To examine the impact of hypertension on cardiovascular health in patients with symptomatic peripheral artery disease and to identify factors associated with uncontrolled hypertension.A cross-sectional study including 251 patients with symptomatic peripheral artery disease . Following hypertension diagnosis, blood pressure was measured to determine control of hypertension. Arterial stiffness  and cardiac autonomic modulation  were assessed.Hypertension was associated with higher carotid-femoral pulse wave velocity, regardless of sex, age, ankle-brachial index, body mass index, walking capacity, heart rate, or comorbidities . Patients with systolic blood pressure ≥120mmHg had higher carotid-femoral pulse wave velocity values than normotensive individuals, and hypertensive patients with systolic blood pressure of ≤119mmHg . Sympathovagal balance was not associated with hypertension (p>0.05).Hypertensive patients with symptomatic peripheral artery disease have increased arterial stiffness. Arterial stiffness is even greater in patients with uncontrolled high blood pressure. Hypertension is one of the most prevalent risk factors for PAD, affecting approximately 80% of patients.–4 It is directly related to fatal and nonfatal cardiovascular events in this patient population..Peripheral artery disease (PAD) affects more than 200 million people worldwide.i.e., systolic blood pressure <140mmHg and diastolic blood pressure <90mmHg) is thought to be a cornerstone of hypertension management. In fact, a prior study showed that blood pressure control can decrease the incidence of cardiovascular disease and overall mortality by 33% (from 3.85% to 2.59% per year) and 32% (from 2.63% to 1.78% per year), respectively. However, associations between hypertension control and cardiovascular function in patients with PAD remain to be determined.Blood pressure control  in one or both legs, absence of critical limb ischemia, rest pain, noncompressible vessels, no limb amputation, or ulcers. Compliance with study criteria was checked by preliminary evaluations.This cross-sectional study followed  checklist.Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo(HCFMUSP), protocol 3.986.124, CAAE: 42379015.3.3002.0068 and of Hospital Albert Einstein(HIAE), protocol 3.959.548, CAAE: 42379015.3.0000.0071. Patients were duly informed of study risks and benefits and gave their written informed consent for participation. Data collection was performed between September 2015 and December 2017.This study was approved by the Human Research Ethics Committees of Measurements were made in a quiet environment. Blood pressure and arterial stiffness were measured with patients in the seated and the supine position, respectively. Patients were instructed to avoid moderate to vigorous physical activity for a minimum of 24 hours prior to the visit, and to avoid smoking, alcohol and caffeine intake for a minimum of 12 hours prior to measurements. Data were collected by blinded investigators.Higher readings were used in the analysis. Patients systolic blood pressure <140mmHg and diastolic blood pressure <90mmHg were allocated to the controlled group. Patients with blood pressure values higher than those established for the controlled group were allocated to the uncontrolled group.Intraclass correlation coefficient for systolic and diastolic blood pressure was 0.85 and 0.92, respectively.Patients taking antihypertensive drugs and with systolic blood pressure ≥140mmHg or diastolic pressure ≥90mmHg were defined as hypertensive. Blood pressure was measured in both arms using an automatic device HEM-742-E . Three consecutive blood pressure readings were taken at one-minute intervals, as described elsewhere. and American Heart Association Scientific Statement: Recommendations for Improving and Standardizing Vascular Research on Arterial Stiffness guidelines. The intraclass correlation coefficient for cfPWV was 0.91.Carotid–femoral pulse wave velocity (cfPWV) was used to assess arterial stiffness. Measurements were made using a high-fidelity applanation tonometer , in compliance with Clinical Application of Arterial Stiffness Task Force III Inter-beat (RR) intervals were obtained using a heart rate monitor ; a minimum of five minutes of stationary RR interval data were used. Frequency domain variables were calculated using the autoregressive method. Signals operating at frequencies between 0.04 and 0.4Hz were considered physiologically significant. Low (LF) and high (HF) frequency components were represented by oscillations ranging from 0.04 to 0.15Hz and 0.15 to 0.4Hz, respectively. The LF/HF ratio was defined as the cardiac sympathovagal balance. Analyses were performed using Kubios HRV software . Task Force for Heart Rate Variability recommendations were followed.Cardiac autonomic modulation assessment was based on heart rate variability analysis, as per previously described procedures.,14 Interarm blood pressure differences >10mmHg were considered to be indicative of upper extremity PAD.Demographic data (age and sex), ankle-brachial index, comorbidities , walking capacity, heart rate, and body mass index were assessed at the beginning of the study, using previously described procedures.Data normality and homogeneity were checked using the Kolmogorov Smirnov and the Levene test respectively. For descriptive statistics, continuous variables were summarized as mean and standard deviation, whereas categorical variables were summarized as relative frequency. Linear regression models were used to investigate associations between cardiovascular variables  and hypertension. Crude analyses were performed first, then adjusted for classical confounding variables. Residual analysis was performed and homoscedasticity examined using graphical analysis (scatterplots). Multicollinearity analysis was conducted assuming variance inflation factors of less than than 5, and tolerance values of less than 0.20.One-way ANOVA was used to compare cfPWV values between normotensive and hypertensive patients . Multiple logistic regression was used to determine factors associated with uncontrolled hypertension in patients with PAD. Variables with a p value <0.30 in bivariate analysis were included in the model, and only those with a p value <0.10 retained in the final model. Model goodness-of-fit was assessed using the Hosmer-Lemeshow test.Pearson’s correlation coefficient was used to examine the relation between systolic blood pressure and cfPWV. The level of significance was set at 5% (p<0.05).Out of 261 patients enrolled in this study, 10 were excluded due to missing blood pressure data. The final sample comprised 251 patients with PAD whose data were available for analysis. All patients had moderate PAD, and 24.8% had signs suggestive of upper extremity PAD. Mean body mass index was 27.4±6.3kg/m². Hypertension was diagnosed in 89.6% patients, of whom 50.2% had uncontrolled hypertension. Clinical characteristics of patients with controlled or uncontrolled hypertension are shown in Associations between hypertension and cardiovascular variables are shown in Systolic blood pressure, diastolic blood pressure, mean blood pressure, heart rate and pulse pressure were positively correlated with cfPWV -1E. PatiOlder age, lower ankle-brachial index and no use of ACEi were associated with uncontrolled hypertension, based on regression analysis .In this study, hypertension was associated with greater arterial stiffness in patients with PAD, regardless of sex, age, ankle-brachial index, body mass index, walking capacity, heart rate or comorbidities. Arterial stiffness was also greater in hypertensive patients with PAD and systolic blood pressure ≥120mmHg than in normotensive and hypertensive patients with PAD and systolic blood pressure ≤119mmHg. Older age, lower ankle–brachial index, and no use of ACEi were associated with uncontrolled hypertension in patients with PAD.–4 This analysis revealed similar findings. The prevalence of hypertension was associated with increased arterial stiffness, even after adjustment for confounding factors, as reported in other studies investigating patients with hypertension and diabetes.,17 From a clinical standpoint, these are relevant findings, since increased arterial stiffness is associated with poorer cardiovascular outcomes, regardless of traditional risk factors.Prior studies have shown that hypertension is the most prevalent comorbidity in patients with PAD.,19 It is also strongly related to atherosclerosis development and should, therefore, be considered a significant clinical marker in patients with PAD.,21 The median cfPWV value was 2.4m/s higher in hypertensive relative to normotensive patients with PAD. This implies a higher cardiovascular risk, given a 1m/s increase in cfPWV is associated with a 14% increase in the odds of having a cardiovascular event and a 15% increase in cardiovascular mortality.Arterial stiffness plays a key role in the pathophysiology of hypertension. have a positive effect on aortic stiffness. In addition to drug treatment, lifestyle modifications, such as physical activity, should be recommended to reduce blood pressure.Patients with controlled hypertension had lower cfPWV values than those with uncontrolled hypertension, suggesting interventions aimed to reducing cfPWV may benefit patients with PAD. For example, medications with proven ability to decrease arterial stiffening, particularly ACEi and calcium channel blockers,,25Increased sympathetic and decreased cardiac parasympathetic modulation are thought to be important predictors of fatal and nonfatal cardiac events. Data in this study failed to reveal a relation between hypertension and sympathovagal balance. This may seem odd at first, since patients with hypertension have an autonomic dysfunction. However, half of patients were taking beta-blockers. Beta-blockers upregulate the fractal behavior of cardiac autonomic modulation in patients with cardiovascular diseases,,28 allowing for better cardiovascular control.Sympathovagal balance of 2.0 in patients with PAD in this study indicated a shift in cardiac autonomic modulation towards increased sympathetic and decreased parasympathetic modulation. Similar findings have been reported elsewhere. poor fitness,low levels of physical activity,,31and more barriers to physical activity, in older patients.,32 These variables are classic predictors of good cardiovascular health. Uncontrolled hypertension was also more likely among patients who did not use ACEi. According to a review study, renin-angiotensin system blockers, especially angiotensin converting enzyme inhibitor inhibitors, may effectively reduce the risk of cardiovascular ischemic events in patients with PAD.In the current study, advanced age, lower ankle-brachial index and no use of ACEi, were associated with uncontrolled hypertension in patients with PAD. Likewise, previous studies revealed lower ankle-brachial index, greater impairment of walking capacity,i.e., controlled blood pressure) are thought to be cornerstones of hypertensive patient management. Hypertension was associated with increased arterial stiffness, regardless of sex, age, ankle-brachial index, body mass index, walking capacity, heart rate or comorbidities. However, hypertensive patients with systolic blood pressure ≤119mmHg had better vascular health . Therefore, these values should be accounted for in the establishment of therapeutic goals, as suggested in American guidelines,is spite of divergences from Brazilian and European guidelines.Findings of this study have important practical implications. For example, systolic blood pressure <140mmHg and diastolic blood pressure <90mmHg  afeta mais de 200 milhões de indivíduos em todo o mundo. De fato, estudo anterior mostrou que o controle da pressão arterial pode reduzir a incidência de doenças cardiovasculares em 33% , e a mortalidade total em 32% . Entretanto, não se sabe se o controle da hipertensão está associado à função cardiovascular em pacientes com DAP.O controle da pressão arterial  é considerado essencial no tratamento da hipertensão.Maior compreensão do impacto da hipertensão controlada e não controlada sobre a saúde cardiovascular pode ajudar os médicos em condutas na saúde cardiovascular, o que consequentemente afeta a sobrevida em pacientes com DAP. É importante identificar fatores associados à hipertensão arterial não controlada em pacientes com DAP.Analisar a influência da hipertensão na saúde cardiovascular em pacientes com doença arterial periférica sintomática, e identificar os fatores associados com a hipertensão não controlada.Strengthening the Reporting of Observational studies in Epidemiology (STROBE). Pacientes com DAP foram recrutados em unidades vasculares em São Paulo, SP, Brasil. Os critérios de inclusão foram pacientes com 40-90 anos de idade com DAP sintomático  em uma ou ambas as pernas, e ausência de isquemia crítica de membros, dor ao repouso, vasos não compressíveis, sem membros amputados, ou úlceras. O cumprimento dos critérios de estudo foi verificado por avaliações preliminares.Este estudo transversal segue a lista de verificação Este estudo foi aprovado pelo Comitês de Ética em Pesquisa em Humanos do Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), protocolo 3.986.124, CAAE: 42379015.3.3002.0068, e do Hospital Albert Einstein (HIAE), protocolo 3.959.548, CAAE: 42379015.3.0000.0071. Cada paciente foi informado dos riscos e benefícios envolvidos no estudo e assinou o termo de consentimento livre e informado para participação. A coleta de dados foi realizada entre setembro de 2015 e dezembro de 2017.Todas as mensurações foram feitas em um ambiente silencioso. A pressão arterial foi verificada com paciente sentado, e a rigidez arterial, na posição supina. Os pacientes foram instruídos a evitar atividade física moderada a vigorosa por, pelo menos, 24 horas antes da visita, e a evitar o fumo, álcool e ingestão de cafeína por, pelo menos, 12 horas antes das mensurações. Os dados foram coletados por pesquisadores cegos para a análise. Para fins do presente estudo, foi utilizada a pressão de braço mais alta. Os pacientes com pressão arterial sistólica <140mmHg e diastólica <90mmHg foram designados para o grupo controlado, enquanto aqueles com valores de PA acima dos indicados para o grupo controlado foram classificados para o grupo não controlado. O coeficiente de correlação intraclasse foi 0,85 e 0,92 para pressão arterial sistólica e diastólica, respectivamente.Os pacientes hipertensos foram definidos como aqueles em uso de antihipertensivos e com pressão arterial sistólica de ≥140mmHg ou pressão diastólica de ≥90mmHg. A pressão arterial foi avaliada usando um dispositivo automático HEM-742-E . A pressão arterial foi medida três vezes, em ambos os braços, com um intervalo de um minuto entre cada medida, como descrito anteriormente.carotid-femoral pulse wave velocity), usando um tonômetro de aplanação de alta fidelidade . Foram seguidas as diretrizes da Clinical Application of Arterial Stiffness Task Force III e da American Heart Association Scientific Statement: Recommendations for Improving and Standardizing Vascular Research on Arterial Stiffness. O coeficiente de correlação intraclasse para cfPWV foi 0,91.A rigidez arterial foi avaliada através da medição da velocidade da onda de pulso carotídeo-femoral  foram obtidos usando um monitor de frequência cardíaca ; pelo menos cinco minutos de dados de intervalo RR estacionário foram usados. As variáveis de domínio de frequência foram calculadas usando o método autoregressivo. Sinais operando em frequências entre 0,04 e 0,4Hz foram considerados fisiologicamente significativos. Os componentes de baixa frequência (LF - low frequency) foi representado por oscilações entre 0,04 e 0,15Hz, e o componente de alta frequência (HF - high frequency), entre 0,15 e 0,4Hz. A relação LF/HF foi definida como o equilíbrio simpatovagal cardíaco. Todas as análises foram realizadas utilizando o programa Kubios HRV  e seguiram as recomendações da Task Force for Heart Rate Variability.A avaliação da modulação autonômica cardíaca foi obtida através da análise da variabilidade da frequência cardíaca, seguindo os procedimentos descritos anteriormente.,14 A diferença de pressão sanguínea entre braços >10mmHg foi considerada indicativa de DAP dos membros superiores.Dados demográficos (idade e sexo), índice tornozelo-braço, comorbidades , capacidade de deambulação, frequência cardíaca, e índice de massa corporal foram avaliados no início do estudo, utilizando procedimentos previamente descritos.scatterplot). Foi realizada uma análise de multicolinearidade, assumindo fatores de inflação de variância inferiores a 5, e tolerância abaixo de 0,20.A normalidade e a homogeneidade foram verificadas utilizando os testes de Kolmogorov-Smirnov e Levene, respectivamente. Para a estatística descritiva, as variáveis contínuas foram apresentadas como média e desvio padrão, enquanto as variáveis categóricas como frequência relativa. Os modelos de regressão linear foram utilizados para analisar a associação entre variáveis cardiovasculares  e hipertensão arterial. As análises brutas foram realizadas primeiro e depois ajustadas para as variáveis clássicas de confusão. Foi realizada análise de resíduos residual, sendo a homoscedasticidade analisada pelo gráfico  foi avaliada com a ANOVA O coeficiente de correlação de Pearson foi utilizado para analisar a relação entre a pressão arterial sistólica e o cfPWV. O valor de p<0,05 foi considerado estatisticamente significativo.Dos 261 pacientes inscritos no presente estudo, 10 foram excluídos por não possuírem medida de pressão arterial. A análise final consistiu de dados de 251 pacientes com DAP. Todos os pacientes tinham DAP moderada, e 24,8% tinham indicação de DAP nos membros superiores. O índice de massa corporal médio foi 27,4±6,3kg/m². Hipertensão foi diagnosticada em 89,6% dos pacientes, dos quais 50,2% tinham hipertensão não controlada. A A Foi observada uma correlação positiva entre pressão arterial sistólica, pressão arterial diastólica, pressão arterial média, frequência cardíaca e pressão de pulso com cfPWV -1E. Os pOs fatores associados à hipertensão não controlada foram idade avançada, menor índice tornozelo-braço e não uso de iECA com base na análise de regressão logística .Neste estudo, hipertensão estava associada à maior rigidez arterial entre os pacientes com DAP, independente do sexo, idade, índice tornozelo-braço, índice de massa corpórea, capacidade de deambulação, frequência cardíaca ou comorbidades. Rigidez arterial também foi maior em pacientes hipertensos com DAP e pressão arterial sistólica ≥120mmHg, do que em pacientes normotensos e hipertensos com DAP e pressão arterial sistólica de ≤119mmHg. Idade avançada, menor índice tornozelo-braço, e não uso de iECA foram associados com hipertensão não controlada em pacientes com DAP.–4 Esta análise mostrou achados semelhantes. A prevalência da hipertensão foi associada a maior rigidez arterial, mesmo após o ajuste para fatores de confusão; como descrito em outros estudos envolvendo pacientes com hipertensão e diabetes.,17 Esses achados são relevantes do ponto de vista clínico, pois o aumento da rigidez arterial está associado a piores resultados cardiovasculares, independente dos fatores de risco tradicionais.Estudos anteriores mostraram que a hipertensão é a comorbidade mais prevalente entre os pacientes com DAP.,19 e se relaciona fortemente ao desenvolvimento da aterosclerose e, portanto, deve ser considerada um marcador clínico importante em pacientes com DAP.,21 O valor mediano de cfPWV foi 2,4m/s maior em hipertensos do que em normotensos com DAP. Isto se traduz em um risco cardiovascular maior, dado que um aumento de 1m/s no cfPWV está associado a um aumento de 14% na probabilidade de ter um evento cardiovascular, e de 15% na mortalidade cardiovascular.A rigidez arterial tem um papel essencial na fisiopatologia da hipertensão,têm um efeito positivo sobre a rigidez aórtica. Além do tratamento medicamentoso, devem ser recomendadas modificações no estilo de vida, como exercícios físicos, para reduzir a pressão sanguínea.Os pacientes com hipertensão controlada tinham valores menores de cfPWV que aqueles com hipertensão não controlada, sugerindo que intervenções para reduzir a cfPWV poderiam ser benéficas para os pacientes com DAP. Por exemplo, a escolha de medicamentos já conhecidos por diminuir a rigidez arterial, particularmente iECA e bloqueadores dos canais de cálcio,,25 O aumento da modulação simpática e a redução da modulação parassimpática do coração foram considerados como importantes preditores de eventos cardíacos fatais e não fatais. Os dados do estudo não mostraram uma relação entre hipertensão e equilíbrio simpático. Esta falta de relação pode parecer estranha no início, já que os pacientes com hipertensão têm disfunção autonômica. Entretanto, metade dos pacientes estava tomando beta bloqueadores. Beta bloqueadores regulam positivamente o comportamento fractal da modulação autonômica cardíaca em pacientes com doenças cardiovasculares,,28permitindo um melhor controle cardiovascular.Demonstramos que o equilíbrio simpatovagal em pacientes com DAP era 2,0, e indicando modulação autonômica cardíaca em direção a maior modulação simpática e menor modulação parassimpática. Achados semelhantes foram descritos em estudos anteriores. pior forma física, baixos níveis de atividade física,,31 e mais barreiras à atividade física, em pacientes mais velhos.,32Estas variáveis são preditores clássicos de boa saúde cardiovascular. Além disso, foi observado que pacientes que não usavam iECA tinham uma maior probabilidade de hipertensão não controlada. Um estudo de revisão demonstrou que o uso de bloqueadores do sistema renina-angiotensina, especialmente os iECA, pode ser eficaz na redução do risco de eventos isquêmicos cardiovasculares em pacientes com DAP.No estudo atual, idade mais avançada, menor índicetornozelo-braço, e não uso de iECA foram associados à hipertensão não controlada em pacientes com DAP. Da mesma forma, estudos anteriores mostraram menor índice tornozelo-braço, maior dificuldade na capacidade de deambulação, A hipertensão, independente de sexo, idade, índice tornozelo-braço, índice de massa corpórea, capacidade de deambulação, frequência cardíaca, ou comorbidades, foram associadas à maior rigidez arterial. Entretanto, observamos que pacientes hipertensos com pressão arterial sistólica ≤119mmHg tinham melhor saúde vascular . Portanto, estes valores devem ser considerados ao estabelecer os objetivos terapêuticos, como sugerido pelas diretrizes americanas, embora com divergências em relação às diretrizes do Brasile europeias.Os resultados do presente estudo têm importantes implicações práticas. Por exemplo, pressão arterial sistólica <140mmHg e a diastólica <90mmHg  são consideradas fundamentais no tratamento de pacientes hipertensos.Este estudo tem limitações. Primeiro, desenho transversal de estudo não deixa inferir sobre causalidade. Portanto, estudos longitudinais são necessários para investigar os mecanismos responsáveis pelas associações observadas. Segundo, incluímos apenas pacientes com DAP sintomática; assim, os resultados não podem ser extrapolados para pacientes com outros estágios da doença. Terceiro, o tamanho da amostra era pequeno, e os pacientes estavam usando diferentes medicamentos; isto pode ter influenciado nas variáveis cardiovasculares, e não foi possível fazer análises estratificadas por medicamentos. Finalmente, os biomarcadores não foram medidos, e isso limita a compreensão dos mecanismos que levam às associações observadas, assim como a extrapolação dos resultados para outros pacientes.A hipertensão estava associada à maior rigidez arterial em pacientes com doença arterial periférica. Pacientes com hipertensão não controlada tinham maior rigidez arterial. Estes resultados demonstram a importância do controle da pressão arterial nesses pacientes.


To date, however, no known studies have investigated the effects of regular practice of voluntary mild hypocapnic breathing on BP in hypertensive patients. The objective of the present research was to test the hypothesis that capnometric feedback training can decrease both resting pCO2 and 24-h BP in a series of mildly hypertensive postmenopausal women.High normal resting pCO2 (etCO2) monitor was constructed and equipped with software that determined the difference between the momentary etCO2 and a pre-programmed criterion range. The monitor enabled auditory feedback for variations in CO2 outside the criterion range. 16 mildly hypertensive postmenopausal women were individually trained to sustain small decreases in etCO2 during six weekly sessions in the clinic and daily sessions at home. 24-h BP monitoring was conducted before and after the intervention, and in 16 prehypertensive postmenopausal women in a control group who did not engage in the capnometric training.A small portable end tidal CO2  while 15 showed decreases in 24-h systolic BP . No significant changes in either measure was observed in the control group. In addition, nighttime  and daytime (− 6.7 ± 0.2 mmHg) systolic BP were both decreased following capnometric training, while no significant changes in nighttime  or daytime  systolic BP were observed in the control group.Following the intervention, all 16 capnometric training participants showed decreases in resting etCO2 reliably decreases 24-h blood pressure in hypertensive postmenopausal women. The extent to which these effects persist beyond the training period or can be observed in other hypertensive subgroups remains to be investigated.These findings support the hypothesis that regular practice of mild hypocapnic breathing that decreases resting etCO Primary hypertension is chronically elevated blood pressure (BP) of unknown origin. It is the most common cardiovascular disorder, and a major risk factor for stroke and coronary heart disease . EpidemiEver since the discovery of the “fight or flight” response almost a century ago , investi2 at or near pre-intervention baselines [2 are not the only possible means by which the set point for BP might be modified. It has been known for many years that voluntary hypocapnic breathing that decreases pCO2 also decreases BP acutely [2 within the normal range sustained for 30 min by capnometric feedback increased BP acutely in normotensive men [2 is a risk factor for BP sensitivity to high sodium intake in older [Others had observed, however, that the decreases in rate during breathing interventions are typically offset by proportional increases in tidal volume (breathing depth) that maintain pCOaselines . Breathi acutely . Converssive men . In neitin older  and younin older  normoten2 on 24-h BP. In the present study, the effects of regular practice of a mild hypocapnic breathing task on BP were investigated in a series of postmenopausal women with hypertensive BP levels.  and hypercapnic (increased) refer to the direction of change in pCO2, not levels beyond the normal range.) The selection of women as participants was based on the results of previous research that found a significant positive correlation between resting pCO2 and resting BP in postmenopausal women, but not age-matched men [2 together with decreases in 24-h systolic BP.To date, no studies have examined the effects of breathing exercises that reliably decrease pCOched men . The corched men . The preParticipants were recruited via the Kaiser Permanente, Northern California (KPNC) health system using a computer algorithm that identified potential candidates via inclusion and exclusion criteria. The inclusion criteria included (a) English speaking females 50–75 years at the time of entry, at least 1 year without menstrual cycle, body mass index (BMI): 19–31, and 24-h systolic BP 140 > 150 mmHg. Exclusion criteria included a history of respiratory, cardiovascular, liver or kidney disease, or diabetes; current medication that influences respiratory function, including benzodiazepines, narcotics or tranquilizers; steroid use within the past 6 months, including hormone replacement therapy; and recent tobacco use. The study was approved by the Institutional Review Boards of University of California, San Francisco (UCSF) and the Kaiser Foundation Research Institute (KFRI). Letters describing the study were mailed to potential candidates. Those who indicated interest were screened by telephone interview to confirm inclusion and exclusion criteria.2 and breathing rate were measured via a nasal cannula attached to a battery-powered respiratory gas monitor that had been customized for continuous recording. To avoid the influence of digestion on pCO2, candidates were asked to fast for 2 h before the session. The capnometer was calibrated before each clinic session using a known CO2 concentration. Measurements of systolic and diastolic BP and heart rate were recorded every 6 min, using an ambulatory monitor . The first BP measurement was discarded and means of the remaining measurements were averaged. After this 25 min session, the candidate wore the ambulatory BP monitor for the next 24 h in the natural environment, during which BP and heart rate were recorded once per hour.Twenty-six candidates were invited for in-person physiological screening. During a first pre-intervention screening session, study objectives and procedures were described, and informed consent was obtained. Monitoring of breath-to-breath respiratory variables occurred during 25 min of seated rest in a recliner chair in a quiet room. etCO2 decreased below the lower limit of the criterion range . When this contingency proved inadequate to generate consistently effective decreases in etCO2 within that range, a more complex contingency was instated whereby auditory feedback was presented whenever etCO2 drifted above or below the criterion range. The auditory stimulus was terminated as soon as etCO2 returned within the criterion range. The data analyzed in the present study were obtained from the 16 women who were trained under this latter contingency.Each candidate returned to the clinic setting within 72 h. If the 24-h SBP or DBP mean was outside the inclusion range, the candidate was excused and referred to her physician, as appropriate. For qualifying candidates, a second 25 min clinic baseline session was conducted, with means of each resting measure calculated as in the first session. Of the 26 participating women, the first 10 were studied with a contingency that involved auditory feedback only when etCOPrior to the onset of capnometric feedback training, each participant was advised to maintain their normal daily exercise regimens and diet throughout the study.Data from 16 prehypertensive postmenopausal women with 24 h mean systolic BP between 130 and 140 mmHg were selected from a larger group of women who were serving as control subjects in a different ongoing study. These participants had also been recruited from KPNC and were screened to establish eligibility for participation via review of medical records and a personal interview, as had been conducted for individuals in the capnometric training group. The same inclusion and exclusion criteria were employed. Their baseline and follow-up respiratory and cardiovascular measures were determined by the same methods as for the capnometric feedback group. The interval between these measurements was equivalent to those employed for the capnometric group. These participants were also advised to maintain their normal physical exercise and dietary habits.2 five mmHg below individual resting mean levels. Each training session was preceded by a 10 min rest interval, followed by a 25-min period during which the feedback contingency was in effect. At the detection of each new breath, the capnometer calculated mean etCO2 for all breaths during the preceding 15 s. Each recorded value was compared with the criterion range that was 3–7 mmHg below the individual baseline mean etCO2. When the observed 15 s mean etCO2 drifted above or below the criterion range, a non-aversive auditory stimulus was onset that remained in effect until etCO2 re-entered the criterion range.Participants who qualified for the study completed six weekly clinic training sessions during which they attempted to sustain etCO2 while maintaining a normal breathing rate. During all subsequent training sessions, the participant engaged in the feedback training task while alone. During each session, etCO2 and breathing rate were determined from inter-breath intervals, while systolic and diastolic BP, and heart rate, were recorded every 6 min.During the first training session, an instructor remained in the room with the participant, encouraging her to adjust breathing depth as needed to stay within the criterion range of etCO2 monitor home for regular practice sessions, 5 days per week. As during clinic sessions, the participant was instructed to rest for 10 min preceding the 25 min training sessions at home. During the home sessions, etCO2 and breathing rate were monitored continuously, but BP and heart rate were not recorded.Following each clinic session, the participant took the portable etCO2 and breathing rate were recorded, while systolic and diastolic BP and heart rate were monitored every 6 min. Following this session, ambulatory BP and heart rate were monitored once per hour for the next 24 h in the natural environment. During this 24-h post-intervention period, etCO2 and breathing rate were recorded during a 25 min rest session at home. The means of the clinic and home rest sessions were averaged, providing post-intervention outcome data.After completion of the capnometric training sessions, a post-intervention 25 min rest session was completed in the clinic, during which etCOThe analysis of the data included calculation of the significance of the correlation coefficients for successive means for each measure across sessions for the capnometric group with training session number. The significance of the differences between baseline and post-intervention means for each measure was determined via two-tailed t-tests for independent samples for both the capnometric training and control group. The significance of the differences between groups in each measure was determined via two tailed t-tests Tables  and 3 an2, resting breathing rate, 24-h diastolic pressure and 24-h heart rate for the capnometric training group and the control group were not significantly different. Baseline mean 24-mmHg systolic pressure was higher in the capnometric feedback group than in the control group. However, baseline daytime mean systolic BP in the capnometric feedback group was not significantly different from that in the control group (see Table Table p < 0.01).Figure 2 over the course of the six clinic feedback sessions . It also shows significant differences in resting etCO2 between baseline and post-intervention monitoring in the feedback group, but not in the control group . However, breathing rate following the intervention was decreased from baseline values . Table 2 = 5.7; p < .009).The upper panel of Fig. p > 0.145), and that group 24-h diastolic mean BP was not significantly different during post-intervention monitoring than at baseline , no significant change in breathing rate following the intervention, and no significant difference between groups , recorded etCO2 continuously, and employed contingencies for the maintenance of breathing depths within or near the normal range of etCO2. Since 24-h ambulatory heart rate was increased following this intervention, the findings are consistent with the conclusion that the changes in 24-h BP were mediated via decreases in peripheral vascular resistance.This study found that 6 weeks of regular practice of hypocapnic breathing reliably decreased 24-h systolic BP in postmenopausal hypertensive women. This is the first application of capnometric feedback applied to hypertensive patients, but far from the first to investigate the effects of instructed deep breathing on BP. Thirteen studies of regular deep breathing effects on resting BP have been reviewed recently . In gene24-h blood pressure monitoring is considered a better index of the set point than resting BP, because it is less susceptible to the confounding effects of “white coat hypertension” and “masked hypertension” and is more prognostic of heart and vascular disease . A sub-n2 and BP found in this study can also be seen in other disorders. For example, obstructive sleep apnea is associated with recurrent episodes of both hypoxia and hypercapnia [2 [2 and BP, and successful treatment is accompanied by a return of both pCO2 and BP to pre-failure levels [The association between the changes in pCOercapnia . Hypoxiaercapnia , but repapnia [2 . In addie levels .2 are a function of several psychological factors. Lower levels have been associated with anxiety [2 is known to decrease with age, perhaps in response to age-associated decreases in plasma pH [2 can change over time in a process known as allostasis, which can override the corrective action of homeostasis [2 was measured 7 days and 6 months after an initial baseline session, no significant group mean changes were observed, but test–retest correlations were lower after 6 months than after 1 week [2 have shown it to be effective in ameliorating panic disorder [Individual differences in resting pCO anxiety , 26, whi anxiety . Restinglasma pH . In addilasma pH . The seteostasis , 30. Forr 1 week . Previoudisorder , 33 and disorder .2 can occur under two behavioral conditions that might over time contribute to disease pathogenesis . Fir flight . It can rtension , but les2 while 15 showed post-intervention decreases in 24-h systolic BP indicates a strong association between the two. The untreated control group of postmenopausal women was added to document that repeated measurements of 24-h BP separated in time by at least 4 weeks do not result in significant changes in 24-h BP in the absence of an intervention [Regarding design, this study sought to determine the consistency with which behaviorally engineered changes in one physiological variable reliably resulted in changes in another physiological variable in individual patients. That all 16 participants showed decreases in resting etCOrvention .2 and resting BP is significant in women, but not in men [2 might decrease 24-h BP in older hypertensive men needs to be investigated.A limitation of the study is that the findings apply only to one subgroup of patients, namely, hypertensive postmenopausal women. They cannot necessarily be extended to men. When estrogen is diminished during menopause, the incidence of hypertension in women rises to become comparable to that of men . In oldet in men . Whether2 monitor and associated methodology required to document the effects of capnometric feedback training did not leave adequate time for recruitment of another group of unmedicated hypertensives fitting the inclusion and exclusion criteria within the grant funded study period. However, a group of unmedicated prehypertensive postmenopausal women with identical inclusion and exclusion criteria was available who had previously participated as controls in a different study. It should be noted that the daytime BP at baseline in the control group in the present study was not significantly different from that in the intervention group  levels following the intervention or control wait-list period. The development of the portable etCOup Table . Other rA third limitation of the study is that the findings apply only to the time period during which the scheduled practice of hypocapnic breathing was in effect. Follow up data will be needed to determine whether the decreases in 24-h BP persist beyond the termination of the intervention.2 in the maintenance of BP in hypertensive patients, but a role for pCO2 in the pathogenesis of a salt sensitive form of experimental hypertension has been documented in studies with large laboratory animals [2 might be effective in the management of salt-sensitive forms of primary hypertension.More generally, hypertension is thought to be a disorder of long-term sodium regulation involving an interaction between dietary sodium intake and factors that impair the ability of the kidneys to restore and maintain normal plasma volume and/or vascular tone –45. The  animals . Togethe2 in hypertensive postmenopausal women was accompanied by significant decreases in systolic 24-h blood pressure, a marker for long-term BP. The study was made possible by the development of a portable etCO2 monitor equipped with software that determined whether current etCO2 was within a pre-programed criterion range and provided contingent auditory feedback. This new technology has the potential to provide a non-pharmacological intervention for some groups of hypertensive patients that might be useful in the management of this most common cardiovascular disorder.This study found that 6 weeks of daily sessions of capnometric feedback training that decreased resting etCO


While Urinary tract infections are the most common infections in kidney transplant recipients, the impact of late acute graft pyelonephritis (AGPN) on graft outcomes remains unknown. Our study was performed to more precisely evaluate the long-term impact of AGPN.We included 9052 kidney and combined kidney-pancreas recipients who underwent transplantation between 2008 and 2018 from a French multicenter cohort. The relationships between AGPN and patient and graft survival were analyzed with a time-dependent multivariate Cox model.The cumulative incidence of AGPN was 20.9%. A first episode of early AGPN is associated with a non-significant increase in the risk of graft failure . Though, cumulative number of AGPN episodes  is associated with an increased risk of graft failure. In contrast, when the first episode of AGPN occurred late , the risk of graft failure is significantly increased , and this risk remains relatively stable with the recurrence of late AGPN episodes. The onset of late AGPN were also associated with a higher risk of patient death. This analysis shows that late AGPN and recurrent AGPN are both risk factors for a poor long-term graft outcome and mortality. Late AGPN should not be considered benign infections in post-transplantation follow-up. Acute graft pyelonephritis (AGPN) is common infection in kidney transplant recipient. While the impact of early AGPN on graft outcomes is well documented, the impact of late AGPN remains unknown. In a French multicentric kidney transplant cohort (DIVAT), the authors assessed the impact of late and recurrent AGPN occurring six months after transplantation on patient survival, graft survival and combined patient-graft survival, in a time manner. They report that late AGPN and recurrent late AGPN are both risk factors for a poor long-term graft outcome and mortality. These infections should therefore not be considered benign and as soon as the first episode of AGPN occurs, patients should be closely monitored to limit the risk of recurrence.Kidney transplantation remains the treatment of choice for end-stage renal disease. However, this requires long-term immunosuppressive treatment that can lead to infectious complications . BecauseThe impact of UTIs, particularly late episodes of AGPN, on kidney transplant recipients remains to be clarified. Our study therefore was performed to assess the impact of AGPN, with a special focus on late episodes of AGPN occurring six months after transplantation, on long-term kidney graft outcomes and mortality in a French multicentric kidney transplant cohort (DIVAT).www.divat.fr, CNIL final agreement, decision DR-2015-087 N°914184). A total of 9052 adult kidney transplant recipients (who received a first or second single kidney transplant or a simultaneous kidney-pancreas transplant) were recruited and included from January 2008 to December 2018. Follow-up was performed in in Nantes, Paris (Necker and Saint-Louis). This study was performed in accordance with the Declaration of Helsinki. All participants enrolled in this study signed informed consent forms.Data were extracted from the French multicentric, observational and prospective DIVAT cohort (AGPN was defined by the simultaneous presence of fever (after exclusion of others causes of fever) with a positive urine culture , 1.5 mg/kg/day (maximum 75 to 100 mg/day) or basiliximab (n=3081) (20 mg Simulect on day 0 and day 4), depending mainly on immunization status and/or transplantation rank. All patients received initial corticosteroid therapy, with at least one preoperative methylprednisolone bolus, followed by maintenance immunosuppressive treatment. Details of the immunosuppressive regimens are given in The following recipient characteristics were collected: age, sex, transplantation rank, initial renal disease, renal replacement therapy, history of diabetes, urological history often associated with recurrent UITs prior to kidney transplantation , the use of ureteral stent during transplantation , pregnancy history, recipient CMV serology and immunization [anti-human leukocyte antigen (HLA) and donor-specific antibodies (DSAs)]. The collected donor features were age, sex, donor type (living or deceased) and CMV serology. The baseline transplantation parameters considered were transplantation type (kidney or combined kidney and pancreas), cold ischemia time, number of HLA A-B-DR incompatibilities, induction therapy, delayed graft function (DGF), recipient transfusion, maintenance treatment and CMV prophylaxis. The collected post transplantation parameters were acute rejection (one or more) and CMV infection. The follow-up and the collection of data stopped upon a patient’s return to dialysis or death.de novo appearance of DSA, defined as the time between transplantation and the first appearance of DSA post transplantation. Finally, we studied the evolution of the estimated glomerular filtration rate (eGFR), estimated by the Modification of Diet in Renal Disease (MDRD) formula, considering all patients as Caucasian, as ethnicity was not available in our database.The main outcome was death-censored graft survival, defined as the time between transplantation and the first event before a return to dialysis or preemptive retransplantation. We additionally investigated patient and graft survival by considering death as an event, and patient survival was defined as the time between transplantation and death with a functioning graft. We also reported the cumulative probability of the occurrence of the The median duration of follow-up was estimated with a reverse Kaplan-Meier analysis . The cumTo explore the associations of the early  or late  occurrence of the first episodes of AGPN and the association of the total number of AGPN episodes with the outcomes, we included AGPN in the model as a time-dependent variable with seven categories , two late episodes of AGPN (none early), and three or more episodes of AGPN (none early). Thus, the time-dependent variable for AGPN allowed patients, initially all in the non-AGPN group, to change category at the time of a new episode. We included acute rejection and CMV infection post transplantation as time-dependent covariates in our cause-specific time-varying Cox models. For these two time-dependent covariates, the patients were considered exposed after their first episode of acute rejection or their first CMV infection.To assess the effect of AGPN on the post transplantation evolution of the eGFR, we used a linear mixed effect model with random patient-specific intercepts and slopes. We compared the random intercept and slope model with a reduced model with only random intercepts using the Akaike information criterion; the full model suggested a better fit. We first estimated the relationship between the number of AGPN episodes at 3 months post transplantation and the evolution of the eGFR. We performed the same analysis for a baseline set at 6-, 12- and 24- months post transplantation. Because of the observed nonlinearity, we modeled the evolution of the eGFR according to two slopes before transplantation and 1-year post transplantation. Using baselines at 12- and 24-months post transplantation, we distinguished the number of AGPN episodes according to whether the first occurred early or late. For patients who returned to dialysis, we fixed the eGFR at 5 ml/min at the time of return to therapy. Residual analyses were performed to check the models’ validity.For each outcome, we included the covariates that were significantly associated with the outcomes (p<0.05) in the univariate models in the multivariable models. We tested one time-dependent interaction term between the first rejection episode and the first AGPN episode in the Cox models and retained it if significant (p<0.05). In the eGRF analyses, we considered an interaction term between AGPN and the time from baseline to allow different evolutions of the eGFR in patients with AGPN. Patients with missing data for the covariates retained in the multivariable models or without measurements of the eGFR at baseline or subsequently were excluded. We described the characteristics of the studied patients and those of the excluded patients. We used R version 3.6.1 for all data analyses.de novo DSA.We included 9052 recipients of kidney (n= 8508) and combined kidney/pancreas (n= 544) transplants in this study. The characteristics of the patients stratified by type of AGPN episodes are described in The cumulative incidence rates of graft failure at 5- and 10-years post transplantation were 12.6% (95% CI from 11.8% to 13.5%) and 25.4% (95% CI from 23.6% to 27.4%), respectively Figure 1The cumulative incidence rates of graft failure or death at 5- and 10-years post transplantation were 21.9% (95% CI from 20.8% to 23.0%) and 45.1% (95% CI from 42.8% to 47.4%), respectively  and 19.6% (95% CI from 18.0% to 21.4%), respectively Figure 1de novo appearance of DSA, and 1699 were excluded due to missing data on DSA post transplantation. In the multivariable analyses, 1799 supplementary patients were excluded due to missing data for covariates. The cumulative incidence rates of the de novo appearance of DSA at 5- and 10-years post transplantation were 38.0% (95% CI from 36.7% to 39.4%) and 55.3% (95% CI from 52.8% to 57.8%), respectively (de novo appearance of DSA (P = 0.2474).A total of 7353 patients were included in the analysis of the Among the 9052 kidney recipients, 7992 patients had at least one measurement of the eGFR at 3 months post transplantation or later. Among them, 588 had one AGPN episode, and 106 had 2 or more AGPN episodes in the first 3 months post transplantation. The mean number of eGFR assessments was 5.7 (range from 1 to 14) after a mean of 29.8 months (range from 1 to 147). The mean 3-month eGFRs were 51.9 ml/min (95% CI from 51.4 to 52.3) for patients without any AGPN episodes at 3 months, 47.1 ml/min (95% CI from 45.5 to 48.8) for patients with one AGPN episode at 3 months and 45.3 ml/min (95% CI from 41.5 to 49.2) for patients with 2 or more AGPN episodes at 3 months. A total of 724 recipients returned to dialysis during follow-up. Therefore, although we did not observe a difference in the evolution of the eGFR, the levels of renal function remained significantly lower at 3- and 6-months post transplantation for patients with early AGPN episodes.For the baseline sets at 12- and 24-months post transplantation, we distinguished the number of episodes according to whether the first AGPN episode occurred within 6 months after transplantation or later  was associated with a twice higher and independent risk of both mortality and long-term graft failure than in patients with no AGPN episodes. To our knowledge, only one study focused on the confounder-adjusted impact of late AGPN after kidney transplantation. Abbott and al, performed a retrospective cohort study on 28 942 kidney transplanted recipients from 1996 to 2000 in the United States Renal Data System. Thanks to an equivalent method, the authors found an increased risk of death (HR = 2.93 (2.22 – 3.85)) and graft loss (HR = 1.85 (1.29 – 2.64)) when UTI occurred 6 months after transplantation . Despiteth missing data to calculate CNI through level during follow-up in our cohort. At last, the proportion of relevant urological medical history  in our cohort at baseline was significantly higher in recipients with AGPN than recipients without AGPN (early and late) during follow-up . No difference was observed between recipients with early and late AGPN . Dupont et al, also highlighted that vesicoureteral reflux but not exclusively was associated with cortical scarring and poor long-term graft function . We reported that patient death, graft failure and combined patient-graft death were significantly increased in case of repeated AGPN episodes, especially when the first episode occurred early within the first 6 months after transplantation. The impact of recurrent UTI in kidney transplanted recipients has been poorly explored. Two recent retrospective cohort studies also associated recurrent UTIs with a twice higher risk of graft loss all the more so one episode of UTI occurred within the first year after transplantation , 24. Of  = 4x10- ; Chi2). function . CombiniIn our cohort, we did not find neither any interaction between AGPN onset and acute allograft rejection nor any association with the outcomes of our study . In a prEscherichia coli, could have a larger impact on the fate of grafts  after a single episode of APGN in kidney transplanted recipients. Low dose long-term antibiotics could be discussed bearing in mind that multidrug resistant bacteria in the urine of kidney transplanted recipients could be a risk factor for AGPN , 29. AddThe original contributions presented in the study are included in the article/Nantes: Gilles Blancho, Julien Branchereau, Diego Cantarovich, Agnès Chapelet, Clément Deltombe, Lucile Figueres, Claire Garandeau, Magali Giral, Caroline Gourraud-Vercel, Maryvonne Hourmant, Georges Karam, Clarisse Kerleau, Aurélie Meurette, Simon Ville, Christine Kandell, Anne Moreau, Karine Renaudin, Anne Cesbron, Florent Delbos, Alexandre Walencik, Anne Devis; Paris-Necker: Lucile Amrouche, Dany Anglicheau, Olivier Aubert, Lynda Bererhi, Christophe Legendre, Alexandre Loupy, Frank Martinez, Rébecca Sberro-Soussan, Anne Scemla, Claire Tinel, Julien Zuber.MP: Conceptualization, Methodology, Formal analysis, Writing - original draft. LC: Methodology, Writing - original draft, review and editing. JD: Conceptualization, Methodology, Writing - review and editing. SB: Conceptualization, Methodology, Writing - review and editing. CK: data management. FB: Methodology, Statistical analysis, Review and editing. MG: Data acquisition, Writing. All authors contributed to the article and approved the submitted version.www.fondation-centaure.org), which supports a French transplantation research network, the IHU-Cesti project, the DHU Oncogreffe and the LabEX IGO courtesy of French government financial support managed by the National Research Agency via the “Investment into the Future” program (ANR-10-IBHU-005 and ANR-11- LABX-0016-01). The IHU-Cesti project is also supported by Nantes Métropole and Région Pays de la Loire. This work was performed in the context of DHU Oncogreffe, LabEX IGO (ANR-11- LABX-0016-01), ANR project BIKET (ANR-17-CE17-0008) and ANR project KTD-innov (ANR-17-RHUS-0010) courtesy of French government financial support managed by the National Research Agency. The laboratory received funding from the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement No. 754995.This work was supported by the CENTAURE foundation (FB is employed by IDBC-A2COM.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


PWVao in 68% of patients; for VAAIao in 52% of patients. By contrast, VA derived from cIMT delivered opposite results: e.g. according to VAtotal-cIMT accelerated vascular aging in 75% of patients. To strengthen the concept of VA, further efforts are needed to better standardise the current approaches to estimate VA and, thereby, to improve comparability and clinical utility.Communicating cardiovascular risk based on individual vascular age (VA) is a well acknowledged concept in patient education and disease prevention. VA may be derived functionally, e.g. by measurement of pulse wave velocity (PWV), or morphologically, e.g. by assessment of carotid intima-media thickness (cIMT). The purpose of this study was to investigate whether both approaches produce similar results. Within the context of the German subset of the EUROASPIRE IV survey, 501 patients with coronary heart disease underwent (a) oscillometric PWV measurement at the aortic, carotid-femoral and brachial-ankle site  and derivation of the aortic augmentation index (AIao); (b) bilateral cIMT assessment by high-resolution ultrasound at three sites . Respective VA was calculated using published equations. According to VA derived from PWV, most patients exhibited values below chronological age indicating a counterintuitive healthier-than-anticipated vascular status: for VA Cardiovascular risk prediction models  allow an estimation of absolute risk. However, these models have limitations: the widely used Framingham-based risk scores seem to underestimate coronary heart disease risk in older adults, while SCORE algorithms exclusively predict fatal cardiovascular events2. Nevertheless, current guidelines recommend their use for total cardiovascular risk estimation for adults > 40 years of age unless they are categorised as being at high-risk or very-high risk3.Communicating cardiovascular risk to the patients remains challenging for doctors. Successful uptake of advice and sustained adherence to recommendations, including lifestyle and medication, may heavily depend on appropriate illustration and communication of such risk to the individual patient4. It relates the chronological age to the vascular status of an individual and is easy to understand. Its use has been suggested as a powerful tool aiding primary and secondary prevention strategies5. There are various approaches to calculate vascular age, relying on functional or morphological surrogates of atherosclerosis. From a conceptual point of view, vascular age is the result of the exposure over time to unfavorable levels of cardiovascular risk factors leading to accelerated development of atherosclerosis. Hence, structural measurements may be expected to better reflect “true” vascular age than functional measurements, since the latter depend heavily on less stable external and internal factors such as arterial blood pressure and heart rate6.The concept of vascular age is considered a helpful alternative to communicate risk of individual patients7. PWV is the speed of the pressure wave propagated from the aorta to the arterial tree through contraction of the left ventricle. Progressive atherogenesis diminishes compliance of the arterial wall, which becomes evident by increased vascular stiffness and an accelerated pressure wave. Depending on the approach, PWV can be measured between several reference points thus describing stiffness across respective vascular compartments, e.g. aortic PWV (PWVao) measured from aortic arch to aortic bifurcation and brachial-ankle PWV (PWVba) measured between brachial and anterior tibial artery. The acknowledged reference standard for the assessment of arterial stiffness, however, is the carotid-femoral PWV (PWVcf), which has good reproducibility8. Whereas PWVcf has been measured in the past using time-consuming tonometric or piezo-electric methods, alternative approaches deploying only one blood pressure cuff around the upper arm (oscillometric method) are currently entering clinical routine10. The latter technique also allows to record peripheral arterial pressure waves, which can be transferred into central pressure waves via transfer functions11. From this, the aortic augmentation index (AIao) can be derived, which indicates the magnitude of peripheral pulse wave reflection and the resulting effect on central blood pressure. In a recent meta-analysis including 11 prospective studies with both healthy and diseased subjects, the AIao was an independent predictor of future cardiovascular events and all-cause mortality risk12. The AIao appears to increase fairly steeply in early adulthood and to flatten after the 5th decade13. Consequently, the prognostic utility of the AI appears highest in younger adults.Pulse wave velocity (PWV) and the augmentation index (AI) are acknowledged functional indicators of vascular stress14 and myocardial infarction15, progression of cIMT over time has been used as surrogate for cardiovascular morbidity and mortality in many randomised trials16. Some studies, e.g. the ARIC study reporting on 13 824 subjects from the US examined in the late 80s17, published age-specific reference values for cIMT that allow to derive vascular age.The ultrasonic measurement of the carotid intima-media thickness (cIMT) for assessing local atherosclerotic burden is a widespread approach in cardiovascular risk prediction. Besides its strong association with clinical endpoints, such as strokeThe purpose of the present study was to compare the agreement of different approaches of vascular age measurements using functional versus morphological methods, in patients with CHD.19. Inclusion criteria were admission to hospital due to first or recurrent diagnosis or treatment of acute myocardial ischaemia, acute myocardial infarction, elective or emergency PCI (percutaneous coronary intervention), and elective or emergency CABG (coronary artery bypass graft) between 6 to 36 months prior to the examination date. Patients were between 18 and 79 years of age at the time of their index event or procedure. All patients provided written informed consent prior to any study related investigation. The study protocol was approved by the Ethics Committee of the Medical Faculty of the University of Würzburg (Vote 58/12). The data protection concept was approved by the data protection officers of both the University and University Hospital of Würzburg.Between August 2012 and March 2013, 536 patients  with coronary heart disease were examined in the German study centre of the EUROASPIRE IV study in Würzburg, coordinated by the Comprehensive Heart Failure Centre (CHFC) and the Institute for Clinical Epidemiology and Biometry (ICE-B) of the University of Würzburg. The study design and main results of the EUROASPIRE IV study have been publishedMeasurements of PWV  and the corresponding AIao were performed in 501 patients by trained personnel following predefined standard operating procedures using the Vascular Explorer . Patients were told to refrain from alcohol and hot drinks for 12 h prior to the examination. Patients rested for 5 min supine in a temperature-controlled room. During the examination, patients were asked not to move, speak, or cough. For the measurement of the PWVao it was additionally required to approximate the length of the aorta by measuring the distance (in cm) between pubic bone and suprasternal notch. In some subjects, unrealistically small values for the distance between notch and pubic bone  were documented without a definite cause; these subjects were excluded from subsequent analyses (n = 29).Prior to the determination of the stiffness parameters, systolic and diastolic blood pressure was measured at the left and right upper arm and lower leg. The PWV measurement was done with blood pressure cuffs inflated at the right upper arm  and the right lower leg  to oscillometrically detect pulsatile pressure changes in the brachial and anterior tibial artery. The examination was divided into two parts. First, PWVba was determined by inflating both cuffs at the predetermined diastolic pressure level for 15 s. Afterwards, PWVao and AIao were obtained by applying a cuff pressure of 35 mmHg above the systolic blood pressure at the upper arm. Then, the Vascular Explorer software analysed all recorded pressure waves of each cycle and calculated the mean measured values. The pressure wave who´s measured values came closest to the mean values was chosen for quantitative analysis. In case of motion artefacts or inappropriate signal quality, the examiner was requested to repeat the measurement. If automated detection and selection algorithms of the Vascular Explorer software failed to yield optimal results, the selection could be manually overridden by the examiner.For the calculation of PWVba, the Vascular Explorer software a) imputes further distances  derived from patient´s height, and b) utilises the pulse transit time , LLC = lower leg cuff, UAC = upper arm cuff, PTT = pulse transit time .9.The approach for the measurement of PWVao has been validated against invasive measurements of the PWVao, and a correlation coefficient of 0.91 was observed20. According to the model applied by the Vascular Explorer for PWV measurement the second pressure wave in the brachial artery pressure contour represents the wave reflection at the aortic bifurcation. The additional distance travelled by this reflected wave compared to the initial pressure wave in the brachial artery thus represents an approximation of two times the length of the aorta. By measuring the time difference between the arrival of both pressure waves in the brachial artery , PWVao can be determined non-invasively Jug = Jugulum , Sym = Symphysis (= pubic bone), RT = return time.11.The PWVcf is derived from the PWVao and PWVba by applying an unpublished formula (company secret). Transfer functions that are also spent from the Vascular Explorer software then provide central pressure waves allowing the calculation of AIao via peripheral pressure wavesPWVao, VAPWVba, and VAAIao. The vascular age was based on nomograms provided by McEniery et al.13. Each measured value was assigned to an age, at which it corresponds to the 50th percentile in the named cohort  depending on respective PWV and AI measurements: VAMeasurement of cIMT was performed in 501 subjects using high-resolution ultrasound on a Vivid Q system equipped with a 10 MHz linear transducer . Examiners were certified according to a protocol provided by an external supervisor , and iteratively completed quality checks every two months. The cIMT assessment included bilateral measurements of the far walls of the common carotid artery (CCA), the carotid bulb, and the internal carotid artery (ICA), thus resulting in 6 values per patient. Ultrasound images were frozen at the end-diastolic phase (R wave peak of concomitantly run electrocardiogram) and had to display at least 10 mm of vessel wall length. If image quality was insufficient , the CCA of that particular side was examined more extensively, i.e. from 3 different angles. All images were stored in DICOM format and imported into a dedicated workstation for cIMT quantification .21. If needed, the reader could edit the intima-media layer delineations suggested by the software. Subsequently, the crude measurement values per site were stored digitally. Besides crude values also the average of all 6 means is reported .Images were semi-automatically analysed using the Syngo Arterial Health PackagerCCA and VAlCCA) and the total-cIMT  and calculated using nomograms provided by the ARIC investigators17 considering age, sex, and ethnicity, respectively. Each measured value was assigned to an age at which it corresponds to the 50th percentile in the ARIC cohort 23. Impaired fasting glucose (IFG) was defined as fasting glucose ≥ 6.1 mmol/l but < 7.0 mmol/l with 2-h plasma glucose < 7.8 mmol/l23. Dyslipidaemia was defined as LDL cholesterol > 1.8 mmol/l24 and nutritional status was classified according to WHO25. Central obesity was defined as waist circumference ≥ 88 cm for women and ≥ 102 cm for men26.Variables used for the statistical analysis were defined according to current guidelines. Hypertension was defined as systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHgrCCA, VAlCCA and VAtotal-cIMT, including age adjustment. In cases, where parameters  did not fulfil requirements for linear and censored regression, quantile regression was applied. Linear regression analyses were used to identify correlates of total-cIMT and PWVcf. As independent variables mean arterial pressure (MAP) [mmHg]/10, age [years]/10, LDL-HDL ratio, waist circumference [cm]/10, smoking status (current smokers vs ex-smokers and never-smokers), sex, diabetes mellitus, IFG, statin medication, log hsCRP [mg/dl] and duration of coronary heart disease [years]/10 were individually included into a multivariable model with fixed adjustment for age and sex. Since values for cIMT-derived vascular age were right-censored at a value of 81 (“ > 80”) years, we used the R-package “censReg” for the application of censored linear regression analysis27. To assess the association between vascular age obtained by cIMT versus PWA, we calculated Spearman rank correlations. For the correlation analyses and the calculation of the difference between estimated VA and age, the value 81 as cIMT-VA was assigned to patients with censored results. IBM SPSS Statistics 23.0  and R version 3.1.4  were used for the statistical analyses. All methods were performed in accordance with the relevant guidelines and regulations.Patient characteristics are presented using absolute and relative frequencies, mean (SD), and median (quartiles), as appropriate and were compared across categories using χ2 test. Due to sex differences in stiffness parameters, results of PWA and cIMT were compared between male and female patients. We used linear regression for PWVao, PWVcf, AIbr, AIao and AIao75 and censored regression analysis for VAThe characteristics of the study population (n = 536) stratified by sex are summarised in Table In total, 501 subjects of the study population underwent the vascular explorer examination and the cIMT measurement. Reasons for dropouts for both crude values and derived vascular ages are explained in Methods .P = 0.459); respective measurements on left arm were 105 mmHg (101–115 mmHg) in men vs 113 mmHg (101–122 mmHg) in women (age-adjusted P = 0.169). No sex differences were found for PWVao, PWVba, PWVcf, mean of the maximum cIMT, PWA-VA and cIMT-VA using regression analyses including age as covariate.Median blood pressure measurements performed with the Vascular Explorer showed no significant differences between men (n = 416) and women (n = 85): right arm MAP in men was 104 mmHg (quartiles 94–114 mmHg) vs 104 mmHg (94–115 mmHg) in women  higher in women, median total-cIMT was − 0.09 mm  lower in women. For further details, see Table Linear regression analysis for PWVcf revealed considerable associations for mean arterial pressure, age, smoking and duration of coronary heart disease , we created bar charts showing the distribution of the difference of vascular and chronological age see Fig. . Since aDespite their meaning in today’s cardiovascular risk prediction, cIMT measurement and the PWA showed largely different results in the determination of the individual vascular age as a correlate of vascular stiffening. On the one hand, while being easier to perform and more economic, PWA conducted with the Vascular Explorer seems to underestimate the cardiovascular risk systematically. On the other hand, cIMT is more reliable in detecting patients with high risk for cardiovascular disease but only half of our study population fulfilled the requirements for the vascular age determination via normal values from the ARIC cohort.28. Amongst measurements obtained with one method, we found moderate correlations (except for VAPWVba that showed poor correlation with both VAPWVao and VAAIao). As underlying problem for these inconsistencies, we assume a methodological issue. The statistically determined distance travelled by the pulse wave and used for the calculation of the PWVba seems to overestimate the real distance. By contrast, the distance used for the calculation of the PWVao was measured by the examiner. Poor correlation may also be attributed to the fact that, compared to PWVba, measurement of PWVao and PWVcf with the Vascular Explorer is based on a model, in which the second systolic pressure wave detected at the brachial artery is solely the result of pulse wave reflection at the aortic bifurcation. While there is evidence of good correlation of this approach with invasive PWV measurement 9, data from Trachet et al. suggest that the second wave is rather a result of brachial artery stiffness than aortic stiffness 29.We investigated Spearman´s rank correlations between the vascular ages derived from the cIMT measurement and the PWA. In general, correlations were poor between cIMT and PWA, which is in line with studies investigating crude values of both examinations13. In contrast to the Vascular Explorer, this device analyses carotid and femoral artery wave forms which are sequentially recorded by gated electrocardiogram30. So far, the association between PWV/AI measured with the Vascular Explorer and the SphygmoCor device was determined in a small study cohort (n = 44)31. A strong correlation for AI  and a moderate correlation for PWV  between the measured values of both devices was reported. Furthermore, regarding the PWV, Bland–Altman-Analysis showed a systemic bias by the Vascular Explorer with overestimating low PWV values and underestimating high PWV values. With most of our patients being situated in the latter PWV range, the reference values obtained with a different device may be an explanation for the unexpected results of the VA determination. The need for device-specific normal values is emphasised by moderate or poor correlation between PWV measured with the Vascular Explorer and the Arteriograph  or the VICORDER 32. In a comparable study cohort of medicated patients with coronary heart disease  examined with the Arteriograph, mean PWVao was 12.24 m/s compared to 8.16 m/s in our study33. Differences in that order of magnitude raise doubts regarding the reliability of these PWV measurements and hence their utility for the diagnosis of an end organ damage of the arteries34.To compare the vascular status according to the cIMT and the PWA, we determined the difference between vascular age and chronological age. Although the study participants by definition belonged to a group considered at high risk for cardiovascular diseases, PWA found accelerated vascular aging in less than 50% of our patients. These unexpected findings may be attributed to the reference values used by the Vascular Explorer software for the VA determination. In the reference study an alternative device, the SphygmoCor , had been used to measure the AI in 4 001 healthy individuals aged 18 to 90 years, and the carotid-femoral (but not aortic) PWV in a subset of 998 subjects35. Best reproducibility was shown for the mean cIMT compared to the maximum and minimum value21. In contrast to PWA, when comparing the patients´ vascular age to the chronological age, we found accelerated vascular aging in most of our patients – as we had expected. However, determination of vascular age via cIMT was limited to patients aged 40–70 years (according to specifications of pre-sets of the software package) with 6 measured values. As a result, cIMT-VA was available for about half of our study sample. Furthermore, reference values for determination if cIMT-VA have been derived in the early 1990ies in the US by the ARIC investigators. Hence, the comparison of the technical equipment as the characteristics of the population under study is compromised. Alternatively, in the community-based Gutenberg-Heart Study performed in Germany between 2007 and 2008, normal CCA-cIMT values were established in a subgroup of 1,025 subjects without classic cardiovascular risk factors or previous cardiovascular disease36. These normal values allow the VACCA determination in a slightly larger age range (35–74 years of age). The insecurity about normal values for the cIMT is illustrated by the fact that the former threshold of 0.9 mm for the diagnosis of a target organ damage is being questioned in the latest guidelines of the ESC/ESH22.For the determination of our patients´ individual VA via cIMT, both the mean of the left and right CCA and the mean of all means were used. There is evidence that one single site of measurement may be sufficient to assess individual cardiovascular risk37. We strived to maintain a stable peripheral temperature thus avoiding cooling effects when measuring stiffness parameters.We acknowledge that our study has certain limitations. Our analyses involved data based on a German study population (98.5% Caucasian) and might not be transferable to other ethnicities. We examined medicated CHD patients. Consequently, the results of the vascular examination may have been influenced by drug therapy, but we did not detect major effects of medication on actual measurements. The length of the aorta for PWA was measured along the body surface, resulting in falsely higher values in case of abdominal obesity. Using a measuring loop and having the examiner palpate the pubic bone may have resulted in higher precision in the length determination. In our analyses, however, we did not find confirmation of a systematic deviation caused by obesity. Finally, cold exposure may enhance the augmentation of wave reflection thus overestimating AIIn conclusion, vascular age if measured by cIMT but not if measured by PWA showed the accelerated aging expected in the investigated high-risk sample. The findings of the PWA performed with the Vascular Explorer may be explained, amongst other things, by the usage of inappropriately derived normal values. Device-specific normal values are needed to strengthen the reliability of the vascular age determination via PWA, which is potentially a feasible option in predicting individual vascular risk. However, longitudinal studies are necessary to further evaluate the prognostic value of both examinations.Supplementary Information.


Background: Sarcopenia involves an age-related decline in skeletal muscle mass with functional disability or low muscle strength. Vascular calcification (VC) occurs commonly in patients with chronic kidney disease, in whom it is associated with cardiovascular disease. We aimed to investigate the correlations of low muscle mass with the quantified vascular calcification score (VCS) of the arm of vascular access, as well as whether low muscle mass is associated with the incidence of vascular access failure. Methods: The VCS was measured on non-contrast, arm computed tomography using the Agatston method. The lower muscle mass (LMM) group comprised subjects whose skeletal muscle mass of the lower extremities, as measured using bioelectrical impedance, was lower than the median. Higher VC was defined as a score of 500 or above, corresponding to the highest 40% of VCS. The relationship between LMM and VC was explored using univariate and multivariate logistic regression analyses. Results: Seventy-five patients were included, of whom forty-two (56.0%) were men. The median age was 64 years (interquartile range 58–72 years). Of the 75 patients, 73 satisfied the diagnostic criteria for sarcopenia. The median hemodialysis vintage was 49.4 months (range 32.1–99.2 months). No significant differences were found between the non-LMM and LMM groups in sex, end-stage renal disease etiology, and type of vascular access, although the LMM group showed significantly older age and hemodialysis vintage. LMM presented a significant association with VC (hazard ratio (HR) 3.562; 95% CI, 1.341–9.463; p = 0.011). Upon adjustment for hemodialysis vintage, diabetes, and systolic blood pressure, LMM demonstrated an independent association with VC . The risk of vascular access failure was higher in the LMM group . VC was a full mediator in the relationship of LMM with recurrent vascular access failure. Conclusions: We quantified LMM via bioimpedance analysis and found a heretofore-unreported association between LMM and vascular access failure. LMM increases the risk of VC and has the potential to predict vascular access failure. It was mpedance .Cardiovascular events constitute the most common cause of death in CKD patients . For thiTo address the above-described gap in the research, we quantified VC in patients with ESRD using the Agatston method and investigated the correlations of VC with sarcopenia and vascular access failure. We also aimed to clarify whether low muscle mass was associated with access failure in the context of VC at the vascular access site.http://gpower.hhu.de/ accessed on 3 June 2019). This cross-sectional study included 75 patients who received hemodialysis on an outpatient basis for at least 3 months. Study patients were enrolled from January 2019 to May 2019 at a single center. Patients with an arteriovenous fistula or arteriovenous graft in the forearm or upper arm, but not those with a hemodialysis catheter, were included. This study excluded patients who (1) were unable to move without walking aids; (2) had an active malignancy; (3) had a history of chronic heart failure; or (4) had a history or current diagnosis of a systemic disease affecting the prevalence of sarcopenia. CT scans were used to determine the vascular calcification score (VCS). Ferritin, albumin, cholesterol, hemoglobin, chronic kidney disease–mineral and bone disorder (CKD-MBD) parameters, and single pool (sp) Kt/V were recorded. A retrospective review of patients’ medical records from January 1985 to May 2019 was conducted to collect information on patients’ medical history, including blood pressure, comorbidities, ESRD etiology, hemodialysis vintage, details of vascular access, ultrafiltration volume, height, weight, and dry weight. There were 43 men and 33 women. One patient with a femoral arteriovenous graft was excluded; therefore, the final analysis included 75 patients. Vascular interventions, such as surgical thrombectomy or percutaneous transluminal angioplasty (PTA), were carried out in patients who developed access dysfunction, such as acute thrombotic occlusion, delayed hemostasis at the puncture site, and elevated venous pressure. All procedures were conducted in accordance with the relevant ethical standards of institutional and national research committees and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study protocol received approval from the institutional review board .To estimate the sample size, we used results from a previous clinical study of the association between VC and sarcopenia . Assumin2). The height-corrected LSM was termed the leg skeletal muscle index (LSMI). The lower muscle mass (LMM) group was defined as subjects with a lower LSMI than the median for each sex as an operational definition of sarcopenia.Bioimpedance analysis (BIA) measurements were obtained at dialysis sessions held in the middle of the week. Patients were told to consume meals 2 h before dialysis to prevent interference from the meal, and they were not permitted to eat while dialysis was being performed. After dialysis, patients were instructed to lie flat on the bed after their post-hemodialysis weight was measured. Thereafter, patients rested for 10 min in the lying position, and then BIA measurements were recorded using an S10 device . Electrodes were attached to both the feet  and the hands (middle finger and thumb). BIA estimates muscle mass indirectly using electrical conductivity. The muscle quantity of the upper extremities can be influenced by the presence of the hemodialysis shunt in the arm. However, the muscle mass of the lower extremities is not directly influenced by the hemodialysis shunt. Thus, when quantifying muscle mass, leg skeletal muscle (LSM) was calculated as the sum of the skeletal muscle mass of both legs. Since muscle mass is fundamentally correlated with body size, LSM was adjusted using height squared . The radiation dose was calculated using the median direct dose profile integral (DPI). A value of approximately 500 DPI was obtained, corresponding to a similar or lower amount of radiation than the dose of a non-contrast CT scan of the same area. The Agatston method was used to calculate the VCS by multiplying the area of each calcified lesion by a weighting factor derived from Hounsfield units. The 75 patients were classified based on their VCS score (≤500 or >500). In a previous study, a cutoff value of 500 predicted a high risk of MACCEs. A detailed description of the methods and rationale was presented in a previous study .Data are presented as median and interquartile range  for continuous variables or as frequency (percentage) for categorical variables. The Mann–Whitney U test was used to determine the statistical significance of between-group differences in clinical characteristics for continuous variables, whereas the chi-square test was used for categorical variables. The association between LMM and VC was investigated using univariate and multivariate logistic regression analyses, adjusting for confounders.Mediation analyses using the Baron and Kenny model were performed to assess the proportion of the total effect on vascular access failure that could be explained by LMM. All analyses were carried out in SPSS version 23.0 .p = 0.001). No significant differences were found between the two groups in sex, access type, or the prevalence of diabetes. Other clinical markers such as blood pressure, hemoglobin, and uric acid also did not show significant differences.p = 0.036). However, the two groups showed no statistically significant differences in other hemodialysis-related parameters, such as the urea reduction ratio, spKt/V, height, or ultrafiltration volume.As related to hemodialysis, dry weight was significantly lower in participants with LMM . The levels of other nutritional parameters, such as triglycerides, albumin, and ferritin, did not show significant differences. The remaining variables related to CKD-MBD were also not significantly different between the two groups.Patients with LMM showed significantly lower 25(OH) vitamin D levels , p = 0.003). Among the anthropometric measurements, low BMI showed a significant relationship with VC . Nutritional parameters were not associated with VC, except albumin . Finally, LMM presented a significant association with VC (OR 3.562 (95% CI 1.341–9.463), p = 0.011) , = 0.011) .p = 0.006, HD vintage: OR 1.022 (95% CI 1.009–1.035), p = 0.001, LMM: OR 4.970 (95% CI 1.454–16.983), p = 0.008) , longer hemodialysis duration, and low muscle mass showed independent associations with VC (vascular access: OR 10.136 (95% CI 1.913–53.700), = 0.008) .p < 0.001).In the group with higher VCS, 21 (72.4%) patients received interventions , whereas only nine (19.6%) of the patients in the group with lower VCS experienced interventions. In the group with higher VCS, there were 15 (51.7%) subjects who received two or more interventions. However, only two (4.3%) subjects underwent at least two interventions in the group with lower VCS. In this study, the requirement for two or more interventions was defined as recurrent vascular access failure. The higher-VCS group also had a higher number of annual interventions . The LMM group also had a higher number of annual interventions . (p = 0.016) and recurrent access failure  than patients with AVF.LMM was also correlated with vascular access failure. In the LMM group, 17 (48.6%) subjects underwent interventions including PTA or surgical thrombectomy or revision. In the non-LMM group, 13 (32.5%) subjects received interventions, but this difference from the LMM group did not reach statistical significance. The LMM group contained significantly more subjects who experienced recurrent vascular access failure than the non-LMM group (non-LMM: 5 (12.5%) vs. LMM: 12 (34.3%);  0.042). . AlthougWe assessed the potential role of VC as a mediator in the relationship between LMM and recurrent vascular failure. LMM was independently associated with VC or recurrent vascular failure. The mediation analysis showed no significant association between LMM and recurrent vascular failure when VC did not mediate the relationship . When VCIn this study, the LMM group classified by the median value of LSMI showed a significant association with VC. This significant association persisted after adjusting for several possible confounders. As expected, VC was significantly associated with recurrent vascular access failure requiring interventions, including PTA or surgical thrombectomy. Low muscle mass was also associated with recurrent vascular failure. VC functioned as a full mediator in the relationship between muscle mass and recurrent vascular failure. This means that VC was an essential factor linking LMM with recurrent vascular access failure.Several age-related changes contribute to sarcopenia . Aging iBones are the main reservoir of total body calcium. Calcium salts are also stored in tissues and organs outside the bones, which is commonly called extraskeletal calcification . Some tyA main cause of VC is oxidative stress and inflammation leading to a loss of the balance between endothelial damage and repair . HormonaVC induces vascular access failure through several molecular mechanisms . The risHowever, there are several limitations to this study. First, the cross-sectional nature of the study design precludes an interpretation in terms of causal relationships. Second, bioimpedance was used to estimate skeletal muscle mass. Bioimpedance measurements of muscle mass depend on the relationship between body composition and body water. Thus, bioimpedance can be inaccurate in some conditions that cause hypervolemia, such as CKD or heart failure. However, in patients with CKD, skeletal muscle mass measurements using bioimpedance are as reliable as those obtained using DXA . MoreoveIn conclusion, LMM showed independent relationships with VC and recurrent vascular access failure. VC was found to play a crucial role in the relationship between LMM and recurrent vascular access failure. LMM may be valuable to consider as a risk factor for vascular access failure in the context of VC at the vascular access site.