SETTING: Hospital. PATIENTS: Hypertensive patients with an echocardiographically documented left ventricular mass index (LVMI) 120 g/m(2) (men) or 105 g/m(2) (women). INTERVENTIONS: Patients allocated randomly to groups received either losartan or atenolol 50 mg/day for 36 weeks, with possible titration to 100 mg/day, and addition of hydrochlorothiazide 12.5 or 25 mg/day. MAIN OUTCOME MEASURES: Changes in LVMI and sitting systolic (SBP) and diastolic (DBP) blood pressures after 36 weeks of treatment (study powered for non-inferiority hypothesis). All echocardiographic data were read in a central laboratory by staff blinded to the treatments and sequence of echocardiographic tapes. RESULTS: The estimated treatment difference between the losartan and atenolol regimens (mean change from baseline at week 36) in LVMI was -2.5 g/m(2) [95% confidence interval (CI) -7.36 to 2.37 g/m(2) ] in favor of losartan, indicating that losartan was significantly non-inferior ( 0.001, non-inferiority limit 8 g/m(2) ) and numerically superior to atenolol in reducing LVMI. The losartan-based regimen significantly reduced LVMI after 36 weeks compared with baseline (-6.56 g/m(2) , 95% CI -10.24 to -2.88 g/m(2) , P<0.001), whereas the atenolol-based regimen had no significant effect (-3.71 g/m, 95% CI -7.75 to 0.32 g/m(2) , P= NS). In a subset of 82 patients, significant changes in serum concentrations of atrial natriuretic peptide, brain natriuretic peptide and immunoreactive amino-terminal pro-brain natriuretic peptide were recorded in losartan-treated ( 0.01) but not atenolol-treated patients. Losartan and atenolol significantly decreased SBP and DBP from baseline after 6, 12, 24 and 36 weeks. The changes from baseline in DBP were greater in the atenolol group at weeks 6 and 36 [difference -2.6 mmHg ( P= 0.016) at week 36]. However, both treatment regimens achieved similar SBP/DBP values at week 36 (141.1 +/- 12.8/86.8 +/- 8.2 mmHg for losartan and 141.4 +/- 17.2/85.0 +/- 10.1 mmHg for atenolol, respectively). Overall, losartan treatment was associated with significantly fewer drug-related clinical adverse events, compared with atenolol (10 and 22%, respectively, P= 0.028). CONCLUSIONS: Both losartan- and atenolol-based regimens effectively decreased blood pressure. Losartan was non-inferior and numerically superior to atenolol in regression of LVH. The reduction in hypertrophy with losartan treatment was accompanied by reductions in circulating concentrations of cardiac natriuretic peptides. Losartan, by specifically blocking angiotensin II, may therefore have effects on the heart beyond those expected from the decrease in blood pressure alone. Losartan was better tolerated than atenolol.

Effects of omapatrilat on the renin-angiotensin system in salt-sensitive hypertension.

The contribution of angiotensin-(1-7) [Ang-(1-7)] to the antihypertensive actions of omapatrilat, a novel vasopeptidase inhibitor, was evaluated in 22 salt-sensitive, low renin, hypertensive subjects as a substudy of a multicenter randomized, double-blind, parallel study of 4 weeks duration. A total of 25 other subjects received lisinopril as the active control. Omapatrilat (40 mg) produced sustained control of blood pressure (BP) (as assessed by 24-h ambulatory BP measurements) that was significantly greater than that produced by 20 mg daily of lisinopril. The antihypertensive response to either drug was accompanied by similar sustained inhibition of angiotensin converting enzyme activity. Plasma levels of angiotensin I (Ang I), angiotensin II (Ang II) and Ang-(1-7) were not altered by treatment with either omapatrilat or lisinopril, even though both regimens produced a modest rise in plasma renin activity. In contrast, urinary excretion rates of Ang I and Ang-(1-7) but not Ang II increased significantly throughout the dosing period of subjects who were given omapatrilat, whereas the smaller antihypertensive response produced by lisinopril had a smaller and transient effect on increasing urinary excretion rates of Ang-(1-7). Omapatrilat, being a single molecule inhibiting neutral endopeptidase and converting enzyme simultaneously, controlled salt-sensitive hypertension by a mechanism that was associated with sustained increases in urinary Ang-(1-7) excretion. We suggest that Ang-(1-7) may be a component of the mechanisms by which omapatrilat induces an antihypertensive response in salt sensitive hypertension.

Losartan in patients with type 2 diabetes and proteinuria: observations from the RENAAL Study.

BACKGROUND: Recently, the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) Study demonstrated the benefit of losartan in reducing renal outcomes in patients with type 2 diabetes and proteinuria. Additional questions concerning the reduction of proteinuria and its relationship to end-stage renal disease (ESRD) as well as cardio-renal outcomes and the safety and tolerability of losartan remain to be addressed. METHODS: Three analyses were performed: (a) the impact of losartan on the relationship between the reduction of proteinuria and ESRD; (b) a time-to-event analysis of the cardio-renal composite endpoint of ESRD, myocardial infarction, stroke or all-cause death; and (c) additional analyses of adverse events, particularly in patients with serum creatinine >or=2.0 mg/dL. RESULTS: After adjusting the values for proteinuria over the entire study, the reduction of proteinuria accounted for approximately half of the treatment effect of losartan on the risk reduction for ESRD. In addition, losartan was associated with a 21% risk reduction for the composite cardio-renal outcome (P=0.003). The addition of losartan to a conventional antihypertensive regimen did not increase the overall incidence of adverse events, regardless of severity of renal impairment. CONCLUSIONS: Losartan significantly reduced the risk of cardiorenal outcomes and was well tolerated by patients, including those with serum creatinine levels >or=2.0 g/dL. In addition, although this study shows that the reduction of proteinuria does not completely explain the impact of intervention on outcomes such as ESRD, reduction of proteinuria must remain an important consideration when treating patients with type 2 diabetes and nephropathy. However, the reduction of outcomes such as ESRD should remain the goal of therapy when evaluating renal protection in this patient population.

Comparison of the effects of losartan and atenolol on common carotid artery intima-media thickness in patients with hypertension: results of a 2-year, double-blind, randomized, controlled study.

BACKGROUND: Hypertension induces progressive pathologic changes in the arterial wall. Experimental findings suggest that these changes, which include intima-media thickening, may be mediated, at least in part, by angiotensin II (AII). OBJECTIVE: The Losartan Vascular Regression Study (LAARS) was a double-blind, parallel-group, randomized, controlled, multicenter study designed to compare the effects of the AII antagonist losartan and the beta-blocker atenolol on ultrasonographically determined intimamedia thickness (IMT) of the common carotid artery (CCA) in patients with mild to moderate essential hypertension. METHODS: The primary end point of the study was the yearly rate of change (YRC) from baseline of the mean IMT of the CCA (CCA-IMT(mean)) averaged over 2 years of treatment. Secondary end points included IMT of the common femoral artery and sitting systolic and diastolic blood pressures (SiSBP/SiDBP). Safety assessments of losartan and atenolol were made by statistical and clinical review of the incidence of adverse experiences as well as review of vital signs and laboratory values. A total of 414 patients with essential hypertension were screened for study inclusion at 36 study centers in Germany and Brazil. Patients received losartan (50 mg once daily) or atenolol (50 mg once daily) for 24 months. Target blood pressure (SiSBP/SiDBP <140/<90 mm Hg) was achieved by adding hydrochlorothiazide 12.5 mg once daily, doubling the dose of study drug, or adding an open-label calcium channel blocker sequentially, as needed. RESULTS: Of the original 414 patients screened, 280 hypertension patients (SiDBP 95-115 mm Hg), aged 35 to 65 years, with an IMT of 0.8 to 1.5 mm of the right or left CCA, were randomized to treatment with either losartan (n = 142) or atenolol (n = 138). Both losartan and atenolol therapy produced comparable reductions in CCA-IMTmean over 24 months compared with baseline; the average YRC was -0.038 +/- 0.004 mm/y (P < or = 0.001) for losartan and -0.037 +/- 0.004 mm/y (P < or = 0.001) for atenolol. There were no significant differences between groups. Losartan showed a greater reduction of femoral artery IMT than did atenolol; the average YRC was -0.024 mm/y (P < or = 0.05) for losartan and -0.017 mm/y for atenolol (P = NS), with no significant difference between groups. Both agents produced similar significant reductions in SiSBP and SiDBP and were generally well tolerated. Approximately 7% of losartan patients had drug-related clinical adverse events, compared with 12% of atenolol patients. CONCLUSIONS: The findings of LAARS, the first large study with an AII antagonist that examined IMT, suggest that AII antagonism reverses the early stages of vascular hypertrophy in patients with hypertension. Further studies are needed to delineate the relative importance of AII antagonism versus blood pressure reduction per se in mediating the beneficial vascular effects of losartan.

Comparison of the blood pressure-lowering effects and tolerability of Losartan- and Amlodipine-based regimens in patients with isolated systolic hypertension.

BACKGROUND: Elevated systolic blood pressure is a more important risk factor for cardiovascular and renal disease than elevated diastolic blood pressure. Isolated systolic hypertension (ISH) is the predominant form of hypertension in the elderly. Effects of angiotensin II on the vascular wall and endothelium may contribute to development of ISH. OBJECTIVE: The primary objective of this study was to compare the effects on trough sitting systolic blood pressure (SiSBP) of a regimen of losartan, a selective angiotensin II-receptor antagonist, and an amlodipine-based regimen in patients with ISH. METHODS: This multicenter, prospective, randomized, double-blind, parallel-group study consisted of a 4-week placebo phase and an 18-week active-treatment phase. The losartan-based regimen consisted of losartan 50 mg, increased as needed to losartan 50 mg/hydrochlorothiazide (HCTZ) 12.5 mg at week 6 and to losartan 100 mg/HCTZ 25 mg at week 12 to achieve a target SiSBP <140 mm Hg. the amlodipine-based regimen consisted of amlodipine 5 mg, increased as needed to amlodipine 10 mg at week 6 and to amlodipine 10 mg/HCTZ 25 mg at week 12. The primary efficacy measure was change in trough SiSBP from baseline to week 18. Information on the tolerability of study treatments was collected at each visit, including the investigator's and patient's observations of clinical adverse experiences (CAEs), laboratory adverse experiences, and responses to a symptom questionnaire. RESULTS: Eight hundred fifty-seven patients (65.6% female) were randomized to treatment, 432 in the losartan group and 425 in the amlodipine group. Their mean age was 67.6 years, and they had a mean duration of hypertension of 6.7 years at baseline. The losartan and amlodipine groups (intent-to-treat population) had baseline mean SiSBP values of 171.2 and 171.9 mm Hg, respectively. At week 18 (the primary end point), the mean change from baseline in SiSBP was -27.4 mm Hg for 426 patients who received losartan and -28.1 mm Hg for 419 patients who received amlodipine (estimated least-square mean difference, 0.3 mm Hg; 95% CI, -1.4 to 2.0), indicating that losartan's effect on systolic blood pressure was noninferior to that of amlodipine. The proportion of patients who responded (SiSBP <140 mm Hg or a > or =20-mm Hg decrease in SiSBP from baseline) was comparable between groups (73.9% losartan, 75.4% amlodipine). The incidence of CAEs and drug-related CAEs was significantly greater in the amlodipine group (amlodipine, 79.8% and 43.8%, respectively; losartan, 67.8% and 25.5%; P < or = 0.001). In addition, more patients in the amlodipine group discontinued therapy due to a drug-related CAE compared with patients in the losartan group (12.9% vs 4.4%, respectively; P < or = 0.001). Lower-extremity edema was the most common drug-related CAE in the amlodipine group (24.0% amlodipine, 2.5% losartan; P < or = 0.001); dizziness was the most common drug-related CAE in the losartan group (6.0% losartan, 4.0% amlodipine). CONCLUSIONS: In these patients with ISH, losartan and amlodipine produced comparable clinically relevant reductions in SiSBP; however, losartan was better tolerated, as evidenced by fewer CAEs and discontinuations compared with amlodipine. Losartan may be considered for the initial treatment of ISH.

Association between antihypertensive agent use and hospital admissions in a managed care population.

BACKGROUND: Utilization of medical care services has been used as a surrogate for outcome of patient compliance with treatment regimens. Antihypertensive treatment status and selection of drug agents may influence medical utilization. The purpose of this study was to determine the association between medically untreated hypertension and treated hypertension according to class of antihypertensive agent with the rate of hospitalization. METHODS: This is a retrospective, observational study on adult hypertensive patients based on claim data from a network-model HMO. The 12,548 patients were identified by ICD-9-CM hypertensive codes over a 3-year period. The hospital admission rate was the outcome measurement. The exploratory variables included antihypertensive treatment status and drug class. Patients' age, gender, and coexisting medical conditions were treated as confounding factors. Descriptive analyses and multivariate regression analyses were performed. RESULTS: Coexisting medical conditions were significant factors in hospital admission rates. Compared with diuretic treatment, there were no differences in hospital admission rates among hypertensive patients treated with an angiotensin II antagonist or angiotensin-converting enzyme inhibitor. Untreated patients or those treated with beta-blockers or calcium channel blockers experienced higher hospitalization rates (95% CI, 1.25-1.90, 1.03-1.44, and 1.08-1.46, respectively). CONCLUSIONS: Compared with the major antihypertensive agents or no therapy for hypertension, diuretic or angiotensin-converting enzyme inhibitor therapy may result in a reduced rate of hospital utilization.