We respond to recent correspondence relating to the Conduit Artery Function Evaluation study (CAFE), 1 published in Circulation earlier this year.We thank Drs Nieminen, Kahonen, and Kobie for their remarks and suggestions. We agree that increased stroke volume at lower heart rates should be considered as a contributor to the elevated pulse pressure (PP) seen with atenolol-based treatment in the CAFE study. We did not assess stroke volume, and further studies are required to define the impact of blood pressure (BP)-lowering therapies on stroke volume and its contribution to central aortic pressures. Nevertheless, our data do suggest an important role for increased wave reflections in determining higher central aortic pressures with atenolol-based when compared with amlodipine-based treatment. Indeed, the higher central but not brachial PP with atenolol-based therapy in the CAFE study supports the hypothesis that the main driver of differential central aortic pressures was drug effects on pressure wave reflections rather than changes in stroke volume.We agree with Drs Safar and Fournier that the findings of the CAFE study are consistent with their report of differential drug effects on central aortic pressures in the Preterax in Regression of Arterial Stiffness in a Controlled Double-Blind Study (REA-SON). 2 We concur with the view that vascular structural changes are likely to make an important contribution to the long-term hemodynamic effects of BP-lowering therapy, especially wave reflection, and we suggested in our article that different BPlowering treatments may modify central aortic pressures and hemodynamics through differential effects on vascular structure. 1 The fact that the most beneficial effects on central aortic pressure have been observed with vasodilator therapy, in contrast to ␤-blockade, supports the view that a reduction in vascular resistance, by vasodilation and subsequent vascular remodeling, is an important determinant of reduced wave reflection and central aortic pressure, thereby defining the characteristics of optimal BP-lowering therapy.Cameron and colleagues are concerned that the data in their article 3 may have been misinterpreted. We clarify that our reference to their work related to the accuracy and validation of the transfer function rather than the derivation of central aortic pressures, which are prone to and dependent on the same level of inaccuracy as the measurement of brachial BP by cuff sphygmomanometry.We thank Dr Dart et al for their comments and interest in our study but would like to point out fundamental differences between the design and objectives of the CAFE study and The Australian National Blood Pressure Study 2 (ANBP2). substudy of central aortic pressures. 4 The prespecified primary objective 5 of the CAFE study was to examine the hypothesis that 2 different BP-lowering regimens would have different effects on derived central arterial pressures and hemodynamics despite similar effects on brachial pressures. This was convincingly demonstrated by the findings of ...

Self-assembled nanostructures obtained from natural and synthetic amphiphiles serve as mimics of biological membranes and enable the delivery of drugs, proteins, genes, and imaging agents. Yet the precise molecular arrangements demanded by these functions are difficult to achieve. Libraries of amphiphilic Janus dendrimers, prepared by facile coupling of tailored hydrophilic and hydrophobic branched segments, have been screened by cryogenic transmission electron microscopy, revealing a rich palette of morphologies in water, including vesicles, denoted dendrimersomes, cubosomes, disks, tubular vesicles, and helical ribbons. Dendrimersomes marry the stability and mechanical strength obtainable from polymersomes with the biological function of stabilized phospholipid liposomes, plus superior uniformity of size, ease of formation, and chemical functionalization. This modular synthesis strategy provides access to systematic tuning of molecular structure and of self-assembled architecture.

Polyamines are essential for the growth and function of normal cells. They interact with various macromolecules, both electrostatically and covalently and, as a consequence, have a variety of cellular effects. The complexity of polyamine metabolism and the multitude of compensatory mechanisms that are invoked to maintain polyamine homoeostasis argue that these amines are critical to cell survival. The regulation of polyamine content within cells occurs at several levels, including transcription and translation. In addition, novel features such as the +1 frameshift required for antizyme production and the rapid turnover of several of the enzymes involved in the pathway make the regulation of polyamine metabolism a fascinating subject. The link between polyamine content and human disease is unequivocal, and significant success has been obtained in the treatment of a number of parasitic infections. Targeting the polyamine pathway as a means of treating cancer has met with limited success, although the development of drugs such as DFMO (alpha-difluoromethylornithine), a rationally designed anticancer agent, has revolutionized our understanding of polyamine function in cell growth and provided 'proof of concept' that influencing polyamine metabolism and content within tumour cells will prevent tumour growth. The more recent development of the polyamine analogues has been pivotal in advancing our understanding of the necessity to deplete all three polyamines to induce apoptosis in tumour cells. The current thinking is that the polyamine inhibitors/analogues may also be useful agents in the chemoprevention of cancer and, in this area, we may yet see a revival of DFMO. The future will be in adopting a functional genomics approach to identifying polyamine-regulated genes linked to either carcinogenesis or apoptosis.

Intracoronary resistance is naturally constant and minimized during the wave-free period. The instantaneous wave-free ratio calculated over this period produces a drug-free index of stenosis severity comparable to FFR. (Vasodilator Free Measure of Fractional Flow Reserve [ADVISE]; NCT01118481).

BP-lowering drugs can have substantially different effects on central aortic pressures and hemodynamics despite a similar impact on brachial BP. Moreover, central aortic pulse pressure may be a determinant of clinical outcomes, and differences in central aortic pressures may be a potential mechanism to explain the different clinical outcomes between the 2 BP treatment arms in ASCOT.

Background-Coronary blood flow peaks in diastole when aortic blood pressure has fallen. Current models fail to completely explain this phenomenon. We present a new approach-using wave intensity analysis-to explain this phenomenon in normal subjects and to evaluate the effects of left ventricular hypertrophy (LVH). Method and Results-We measured simultaneous pressure and Doppler velocity with intracoronary wires in the left main stem, left anterior descending, and circumflex arteries of 20 subjects after a normal coronary arteriogram. Wave intensity analysis was used to identify and quantify individual pressure and velocity waves within the coronary artery circulation.A consistent pattern of 6 predominating waves was identified. Ninety-four percent of wave energy, accelerating blood forward along the coronary artery, came from 2 waves: first a pushing wave caused by left ventricular ejection-the dominant forward-traveling pushing wave; and later a suction wave caused by relief of myocardial microcirculatory compression-the dominant backward-traveling suction wave. The dominant backward-traveling suction wave (18.2Ϯ13.7ϫ10 3 W m Ϫ2 s

Background High-throughput profiling of circulating metabolites may improve cardiovascular risk prediction over established risk factors. Methods and Results We applied quantitative NMR metabolomics to identify biomarkers for incident cardiovascular disease during long-term follow-up. Biomarker discovery was conducted in the FINRISK study (n=7256; 800 events). Replication and incremental risk prediction was assessed in the SABRE study (n=2622; 573 events) and British Women’s Health and Heart Study (n=3563; 368 events). In targeted analyses of 68 lipids and metabolites, 33 measures were associated with incident cardiovascular events at P<0.0007 after adjusting for age, sex, blood pressure, smoking, diabetes and medication. When further adjusting for routine lipids, four metabolites were associated with future cardiovascular events in meta-analyses: higher serum phenylalanine (hazard ratio per standard deviation: 1.18 [95%CI 1.12–1.24]; P=4×10−10) and monounsaturated fatty acid levels (1.17 [1.11–1.24]; P=1×10−8) were associated with increased cardiovascular risk, while higher omega-6 fatty acids (0.89 [0.84–0.94]; P=6×10−5) and docosahexaenoic acid levels (0.90 [0.86–0.95]; P=5×10−5) were associated with lower risk. A risk score incorporating these four biomarkers was derived in FINRISK. Risk prediction estimates were more accurate in the two validation cohorts (relative integrated discrimination improvement 8.8% and 4.3%), albeit discrimination was not enhanced. Risk classification was particularly improved for persons in the 5–10% risk range (net reclassification 27.1% and 15.5%). Biomarker associations were further corroborated with mass spectrometry in FINRISK (n=671) and the Framingham Offspring Study (n=2289). Conclusions Metabolite profiling in large prospective cohorts identified phenylalanine, monounsaturated and polyunsaturated fatty acids as biomarkers for cardiovascular risk. This study substantiates the value of high-throughput metabolomics for biomarker discovery and improved risk assessment.

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