Background: The global prevalence of peripheral artery disease (PAD) in 2010 was more than 200 million people, with an estimated 54.8 million of those found in southeast Asia. Disability-adjusted life years (DALYs) in 2014 were reported higher in developing countries than in developed ones. Moreover, the wide spectrum of manifestations from asymptomatic to limb threatening PAD posed unique challenges to clinicians and researchers. Nitric oxide, a signaling molecule involved in endothelial function, is known to have correlation with symptoms in PAD patients. However, little is known about the role of nitrate or nitric oxide administration to improve symptomatic PAD patients. Therefore, the purpose of this study is to observe the effect of nitrate administration on peak systolic velocity (PSV) ratios in PAD patients.
Methods: We conducted a pre-post experimental analytic study. The subjects of this study were patients with PAD at Dr. Sardjito Hospital in Yogyakarta, Indonesia, who were registered in our hospital vascular registry. The primary endpoint was the change in PSV ratio after short-term administration of oral nitroglycerin, given 2.5 mg once daily (4 hours) and long term (7 days).
Results: Primary outcome data was available for 33 patients. Nitrate exposure resulted in an improvement in PSV ratios, both for short-term and long-term exposure (ie, a decrease of 0.239 and 0.5, respectively), although only long-term exposure was shown to have evidence in this study (P: 0.163; P: 0.002, respectively).
Conclusion: Long-term use of oral nitrate or nitroglycerin improves PSV ratios in PAD patients. Findings in this study provide additional support for use of nitrate as a therapeutic strategy against worsening symptoms in larger cohorts.
VASCULAR DISEASE MANAGEMENT 2020;17(11):E212-E214.
Key words: Nitrate, peak systolic velocity, nitroglycerin
Peripheral arterial disease (PAD) is a condition in which partial or total obstruction of one or more peripheral arteries results in insufficient blood being supplied to the lower extremities, causing symptoms of pain and dysfunction, as in coronary arteries in coronary heart disease.1,2 Globally, in 2010, there were more than 200 million people with PAD, including 54.8 million in Southeast Asia.3 In patients over 40 years of age, this disease often accompanies atherosclerosis risk factors such as diabetes, tobacco use, or kidney failure.2
Both invasive and noninvasive physical examination used to diagnose peripheral artery disease have several advantages with varying sensitivity and specificity. One type of noninvasive, qualitative and quantitative examination used in anatomical imaging is called Doppler ultrasound. Bright (B) parameter analysis of ultrasound mode, color Doppler imaging, and velocity are used routinely in vascular facilities to accurately identify the location and severity of narrowing lesions in the lower extremities.2,4,5
Nitrate is one of the treatment medications for patients with complaints of angina pectoris through venous dilatation to reduce preload. The component of coronary arterioles vasodilation is also possessed by nitrates to patients who experience coronary artery spasms in the absence of atherosclerosis (Prinzmetal's angina).6 In addition, administration of nitrate is known to increase nitric oxide (NO), thus improving endothelial dysfunction and arterial stiffness, and also increases blood flow in tissues suspected of being hypoxic. In patients with PAD, organic nitrate has the effect of maintaining NO levels while improving intermittent claudication complaints.7
Doppler ultrasound examination is an examination to measure the velocity of blood flow by observing the flow of sound from blood movements. Velocity calculations are used to see the characteristics of arterial hemodynamics because the flow velocity will depend on lumen stenosis. In stenosis, flow velocity or the so-called peak systolic velocity will increase when blood passes through a narrowed area, the ratio between the PSV stenosis area and the proximal stenosis can see the degree of stenosis of the arterial segment.5
Each arterial segment has a different normal PSV value. If there is an aneurysm or arterial dilatation, the PSV number tends to be lower so that the right angle and location are needed in this retrieval. In addition, the overall ultrasound examination is an accurate investigation for the diagnosis of PAD with a sensitivity rate of 82% and specificity of 92%.2,5
Materials and Methods
A prospective, pre-post clinical trial was conducted in this study. The research subjects were PAD patients registered in the vascular registry at Dr. Sardjito General Hospital. The study subjects were enrolled consecutively between March 2017 and November 2018. The inclusion criteria were: (1) Patients who have been diagnosed with PAD based on criteria from the ESC (2011) or AHA guidelines (2016); (2) Age greater than 18 years old; (3) Approved to participate in research. The exclusion criteria were: (1) Patients with intolerance or contraindication to administration of nitrate; (2) Patients with ischemic rest pain or wounds in the lower extremities who cannot walk; (3) Patients with average systolic blood pressure <100 mmHg; (4) Patients with a history of Sildenafil administration within 1 week of study.
Subjects who met the research criteria were recorded in a case report form for demographic, clinical data, and Doppler ultrasound examination results. Demographic data included age, gender, and medication being consumed by the patients. Clinical data included risk factors for atherosclerosis (smoking, diabetes mellitus, family history, hypertension, and dyslipidemia). A Doppler ultrasound examination was carried out by one certified assessor to determine the PSV ratio of the stenosis area in either the femoral or popliteal artery, and then the patient was given long acting nitrate—in this case it was 2.5 mg nitroglycerin. After 4 hours of nitrate administration, the patient is re-examined by Doppler ultrasound to evaluate the PSV ratio of the stenosis area. The subject was then given 2.5 mg nitroglycerin which was taken daily for 7 days. On the seventh day, a Doppler ultrasound examination was conducted again to measure the PSV ratio.
The subjects participated voluntarily and signed an informed consent. The protocol of the research had been approved by The Medical and Health Research Ethics Committee Faculty of Medicine at Universitas Gadjah Mada and Dr. Sardjito Hospital in Yogyakarta, Indonesia.
Basic characteristic data is presented as a mean, value number, or percentage. PSV ratio is presented as a mean ± standard deviation. Descriptive analysis is shown as each variable in the form of numerical data (age, sex, and PSV ratio) and categorical data (hypertension, diabetes mellitus, dyslipidemia, smoking). Analysis of Variance (ANOVA) with Bonferonni post test were performed with more than one measurement (repeat measurements). Moreover, the comparison between normally distributed numerical data was performed using a paired t-test, while the Mann–Whitney test was used for not normally distributed numerical data. All data is displayed in the form of a barline. A P value <0.05 was deemed statistically significant.
Thirty three subjects (n=33) were enrolled in this study. After the screening was completed and participants were willing to take part in the study, a Doppler ultrasound examination was conducted. Then patients were given 2.5 mg oral, long-acting nitroglycerin, based on the study protocol. A limitation of this study was that study personnel were not blinded. All participants were analyzed by the end of the study. Most subjects were males (n = 24; 72.7%). The range of age was between 31 to 73 years old with a mean of age 62.31 ± 9.2 years old. Most subjects were hypertensive (78.8%), almost half of them were diabetic (48.5%), dyslipidemic (42.4%), and active smokers (54.4%). Table 1 shows the characteristics of all subjects.
The PSV ratio in the pre group, that is, before administration of long acting nitrate, obtained an average of 2.87 ± 1.38. Whereas in the post-4-hour group, that is, after 4 hours of administration of long acting nitrate, the mean PSV ratio was 2.62 ± 1.14. The PSV ratio between the pre-group and the post-4-hour group showed a reduction, although not statistically significant (P = 0.163). The mean PSV ratio in the post-7-day group was 2.37 ± 0.99 with a statistically significant reduction (P = 0.002) between the pre group and the post-7-day group, as well as the post-4-hour group compared to post-7-days group (P = 0.046) (Figure 1).
The Doppler ultrasound examination with parameters measured by PSV ratio was found to improve the average PSV ratio of 0.249 at 4 hours after nitrate administration which showed an improvement in flow through the peripheral artery stenosis, although not statistically significant. This is possible because of the acute vasodilation in arterial stiffness after administration of nitrate as a vasodilator.8 On the second visit, a decrease in the PSV ratio was also found when compared with the pre- and post-4-hours group (0.5 and 0.25) with significant statistical evidence. A study by Stoeckelhuber (2003) showed that in the upper extremities vascular angiography, the intravenous administration of nitroglycerin has an effect on vasodilation that can be seen on imaging examinations.9 To date, there is no other study that shows peak systolic velocity after acute ingestion of nitrate.
The principle of nitrate administration is vasodilation. The mechanism includes the conversion of drugs to nitric oxide (NO) on or near the plasma membrane of vascular smooth muscle cells. Then, NO, as in the physiology of NO, will activate guanylate cyclase to produce cyclic guanosine monophosphate (cGMP) and the accumulation of cGMP will cause smooth muscle relaxation. This mechanism of action is also the same as giving nitroprusside. In small doses, nitrates will cause vasodilation in the veins, but if given a higher dose will result in arterial dilatation.6
The administration of a nitrate diet has an effect on increasing endothelial function and reducing microvascular inflammation associated with a decrease in NO production, and inhibiting the increase in leukocyte adhesion to endothelium, which is seen from changes in previously high CRP levels to normal. The administration of nitrate also has an effect on reducing arterial stiffness by restoring carotid dilatation to impaired acetylcholine and reducing oxidative stress markers, including nitrotyrosine. Administration of nitrate in PAD patients increased the time before claudication onset by 18% and increased walking time by 18%.7
The limitation of this study was that it was not placebo controlled, so that the intention to treat design could not be done to ensure the effect of nitrate administration on the results of the 6-minute walk test. Furthermore, this was not a blinded study therefore the possibility of bias could be quite high. n
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no financial relationships or conflicts of interest regarding the content herein. The research is sponsored in part by Dana Masyarakat Faculty of Medicine, Public Health and Nursing Universitas Gadjah Mada Yogyakarta Indonesia fiscal year 2017.
Address for correspondence:
Hariadi Hariawan, MD
Department of Cardiology and Vascular Medicine, Faculty of Medicine, Public Health, and Nursing
Gadjah Mada University
Radiopoetra Building; 2nd Floor, West Wing
Jalan Farmako Sekip Utara, Yogyakarta, Indonesia 55281
Phone/Fax. +62 27 456 0300
Email: firstname.lastname@example.org; email@example.com
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