|Year : 2016 | Volume
| Issue : 2 | Page : 92-97
Frailty and flow-mediated dilation: A pilot study in hospitalized elderly
Elpidio Santillo, Monica Migale, Fabrizio Balestrini
Department for Cardiovascular Disease, Italian National Research Center on Aging, Fermo, Italy
|Date of Submission||29-May-2016|
|Date of Acceptance||10-Oct-2016|
|Date of Web Publication||13-Jan-2017|
Dipartimento Geriatrico Riabilitativo ad Indirizzo Cerebro.Cardiovascolare, Italian National Research Center on Aging, Fermo 63900
Source of Support: None, Conflict of Interest: None
Background: Frail elderly persons, who are characterized by a greater vulnerability to stressing factors, often present with comorbid cardiovascular diseases. Endothelial dysfunction, a pathological process involved in the development of cardiovascular diseases, can be examined noninvasively through the technique of flow-mediated dilation (FMD). We studied a group of hospitalized elderly persons analyzing their endothelial function by FMD aiming to investigate the relationship between their frailty status and endothelial dysfunction.
Materials and Methods: Thirty hospitalized elderly patients were evaluated by ultrasound examination of endothelium-dependent vasodilation of the brachial artery. The Study of Osteoporotic Fracture Criteria for Frailty index was used for the definition of frailty status of enrolled cases.
Results: Statistical analysis revealed the existence of significant associations between frailty status, ischemic heart disease (P = 0.013 by Chi-square), and cognitive impairment (P = 0.001 by Chi-square). Moreover, frail cases showed lower values of diastolic blood pressure (61 mm Hg vs. 71 mm Hg P< 0.001 by Student's t-test) and a reduced FMD compared to not frail ones (5.45% vs. 10.42%, P= 0.021 by Student's t-test).
Conclusions: The identification of reduced FMD in frail elderly may suggest endothelial dysfunction as a pathological “common ground” shared by cardiovascular diseases and frailty. FMD could help clinicians in the management of elderly at risk of developing frailty and cardiovascular disease. In further multicenter studies, FMD could be used to evaluate which early interventions have the potential of preventing the disastrous consequences related to both cardiovascular events and frailty.
Keywords: Cardiovascular risk, endothelial dysfunction, flow-mediated dilation, frailty
|How to cite this article:|
Santillo E, Migale M, Balestrini F. Frailty and flow-mediated dilation: A pilot study in hospitalized elderly. J Curr Res Sci Med 2016;2:92-7
|How to cite this URL:|
Santillo E, Migale M, Balestrini F. Frailty and flow-mediated dilation: A pilot study in hospitalized elderly. J Curr Res Sci Med [serial online] 2016 [cited 2020 Nov 27];2:92-7. Available from: https://www.jcrsmed.org/text.asp?2016/2/2/92/198368
| Introduction|| |
The term “frailty” denotes a condition characterized by extreme homeostatic instability exposing elderly to serious complications such as loss of independence, institutionalization, and death even for minor events.,, It has been observed that a frailty status is often associated with the presence of comorbid cardiovascular diseases.,
Endothelial dysfunction, an early marker of cardiovascular disease, can be reliably and noninvasively assessed through the study of flow-mediated dilation (FMD).
Previous retrospective and prospective studies have shown that the assessment of endothelial function by FMD can identify individuals at high risk for the development of atherosclerosis and to contribute in cardiovascular risk stratification also in elderly patients.,
However, to date, studies investigating the association between frailty and the endothelium-dependent vasodilation in elderly cases are lacking. The recognition of a possible contribution of endothelial dysfunction in determining frailty could have a significant impact on the elaboration of new clinical and preventive strategies.
Therefore, we wanted to evaluate in a group of inpatients over 65 years of both sexes if a frailty status was associated with reduced FMD.
| Materials and Methods|| |
Subjects in the study
This study is called Frail Elderly Research on flow-Mediated dilation on Outcomes (F.E.R.M.O.) cardiovascular study. The study was approved by the Scientific Direction of the Institute and was included into institutional current research plan for the period of 2013-2015.
Thirty patients over 65 years hospitalized at the INRCA Research Hospital of Fermo, Marche, Italy, were included in the study.
Enrolled cases underwent assessment of frailty and noninvasive evaluation of endothelium-dependent vasodilation of the brachial artery through FMD. Active smokers were not included in the study. Weight and height measures were performed in all participants, and the body mass index (BMI) was calculated according to the following formula: weight (kg)/height (m 2). All patients underwent standard echocardiographic examination. Heart chambers' size and ejection fraction of left ventricle were measured according to the American Society of Cardiology guidelines.
The study was conducted in conformity with Helsinki Declaration. Each case enrolled in the study provided informed consent to the processing of personal data for scientific research and for statistical analysis.
Definition of frailty
For the definition of frailty, we used an index already validated in the literature: The Study of Osteoporotic Fracture Criteria for Frailty (SOF) index. The frailty defined according to SOF index is identified by the presence of two or more of the following components:
- Unintentional weight loss of 5% or more
- Inability of the person to get up from a chair five times without the help of arms and
- Reduced energy level identified by the answer “no” to the question “Do you feel full of energy?” of the Geriatric Depression Scale.
Cases with none of the above components are considered “robust” while those with one of the preceding components are considered as “prefrail.”
Blood samples of each patient were obtained to measure the following analytes: glucose, albumin, creatinine, urea, hemoglobin, cholesterol, triglycerides, and high-sensitive C-reactive protein (hs-CRP).
Definitions for diagnosis
Diagnosis of previous cerebrovascular or cardiovascular disease was made in the presence of one of the following documented conditions: stroke, heart failure, ischemic heart disease, peripheral occlusive arterial disease, and arterial revascularization procedures. For the diagnosis of heart failure, the criteria of the Heart Failure Society of America were required. Requisites to define cases as hypertensive were values of systolic blood pressure ≥140 mm Hg or diastolic blood pressure (DBP) ≥90 mmHg or antihypertensive therapy or a history of documented diagnosis of high blood pressure. Blood pressure was measured with the conventional auscultatory method. Patients were identified as having diabetes according to criteria of the American Diabetes Association or antidiabetic therapy or documented history of diabetes mellitus. The diagnosis of dyslipidemia was made in accordance with the criteria of the Adult Treatment Panel III of the National Cholesterol Education Program or lipid-lowering therapy.
The diagnosis of dementia was made according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision.
The noninvasive ultrasound assessment of endothelium-dependent vasodilation was performed through the measurement of FMD of the brachial artery of the nondominant arm., A skilled sonographer measured the diameter of the brachial artery on echographic images acquired in B-Mode. A 5-10 MHz multifrequency linear probe (Vivid Seven Ultrasound System, GE) was used. The study of FMD was done after an overnight fast (at least 8 h). Patients were required to abstain from smoking, coffee, tea, alcohol, and antioxidant agents in the night before the study. The cases were examined between 8:00 and 10 am after 15 min of rest in the supine position in a room with controlled temperature (20–22°C). The two-dimensional ultrasound images of the brachial artery were recorded before induction of reactive hyperemia and a minute after induction. The same position was preserved during the study. After measurement of the basal diameter of the brachial artery, the cuff of a sphygmomanometer appropriate to the patient's arm was inflated up to a value of 50 mm Hg greater than the systolic blood pressure and deflated after 5 min. Doppler flow signal was registered in baseline and for 15 s after cuff deflation to identify the peak reactive hyperemia. The average arterial diameter at baseline and after hyperemia was measured at the end of diastole determined by simultaneous electrocardiography monitoring. The measurement was performed at the media-adventitia interface of the vessel walls (proximal and distal). For each recording, the diameters were measured in four cardiac cycles, and the average was calculated. The difference between the maximum diameter and the basal diameter was calculated and divided by the maximum diameter. FMD was expressed as percent change from baseline. Brachial artery measurements were characterized for a high level of reproducibility since an intraclass correlation coefficient of 0.982 demonstrated a good intraobserver agreement.
The recorded data were expressed as mean ± standard deviation or as frequency percentage (%). Depending on the score obtained in the SOF, patients were divided into two subgroups: the frail elderly and not frail ones (prefrail and robust). The comparative analysis between the groups of cases was performed using the Student's t-test. To test the null hypothesis for categorical variables, we used the Chi-square test with two tails. A P < 0.05 was considered statistically significant. Data were analyzed using statistical software Openstat 17.0 (by W. Miller, Iowa State University, USA).
| Results|| |
Characteristics of patients in the study divided according to the frailty status
[Table 1] shows the characteristics of frail patients compared to not frail ones.
|Table 1: Characteristics of patients divided according to frailty status|
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Age and gender did not distinguish subgroups, while BMI of frail patients was significantly lower (22.9 kg/m 2 vs. 25 kg/m 2; P = 0.031 by Student's t-test).
Moreover, frail patients differed from not frail ones because of significantly lower mean values of DBP (61 mm Hg vs. 71 mm Hg; P< 0.001 by Student's t-test).
As regard to laboratory data, mean values of serum creatinine was higher in frail elderly (1.29 mg/dL vs. 0.89 mg/dL; P = 0.003 by Student's t-test) such as urea values (89 mg/dL vs. 42 mg/dL; P = 0.013 by Student's t-test).
Hs-CRP mean values tended to be higher in frail patients, but the difference was only near to statistical significance (3.62 mg/dL vs. 1.37 mg/dL; P = 0.052 by Student's t-test).
No significant differences between groups were found comparing mean values of serum glucose, cholesterol, triglycerides, albumin, and hemoglobin.
Interestingly, frail cases were characterized by a significantly lower percentage change in the brachial artery diameter after FMD [5.45% vs. 10.42%; P = 0.021 by Student's t-test; [Figure 1].
|Figure 1: Difference in flow-mediated dilation in elderly divided according frailty status|
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Comorbidities and echocardiographic parameters
As showed in [Table 2], there was no significant difference between the two groups regarding the number of patients with diabetes mellitus, hypertension, dyslipidemia, and heart failure.
|Table 2: Comorbidities and echocardiographic characteristics of patients divided according to frailty status|
Click here to view
Of note, the frail group was characterized by a higher number of cases with dementia (P = 0.001 by Chi-square) and ischemic heart disease (P = 0.013 by Chi-square).
Echocardiographic parameters did not significantly differ between frail and not frail elderly. Left ventricular mass tended to be higher in frail patients without reaching statistical significance (283 g vs. 282 g P = 0.070 by Student's t-test).
| Discussion|| |
Our study has shown a significant reduction in endothelium-mediated dilation of brachial artery in frail and prefrail elderly compared to robust ones. We hypothesize that such finding could result from a greater endothelial dysfunction occurring in frail and prefrail cases and predisposing them both to atherosclerotic disease and to frailty itself. Coherently with this assumption, it is already known that the frail elderly, as observed also in the present study, commonly suffers from comorbid cardiovascular diseases., In particular, the relationship between cardiovascular disease and frailty seems not completely dependent on aging by virtue of the identified association between frailty and a range of cardiovascular risk factors, not all strongly age-related. It has been estimated that more than 50% of older people with heart disease has the characteristics of the frail elderly both in the general population and in the hospitalized elderly., The association between frailty and cardiovascular disease have been investigated and confirmed also prospectively. Specifically, in a longitudinal study of men and women aged 60–90 years, none of whom had a history of cardiovascular disease, high cardiovascular risk scores at baseline were associated with an increased risk of developing prefrailty and frailty. It has been also noted that the frail elderly with heart disease represents a worse expression of the disease, characterized by increased clinical severity, poor functional recovery, and higher mortality. A negative prognostic role could be played by the unfavorable cardiovascular risk profile typical of frail older people. Furthermore, it has been suggested that in the frail elderly, atherosclerosis could affect blood flow to the nerves and muscles of the legs aggravating sarcopenia, an important component of frailty.
A fundamental role of vascular system pathology in the first stage of frailty has been recently evidenced in Toledo Study for Healthy Aging, which showed high levels of asymmetric dimethylarginine (ADMA) in frail elderly. It is well known that ADMA concentrations are higher in conditions characterized by concomitant endothelial dysfunction.
We think that the relationship between frailty and endothelial dysfunction could derive also from factors such as inflammation and insulin-resistance that have a key role in the genesis of frailty and often coexist with cardiovascular diseases.,,,
In particular, it has been suggested that the diseases of aging are not randomly associated, but that an age-related proinflammatory substrate, defined “inflammaging” could represent a common soil between various chronic diseases, including cardiovascular diseases.
With regard to insulin resistance, both cross-sectional and longitudinal studies have suggested an association between frailty and high levels of blood glucose and/or insulin even non-diabetic ranges.,, The pathophysiological mechanisms underlying the association between frailty and impaired glucose metabolism are not fully understood yet. One hypothesis is that the link could be found in the existence of common molecular pathways connected to inflammation. We have not found an association between diabetes mellitus, hs-CRP, and frailty, but it is clear that our pilot study lacked power to detect such correlations.
It has been also proposed that the association between frailty and endothelial dysfunction, previously observed in patients with chronic kidney disease (CKD), could be explained with both sympathetic activation and oxidative stress occurring in CKD patients.
Frail patients in our study exhibited significantly higher values of serum creatinine and urea compared to not frail patients. Such findings suggest that there could be a correlation between frailty and a worse renal function.
There is broad agreement that frailty is associated with an extreme precariousness of homeostasis of the organism due to the simultaneous dysregulation of multiple anatomical and functional systems. Interestingly, in our work, we found a lower DBP in frail cases. It has been hypothesized that low systemic blood pressure in frail elderly could derive from the impairment of the cardiovascular system autoregulation.
In our study, frail patients had a lower BMI. Even if there is evidence that frailty is common in obese elderly, our result is, however, consistent with previous observations that frailty often manifests with sarcopenia., Finally, an association between frailty and cognitive decline was also observed in our study. This is congruent with the demonstration of frailty as a condition often present in patients with forms of both degenerative and vascular dementia, contributing to the heterogeneity of clinical manifestations.
Limitations of the study
Since our study is cross-sectional, we cannot demonstrate causation links. Second, the study could be underpowered due to a small number of participants. However, we believe that present study has its strength in generating an intriguing hypothesis to be assessed in further longitudinal investigations about endothelial dysfunction and frailty.
| Conclusions|| |
Frailty is the end result of a process of accelerated mental and physical decay that tends to progress if not countered with specific therapeutic, rehabilitative, and social interventions. In the present study, frail and prefrail cases presented a lower FMD. This finding suggests that frail and prefrail elderly have a greater endothelial dysfunction.
In this context, therefore, the recognition of the role of endothelial dysfunction studied with FMD, in the induction and progression of frailty, could lead to identify new intervention targets at the clinical level to reduce the risk of development of the same frailty, and its related adverse events.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]