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Amsterdam-Zuidoost, Netherlands

Westerhof N.,VU University Amsterdam | Westerhof B.E.,BMEYE Inc | Westerhof B.E.,Heart Failure Research Center
Journal of Hypertension

Objectives: In treatment of hypertension not only the pressure response is of interest, but also the effect on arterial parameters, for example, stiffness and resistance, is essential. We therefore reviewed what quantitative information on arterial stiffness can be obtained from pressure wave analysis. Methods: Using data from published large cohort studies, we derived relations between stiffness and the pressure-derived variables systolic pressure, pulse pressure, augmentation index (AIx), return time of reflected wave and reflection magnitude. Results: All pressure-derived variables give limited information on arterial function in terms of stiffness and resistance, except AIx (in low stiffness range only). Input impedance as a comprehensive description of the arterial system is too complex to derive and interpret in practice, but is accurately described by three parameters: systemic vascular resistance, total arterial stiffness, and aortic characteristic impedance (outflow tract size and proximal aortic stiffness). These parameters predict aortic pressure well in terms of magnitude and shape: with measured flow the predicted (p) and measured (m) systolic, Ps, and diastolic, Pd pressures relate as P sp = 0.997Psm- 1.63 and Pd, p = 1.03P dm-3.12mmHg (n=17). Therefore, methods should be developed to determine, preferably noninvasively, these three arterial parameters. Conclusion: Variables derived from pressure wave shape alone (e.g. inflection point, AIx among others), and wave separation (e.g. reflection magnitude), while predicting cardiovascular events, give little information on arterial function. We propose to develop new, and improve existing, noninvasive methods to determine systemic vascular resistance, total arterial stiffness, and aortic characteristic impedance. This will allow quantifying the response of arterial function to treatment. © 2013 Wolters Kluwer Health Lippincott Williams & Wilkins. Source

Franco D.,University of Jaen | Christoffels V.M.,Heart Failure Research Center | Campione M.,University of Padua
Trends in Cardiovascular Medicine

The homeobox transcription factor Pitx2 displays a highly specific expression pattern during embryogenesis. Gain and loss of function experiments have unraveled its pivotal role in left-right signaling. Conditional deletion in mice has demonstrated a complex and intricate role for Pitx2 in distinct aspects of cardiac development and more recently a link to atrial fibrillation has been proposed based on genome-wide association studies. In this review we will revise the role of Pitx2 in the developing heart, starting from the early events of left-right determination followed by its role in cardiac morphogenesis and ending with its role in cardiac arrhythmogenesis. © 2013 Elsevier Inc. Source

Westerhof B.E.,BMEYE Inc | Westerhof B.E.,Heart Failure Research Center | Westerhof N.,VU University Amsterdam
Journal of Hypertension

Background: Increased large artery stiffness is a major determinant of systolic pressure and indicator of cardiovascular events. The reflected wave, its arrival time (return time) and magnitude, contributes to systolic pressure, and is a supposed indicator of aortic stiffness. With aortic stiffening, the return time is assumed to decrease inversely with PWV as 2L/PWV, where L is the aortic length. However, several studies reported that the inflection point of aortic pressure, a surrogate of return time, varies little with aortic stiffness. Methods: We studied the effects of aortic stiffness on wave reflection in an anatomically accurate arterial model. Return time is time difference of forward, Pf, and backward, Pb, pressure. Return time, inflection and shoulder points, augmentation index, and reflection magnitude (Pb/Pf) were calculated by standard rules. Results: Peripheral resistance does not affect reflection directly, but only through pressure (stiffness) changes. Magnitude of reflected waves depend about equally on aortic geometry (taper, branches) and distal aortic reflection. Therefore, relations of augmentation index and reflection magnitude with stiffness are nonlinear and complex; augmentation index is most sensitive to stiffness. Between PWV 6 and 12 m/s, representing ages of 20-80 years, return time and inflection and shoulder points change differently with stiffness and PWV cannot be derived from them. Pulse pressure is strongly dependent on aortic stiffness. Taper changes return time by a factor 2, but has little effect on reflection magnitude, augmentation index, and inflection point. Conclusion: Accurate quantitative information on arterial stiffness cannot be obtained from reflection parameters. The augmentation index is most sensitive to stiffness changes. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Schwartz P.J.,University of Pavia | Schwartz P.J.,University of Cape Town | Schwartz P.J.,Stellenbosch University | Schwartz P.J.,King Saud University | And 5 more authors.
Journal of the American College of Cardiology

There are few areas in cardiology in which the impact of genetics and genetic testing on clinical management has been as great as in cardiac channelopathies, arrhythmic disorders of genetic origin related to the ionic control of the cardiac action potential. Among the growing number of diseases identified as channelopathies, 3 are sufficiently prevalent to represent significant clinical and societal problems and to warrant adequate understanding by practicing cardiologists: long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome. This review will focus selectively on the impact of genetic discoveries on clinical management of these 3 diseases. For each disorder, we will discuss to what extent genetic knowledge and clinical genetic test results modify the way cardiologists should approach and manage affected patients. We will also address the optimal use of genetic testing, including its potential limitations and the potential medico-legal implications when such testing is not performed. We will highlight how important it is to understand the ways that genotype can affect clinical manifestations, risk stratification, and responses to the therapy. We will also illustrate the close bridge between molecular biology and clinical medicine, and will emphasize that consideration of the genetic basis for these heritable arrhythmia syndromes and the proper use and interpretation of clinical genetic testing should remain the standard of care. © 2013 by the American College of Cardiology Foundation. Source

Sizarov A.,Heart Failure Research Center | Anderson R.H.,University College London | Christoffels V.M.,Heart Failure Research Center | Moorman A.F.M.,Heart Failure Research Center

Background-Various congenital malformations and many abnormal rhythms originate from the venous pole of the heart. Because of rapid changes during morphogenesis, lack of molecular and lineage data, and difficulties in presenting complex morphogenetic changes in the developing heart in a clear fashion, the development of this region in human has been difficult to grasp. Methods and Results-To gain insight into the development of the different types of myocardium forming the venous pole of the human heart, we performed an immunohistochemical and 3-dimensional analysis of serial sections of human embryos ranging from 22 through 40 days of development. Three-dimensional models were prepared in a novel interactive portable format providing crucial spatial information and facilitating interpretation. As in the mouse, the systemic venous myocardium expresses the transcription factor TBX18, whereas the pulmonary venous myocardium expresses NKX2-5. In contrast to the mouse, a systemic venous sinus is identified upstream from the atrial chambers, albeit initially with nonmyocardial walls. From the outset, as in the mouse, the pulmonary vein empties to a chamber with atrial, rather than systemic venous, characteristics. Compared with the mouse, the vestibular spine is a more prominent structure. Conclusion-The similarities in gene expression in the distinctive types of myocardium surrounding the systemic and pulmonary venous tributaries in man and mouse permit extrapolation of the conclusions drawn from transgenic and lineage studies in the mouse to the human, showing that the systemic and pulmonary venous myocardial sleeves are derived from distinct developmental lineages. © 2010 American Heart Association, Inc. Source

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