Heart Failure Research Center

Amsterdam, Netherlands

Heart Failure Research Center

Amsterdam, Netherlands
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Westerhof N.,VU University Amsterdam | Westerhof B.E.,BMEYE Inc | Westerhof B.E.,Heart Failure Research Center
Journal of Hypertension | Year: 2013

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.

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 | Year: 2013

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.

Westerhof B.E.,BMEYE Inc | Westerhof B.E.,Heart Failure Research Center | Westerhof N.,VU University Amsterdam
Journal of Hypertension | Year: 2012

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.

Franco D.,University of Jaén | Christoffels V.M.,Heart Failure Research Center | Campione M.,University of Padua
Trends in Cardiovascular Medicine | Year: 2014

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.

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
Circulation | Year: 2010

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.

Creemers E.E.,Heart Failure Research Center | Wilde A.A.,Heart Failure Research Center | Pinto Y.M.,Heart Failure Research Center
Nature Reviews Genetics | Year: 2011

Heart failure is an increasingly prevalent and highly lethal disease that is most often caused by underlying pathologies, such as myocardial infarction or hypertension, but it can also be the result of a single gene mutation. Comprehensive genetic and genomic approaches are starting to disentangle the diverse molecular underpinnings of both forms of the disease and promise to yield much-needed novel diagnostic and therapeutic options for specific subtypes of heart failure. © 2011 Macmillan Publishers Limited. All rights reserved.

Chockalingam P.,Heart Failure Research Center | Wilde A.,Heart Failure Research Center
Heart | Year: 2012

The cardiac sodium channel plays an integral role in the evolution of our understanding of the aetiopathogenesis of sudden and unexpected young deaths. New and significant genetic mutations associated with a wide array of potentially lethal clinical conditions are being discovered at a rapid pace, thanks to unsurpassed advances in molecular techniques and medical acumen. A precise understanding of the structure and functions of the ion channels, combined with knowledge of the associated pathological manifestations, will enable appropriate diagnostic and therapeutic decisions to be made for this challenging group of disorders.

Creemers E.E.,Heart Failure Research Center | Pinto Y.M.,Heart Failure Research Center
Cardiovascular Research | Year: 2011

When considering the pathological steps in the progression from cardiac overload towards the full clinical syndrome of heart failure, it is becoming increasingly clear that the extracellular matrix (ECM) is an important determinant in this process. Chronic pressure overload induces a number of structural alterations, not only hypertrophy of cardiomyocytes but also an increase in ECM proteins in the interstitium and perivascular regions of the myocardium. When this culminates in excessive fibrosis, myocardial compliance decreases and electrical conduction is affected. Altogether, fibrosis is associated with an increased risk of ventricular dysfunction and arrhythmias. Consequently, anti-fibrotic strategies are increasingly recognized as a promising approach in the prevention and treatment of heart failure. Thus, dissecting the molecular mechanisms underlying the development of cardiac fibrosis is of great scientific and therapeutic interest. In this review, we provide an overview of the available evidence supporting the general idea that fibrosis plays a causal role in deteriorating cardiac function. Next, we will delineate the signalling pathways importantly governed by transforming growth factor β (TGFβ) in the control of cardiac fibrosis. Finally, we will discuss the recent discovery that miRNAs importantly regulate cardiac fibrosis. © 2010 The Author.

Sergeeva I.A.,Heart Failure Research Center | Christoffels V.M.,Heart Failure Research Center
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2013

The mammalian heart expresses two closely related natriuretic peptide (NP) hormones, atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP). The excretion of the NPs and the expression of their genes strongly respond to a variety of cardiovascular disorders. NPs act to increase natriuresis and decrease vascular resistance, thereby decreasing blood volume, systemic blood pressure and afterload. Plasma levels of BNP are used as diagnostic and prognostic markers for hypertrophy and heart failure (HF), and both ANF and BNP are widely used in biomedical research to assess the hypertrophic response in cell culture or the development of HF related diseases in animal models. Moreover, ANF and BNP are used as specific markers for the differentiating working myocardium in the developing heart, and the ANF promoter serves as platform to investigate gene regulatory networks during heart development and disease. However, despite decades of research, the mechanisms regulating the NP genes during development and disease are not well understood. Here we review current knowledge on the regulation of expression of the genes for ANF and BNP and their role as biomarkers, and give future directions to identify the in vivo regulatory mechanisms. This article is part of a Special Issue entitled: Heart failure pathogenesis and emerging diagnostic and therapeutic interventions. © 2013 Elsevier B.V.

van Wijk B.,Heart Failure Research Center | van den Hoff M.,Heart Failure Research Center
Trends in Cardiovascular Medicine | Year: 2010

During development, the epicardium, an epithelial layer that covers the heart, gives rise to a large portion of the nonmyocardial cells present in the heart. The epicardium arises from a structure, called the proepicardium, which forms at the inflow of the developing heart. By epithelial-to-mesenchymal transformation, mesenchymal cells are formed that will subsequently populate the stroma of the proepicardium and the subepicardium. Based on labeling analysis, the proepicardium and part of the myocardium have been shown to be derived from a common cardiogenic precursor population. In this review, we will discuss the common cardiogenic origin of proepicardial and myocardial cells, the underlying processes and factors that play a role in the separation of the lineages, and their potential role in cardiac regenerative approaches. © 2010 Elsevier Inc.

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