Effect of a reduction in glomerular filtration rate after nephrectomy on arterial stiffness and central hemodynamics: rationale and design of the EARNEST study

Background: There is strong evidence of an association between chronic kidney disease (CKD) and cardiovascular disease. To date, however, proof that a reduction in glomerular filtration rate (GFR) is a causative factor in cardiovascular disease is lacking. Kidney donors comprise a highly screened population without risk factors such as diabetes and inflammation, which invariably confound the association between CKD and cardiovascular disease. There is strong evidence that increased arterial stiffness and left ventricular hypertrophy and fibrosis, rather than atherosclerotic disease, mediate the adverse cardiovascular effects of CKD. The expanding practice of live kidney donation provides a unique opportunity to study the cardiovascular effects of an isolated reduction in GFR in a prospective fashion. At the same time, the proposed study will address ongoing safety concerns that persist because most longitudinal outcome studies have been undertaken at single centers and compared donor cohorts with an inappropriately selected control group.<p></p> Hypotheses: The reduction in GFR accompanying uninephrectomy causes (1) a pressure-independent increase in aortic stiffness (aortic pulse wave velocity) and (2) an increase in peripheral and central blood pressure.<p></p> Methods: This is a prospective, multicenter, longitudinal, parallel group study of 440 living kidney donors and 440 healthy controls. All controls will be eligible for living kidney donation using current UK transplant criteria. Investigations will be performed at baseline and repeated at 12 months in the first instance. These include measurement of arterial stiffness using applanation tonometry to determine pulse wave velocity and pulse wave analysis, office blood pressure, 24-hour ambulatory blood pressure monitoring, and a series of biomarkers for cardiovascular and bone mineral disease.<p></p> Conclusions: These data will prove valuable by characterizing the direction of causality between cardiovascular and renal disease. This should help inform whether targeting reduced GFR alongside more traditional cardiovascular risk factors is warranted. In addition, this study will contribute important safety data on living kidney donors by providing a longitudinal assessment of well-validated surrogate markers of cardiovascular disease, namely, blood pressure and arterial stiffness. If any adverse effects are detected, these may be potentially reversed with the early introduction of targeted therapy. This should ensure that kidney donors do not come to long-term harm and thereby preserve the ongoing expansion of the living donor transplant program.<p></p&gt

Aortic backward waves derived from wave separation analysis, and end-organ changes

Dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Master of Science in Medicine Johannesburg, 2016Aortic backward (reflected) waves are major determinants of cardiovascular events and their impact is independent of brachial blood pressure. Although aortic backward wave pressures (Pb) can be determined using a triangular flow wave form for wave separation analysis, which is a cheaper and time-efficient method, Pb derived from this approach correlates poorly with Pb derived from measured aortic flow waves. However, the comparative ability of these two Pb measurements to predict end-organ changes remains uncertain. Therefore, we aimed to compare Pb obtained using a triangular flow wave method (Pbtri) and Pb obtained using echocardiographic derived aortic flow velocity waves (Pbecho), and their relationships with left ventricular mass indexed to height2.7 (LVMI). In 394 participants from a black African community sample (age>16years), aortic haemodynamics (applanation tonometry, SphygmoCor software), aortic flow velocity and LVMI (echocardiography) were determined. Bland-Altman analysis revealed that Pbtri overestimated the backward wave pressure by an average of 3.65±3.17mmHg. However, the correlation between the two measurements was markedly high (r2=0.82). Independent of confounders, including age, Pbtri was associated with LVMI (partial r=0.14, p=0.02). Importantly, when comparing the association between Pbecho and LVMI (partial r=0.14, p=0.01) no differences were noted (p=0.35, for comparison of partial r values, Z score). The triangular flow wave form employed for wave separation analysis produces Pb values that are as closely associated with LVMI as those derived from echocardiographic aortic flow wave measurements. Thus, risk prediction using simple approaches to aortic wave separation may be employed.MT201

Assessments of Arterial Stiffness and Endothelial Function Using Pulse Wave Analysis

Conventionally, the assessments of endothelial function and arterial stiffness require different sets of equipment, making the inclusion of both tests impractical for clinical and epidemiological studies. Pulse wave analysis (PWA) provides useful information regarding the mechanical properties of the arterial tree and can also be used to assess endothelial function. PWA is a simple, valid, reliable, and inexpensive technique, offering great clinical and epidemiological potential. The current paper will outline how to measure arterial stiffness and endothelial function using this technique and include discussion of validity and reliability

Arterial Stiffness in the Young: Assessment, Determinants, and Implications

Arterial stiffness describes the rigidity of the arterial wall. Its significance owes to its relationship with the pulsatile afterload presented to the left ventricle and its implications on ventricular-arterial coupling. In adults, the contention that arterial stiffness as a marker and risk factor for cardiovascular morbidity and mortality is gaining support. Noninvasive methods have increasingly been adopted in both the research and clinical arena to determine local, segmental, and systemic arterial stiffness in the young. With adoption of these noninvasive techniques for use in children and adolescents, the phenomenon and significance of arterial stiffening in the young is beginning to be unveiled. The list of childhood factors and conditions found to be associated with arterial stiffening has expanded rapidly over the last decade; these include traditional cardiovascular risk factors, prenatal growth restriction, vasculitides, vasculopathies associated with various syndromes, congenital heart disease, and several systemic diseases. The findings of arterial stiffening have functional implications on energetic efficiency, structure, and function of the left ventricle. Early identification of arterial dysfunction in childhood may provide a window for early intervention, although longitudinal studies are required to determine whether improvement of arterial function in normal and at-risk paediatric populations will be translated into clinical benefits

Disfunção vascular nos doentes com coarctação da aorta tratada

RESUMO: As cardiopatias congénitas (CC) afetam aproximadamente 1% dos recémnascidos e são responsáveis pela maior proporção de mortalidade infantil nos países desenvolvidos. A coarctação da aorta (CoA), a 6ª CC mais frequente, consiste numa estenose da aorta descendente proximal. Se não for tratada, tem uma história natural desfavorável. A cirurgia, dilatação com balão e a implantação de stent são atualmente técnicas que podem atingir o objetivo de uma remoção eficaz e duradoura da estenose ístmica, sendo a decisão baseada na idade doente, anatomia da CoA e preferência do operador ou da instituição. Contudo, um bom resultado anatómico não evita morbilidade e mortalidade de longo prazo, apresentando cerca de metade dos doentes hipertensão arterial (HTA), e registando-se mortalidade precoce, maioritariamente devido a complicações cardiovasculares e acidentes vasculares cerebrais. O perfil tensional anómalo sugere que os resultados subótimos possam ser secundários a disfunção vascular, cuja existência foi bem documentada em doentes com CoA tratada. Existem anomalias intrínsecas da estrutura arterial e função, alterações da sensibilidade neuro-hormonal ou da regulação endócrina, e fatores adquiridos, como a idade do tratamento, que contribuem para esta disfunção vascular. Os maus resultados a longo prazo podem resultar igualmente do tipo de tratamento efetuado, que provavelmente impactam de modo diverso a rigidez do istmo aórtico e potencialmente comprometem as funções da aorta. Este efeito da modalidade terapêutica não foi até ao momento estudado. A CoA não é uma simples doença mecânica que fica resolvida quando é removido o obstáculo. Objetivos e Hipóteses: O objetivo deste estudo é comparar a função vascular entre diferentes modalidades terapêuticas de CoA. A hipótese principal é a de que os doentes submetidos a dilatação com balão têm melhor função vascular que os doentes submetidos a cirurgia ou implantação de stent, pois aquela modalidade terapêutica tem menor potencial para danificar a integridade e propriedades biomecânicas da parede da aorta do que estas. Métodos: Avaliação prospetiva da função vascular usando múltiplas modalidades não invasivas, de modo a comparar os resultados de três grupos de doentes com CoA, tratados com dilatação com cirurgia, balão ou implantação de stent, após controle das variáveis de confusão. Em doentes com CoA tratada com sucesso, comparámos prospectivamente a rigidez da aorta com tonometria de aplanação e ressonância magnética cardíaca; função endotelial com tonometria arterial periférica endotelial; analise da onda de pulso com tonometria de aplanação e tonometria arterial periférica endotelial; massa ventricular esquerda e anatomia do arco aórtico com ressonância magnética cardíaca; marcadores séricos de função endotelial, inflamação, função da parede arterial e matriz extracelular; e saúde cardiovascular ideal. A análises estatística incluiu ajuste para as variáveis de confusão. Resultados: O estudo foi realizado em sete grandes centros, de Portugal e Estados Unidos da América. Foram incluídos 75 doentes, tratado por cirurgia (n=28), dilatação com balão (n=23) e implantação de stent (n=24). Os grupos tiveram idade semelhante à data de inclusão, gravidade da CoA, gradiente residual e perfil metabólico, mas eram diferentes quanto à idade à data do tratamento. A HTA, rigidez da aorta, função endotelial e massa ventricular eram semelhantes entre os grupos. Contudo, o grupo da dilatação com balão tinha mais distensibilidade regional da aorta ascendente, menor tensão arterial (TA) sistólica durante o exercício, menos alteração da variação noturna da TA, e dose menor de biomarcadores inflamatórios. Os resultados permaneceram inalterados após ajuste das potenciais variáveis de confusão, incluindo idade à data do tratamento. Conclusões: A modalidade terapêutica não estava associada à presença de HTA, rigidez arterial global e função endotelial. Contudo, os doentes com dilatação com balão tinham um perfil de função vascular mais favorável, caracterizado por maior distensibilidade da aorta ascendente, TA noturna mais baixa, menor resposta hipertensiva no esforço e menores marcadores séricos de inflamação. São necessários mais estudos para confirmar se os nossos resultados poderão contribuir para o refinamento do paradigma de tratamento da CoA, ao adicionar ao objetivo de remoção da estenose, a preservação da função vascular, quando dois ou mais tratamentos são aplicáveis.ABSTRACT: Introduction: Congenital heart disease (CHD) affects approximately 1% of liveborns and accounts for the largest proportion of infant mortality in developed countries. Coarctation of the aorta (CoA), the 6th most common CHD, consists of a narrowing of the proximal descending aorta. If left untreated, it has an unfavorable natural history. Surgery, balloon dilation (BD) or stent implantation are all current treatments that can achieve a successful long-term removal of the stenosis, and the choice is based on age, CoA anatomy, and personal or institutional preference. Coarctation is not a mere mechanical disease that is treated by removing the increased afterload. In fact, a good anatomic result does not avoid long-term cardiovascular (CV) morbidity and mortality, with late systemic hypertension (HTN) in approximately half of the patients, and reduced life expectancy, mostly due to CV complications and stroke. The abnormal blood pressure (BP) phenotype suggests that the suboptimal results are likely due to abnormal vascular function, which has been well documented in patients with repaired CoA. There are inherent changes in the arterial structure and function, impaired neuronal sensitivity or endocrinal auto-regulation, and acquired features, such as age at treatment, that contribute to vascular dysfunction in CoA. The poor long-term vascular outcome may also be impacted by the different types of repair, which likely have differing effects on the stiffness of the repaired segment and potentially compromise both the conduit and cushioning functions of the aorta. The effects of treatment modality on long-term vascular function remain uncharacterized. Aims and Hypothesis: The goal of this study is to assess vascular function in this patient population for comparison among the treatment modalities. The central hypothesis of this study was that patients who have undergone successful BD will have better vascular function than patients who have undergone successful surgical repair or stenting since this modality is least likely to damage the integrity and biomechanical properties of the aortic wall. Methods: Prospective assessment of vascular function using multiple non-invasive modalities, and compare the results among the three groups of CoA patients previously treated using surgery, BD or stent implantation after frequency matching for confounding variables. In successfully repaired CoA patients, we prospectively compared aortic stiffness by applanation tonometry and cardiac magnetic resonance (CMR); endothelial function by endothelial pulse amplitude testing; pulse waveform analysis by applanation tonometry and endothelial pulse amplitude testing; BP phenotype by office BP, ambulatory BP monitoring, and BP response to exercise; left ventricular (LV) mass and aortic morphometrics by CMR; blood biomarkers of endothelial function, inflammation, vascular wall function, and extracellular matrix; and ideal cardiovascular health. In the statistical analysis, we adjusted for potential confounders. Results: This study was done in seven, large volume centers from Portugal and the United States of America. Participants included 75 patients treated with surgery (n=28), BD (n=23), or stent (n=24). Groups had similar age at enrollment, CoA severity, residual gradient, and metabolic profile but differed by age at treatment. Systemic HTN, aortic stiffness, endothelial function, and LV mass were similar among groups. However, BD had more distensible ascending aortas, lower peak systolic BP during exercise, less impairment in diurnal BP variation, and lower inflammatory biomarkers. The results were unchanged after adjustment for potential confounders, including age at treatment. Conclusions: Treatment modality was not associated with major vascular outcomes such as systemic HTN, global aortic stiffness, and endothelial function. However, BD patients had a better vascular phenotype profile characterized by higher ascending aorta distensibility, lower night-time BP, lower peak exercise BP and lower levels of inflammatory markers. Further studies are required to confirm if our results may contribute to refining the CoA treatment paradigm by adding to the goals of therapy the preservation of vascular function when two or more treatment techniques are applicable

The acute effect of maximal exercise on central and peripheral arterial stiffness indices and hemodynamics in children and adults

Xavier Melo is supported by a research grant from the Foundation for Science and Technology (FCT), Ministry of Education and Science of Portugal (grant: SFRH/ BD/ 70515/ 2010). Nuno M. Pimenta is cofinanced by national funds through the Programa Operacional do Alentejo 2007-2013 (ALENT-07-0262- FEDER-001883)This study compared the effects of a bout of maximal running exercise on arterial stiffness in children and adults. Right carotid blood pressure and artery stiffness indices measured by pulse wave velocity (PWV), compliance and distensibility coefficients, stiffness index α and β (echo-tracking), contralateral carotid blood pressure, and upper and lower limb and central/aortic PWV (applanation tonometry) were taken at rest and 10 min after a bout of maximal treadmill running in 34 children (7.38 ± 0.38 years) and 45 young adults (25.22 ± 0.91 years) having similar aerobic potential. Two-by-two repeated measures analysis of variance and analysis of covariance were used to detect differences with exercise between groups. Carotid pulse pressure (PP; η(2) = 0.394) increased more in adults after exercise (p < 0.05). Compliance (η(2) = 0.385) decreased in particular in adults and in those with high changes in distending pressure, similarly to stiffness index α and β. Carotid PWV increased more in adults and was related to local changes in PP but not mean arterial pressure (MAP). Stiffness in the lower limbs decreased (η(2) = 0.115) but apparently only in those with small MAP changes (η(2) = 0.111). No significant exercise or group interaction effects were found when variables were adjusted to height. An acute bout of maximal exercise can alter arterial stiffness and hemodynamics in the carotid artery and within the active muscle beds. Arterial stiffness and hemodynamic response to metabolic demands during exercise in children simply reflect their smaller body size and may not indicate a particular physiological difference compared with adults.info:eu-repo/semantics/publishedVersio

Impact of body tilt on the central aortic pressure pulse.

The present work was undertaken to investigate, in young healthy volunteers, the relationships between the forward propagation times of arterial pressure waves and the timing of reflected waves observable on the aortic pulse, in the course of rapid changes in body position. 20 young healthy subjects, 10 men, and 10 women, were examined on a tilt table at two different tilt angles, -10° (Head-down) and + 45° (Head-up). In each position, carotid-femoral (Tcf) and carotid-tibial forward propagation times (Tct) were measured with the Complior device. In each position also, the central aortic pressure pulse was recorded with radial tonometry, using the SphygmoCor device and a generalized transfer function, so as to evaluate the timing of reflected waves reaching the aorta in systole (onset of systolic reflected wave, sT1r) and diastole (mean transit time of diastolic reflected wave, dMTT). The position shift from Head-up to Head-down caused a massive increase in both Tct (women from 130 ± 10 to 185 ± 18 msec P &lt; 0.001, men from 136 ± 9 to 204 ± 18 msec P &lt; 0.001) and dMTT (women from 364 ± 35 to 499 ± 33 msec P &lt; 0.001, men from 406 ± 22 to 553 ± 21 msec P &lt; 0.001). Mixed model regression showed that the changes in Tct and dMTT observed between Head-up and Head-down were tightly coupled (regression coefficient 2.1, 95% confidence interval 1.9-2.3, P &lt; 0.001). These results strongly suggest that the diastolic waves observed on central aortic pulses reconstructed from radial tonometric correspond at least in part to reflections generated in the lower limbs

The Noninvasive Measurement of Central Aortic Blood Pressure Waveform

Central aortic pressure (CAP) is a potential surrogate of brachial blood pressure in both clinical practice and routine health screening. It directly reflects the status of the central aorta. Noninvasive measurement of CAP becomes a crucial technique of great interest. There have been advances in recent years, including the proposal of novel methods and commercialization of several instruments. This chapter briefly introduces the clinical importance of CAP and the theoretical basis for the generation of CAP in the first and second sections. The third section describes and discusses the measurement of peripheral blood pressure waveforms, which is employed to estimate CAP. We then review the proposed methods for the measurement of CAP. The calibration of blood pressure waveforms is discussed in the fourth section. After a brief discussion of the technical limitations, we give suggestions for perspectives and future challenges