Elsayed Abo-salem*, Mouhamad Abdallah, Mohamed Effat, Said Alsidawi and Myron Gerson
University of Cincinnati, Department of cardiovascular health and diseases, Cincinnati, OH, USA
Received: 06 March, 2016; Accepted: 13 April, 2016; Published: 15 April, 2016
Elsayed Abo-salem, MD, Division of Cardiovascular Diseases, 231 Albert Sabin Way, Room 3461 MSB, PO Box: 670542, Cincinnati, OH, 45267-0542, USA, Tel: 513-558-4231; Fax: 513-558-0852; E-mail:
Abo-salem E, Abdallah M, Effat M, Alsidawi S, Gerson M (2016) Correlation of Cardiac Sympathetic Nervous System Dysfunction with Diastolic Left Ventricular Dysfunction in Patients with Controlled Hypertension. Arch Clin Hypertens 2(1): 019-023.
© 2016 GAbo-salem E, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
123I mIBG: 123I-metaiodobenzylguanidine; H/M: Heart to Mediastinum ratio; WOR: Washout Rate; NE: Norepinephrine; ACE: Angiotensin Converting Enzyme; ARB: Angiotensin Receptor blocker.
Introduction: Sympathetic nervous system activity is increased in patients with systemic hypertension. Angiotensin converting enzyme inhibitors can effectively control hypertension without a reflex sympathetic stimulation. However, limited data are available about the role of sympathetic dysfunction in the pathophysiology of diastolic dysfunction among patients with controlled hypertension receiving angiotensin converting enzyme inhibitors.
Methods: Twenty four non-diabetic patients with controlled hypertension on angiotensin converting enzyme inhibitors without heart failure and not currently on β-blocker therapy were included in the study. Patients were divided into 2 groups based on diastolic function as defined by echocardiography, group A with diastolic dysfunction (10 subjects) and group B without diastolic dysfunction (14 subjects). Patients underwent ambulatory blood pressure monitoring for assessment of nocturnal blood pressure dip and 123I metaiodobenzylguanidine (123I-MIBG) imaging to determine heart to mediastinum ratio. Plasma norepinephrine levels were measured.
Result: Patients with diastolic dysfunction had a higher level of plasma norepinephrine (0.46 vs 0.26 ng/ml, p=0.01) as compared to patients with normal diastolic function. There was no statistically significant difference in the early or late heart to mediastinum ratio (p=0.5) or the wash-out rate (p=0.9) among the two groups. There was no correlation between plasma norepinephrine and 123I-MIBG uptake. There was a statistically significant inverse correlation between E/A ratio and the log of plasma norepinephrine level (r= - 0.43, P=0.03).
Conclusion: Localized cardiac autonomic dysfunction is not significantly worse in grade I diastolic dysfunction, compared to normal diastolic function, in patients with systemic hypertension that is well-controlled on ACE inhibitors.
123I-metaiodobenzylguanidine (mIBG) is a radioactive analogue of norepinephrine (NE) up taken at the sympathetic nerve ending and can be imaged with planar or Single-photon emission computed tomography images. A reduction of the 123I-MIBG uptake by the nerve ending in the heart compared to mediastinum (heart to mediastinum ratio [H/M]) is a marker of localized cardiac autonomic function. Subjects with hypertension have a lower 123I-MIBG uptake and H/M ratio, and a higher washout rate (WOR) compared to subjects with normal blood pressure . In a previous report by Kuwahara T et al., left ventricular mass index had a negative correlation with H/M ratio on both early and delayed images, and a positive correlation with the WOR . Serum NE level is also elevated in subjects with essential hypertension compared to normal blood pressure, and positively correlates with left ventricular muscle mass index and wall thickness [3,4].
Cardiac autonomic dysfunction plays a pivotal role in the pathogenesis of heart failure with reduced left ventricular ejection fraction. Angiotensin II and α1-adrenergic receptor agonist also induce myocardial hypertrophy and diastolic dysfunction in animal models . The role of sympathetic dysfunction in the pathophysiology of diastolic dysfunction without heart failure among subjects treated with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) is unknown. Among subjects with hypertension controlled with ACE inhibitors or ARBs, our hypothesis suggests a lower 123I-MIBG uptake and H/M ratio, and a higher washout rate (WOR) in cases with grade I diastolic dysfunction compared to cases with normal diastolic function.
Patients and Methods
The study was approved by the Institutional Review Boards/Ethics Committees in the University of Cincinnati, OH (Protocol number; 07011201). Informed consent was obtained from the patients. The study design is prospective and enrolled 24 outpatients, 20 to 80 years of age and both genders, with well-controlled hypertension. Well-controlled hypertension was defined as a systolic blood pressure less than 140 mmHg and diastolic blood pressure less than 90 mmHg on study entry. Patients were on stable antihypertensive regimen including an ACE inhibitor or ARBs for at least 2 months prior to enrollment.
Patients were excluded if they had any of the following: 1) known valvular heart disease of more than mild severity, 2) known coronary artery disease defined by an angiographic coronary artery stenosis greater than or equal to 50% luminal diameter narrowing, acute or previous myocardial infarction, or previous coronary revascularization, 3) left ventricular ejection fraction less than 50%, 4) atrial fibrillation, 5) current treatment with a β-adrenergic blocking drug, diltiazem or verapamil 6) current treatment with a psychoactive or other drug known to alter 123I-MIBG uptake, 7) participation in another research study within the prior 30 days, 8) pregnancy or breast feeding, 9) inability or unwillingness to provide informed consent, 10) diabetes mellitus on medical therapy, 11) iodine allergy
Ambulatory blood pressure monitoring was used to record accurate measurements of systolic, diastolic, and mean blood pressures and quantitation of the nocturnal blood pressure dip. 123I mIBG imaging was performed on all study patients to determine heart to mediastinum (H/M) ratio. A ten minute planar image over the anterior chest was obtained beginning at 15 and 240 minutes after injection of 5 mCi of 123I mIBG. Images were acquired using a dual head Siemens camera with a 159 keV symmetric 20% window. Images were stored in a 64x64 matrix, with use of camera zoom factor as appropriate to achieve a normal pixel size of 6.4 mm (range 6.0 to 6.8). The H/M ratio was measured at 15 minutes and 230 minutes using the ratio of heart counts per pixel to mediastinal counts per pixel without background subtraction.
All echocardiograms were performed on Philips ATL HDI 5000 (Serial# 01414Q). Data were digitally analyzed offline on Camtronics Vericis Software at echo reading workstations. Left ventricular diastolic function was comprehensively assessed using a combination of 2D echo and Doppler indices. Early (E) and late mitral inflow (A) diastolic velocities, E/A ratio, deceleration time and isovolumetric relaxation time were obtained from conventional spectral Doppler. Tissue Doppler of the lateral mitral annulus was used to assess early diastolic annular velocity (Ea). E/Ea ratio was used to assess filling pressures. Echocardiograms were read by an independent echocardiographer. Patients were classified as having normal or abnormal diastolic function -according to American Society of Echocardiography guidelines- based on mitral inflow Doppler, tissue Doppler velocity of the lateral and septal mitral annulus and pulmonary vein Doppler flow. Only cases with normal or grade I diastolic dysfunction were included, while cases with grade II, III or IV diastolic dysfunction and elevated filling pressures were excluded.
The echocardiograms and nuclear images were interpreted by independent operators who were blinded to the results of other studies. Blood samples were collected for measurement of plasma NE (ng/ml) and angiotensin II levels (pg/ml). Patients were rested in a quiet dark room for 30 minutes prior to sample collection. All blood samples were collected on ice, centrifuged at 4 degrees Celsius, and stored frozen. Samples were sent to an independent laboratory for analysis.
Continuous data were reported as means and standard deviations, and unpaired t tests were used for 2 group comparisons. Data that didn’t have a normal distribution were reported as medians and compared with Mann-Whitney statistical tests for 2 groups. Nominal data were expressed as percentages and numbers, and analysis was performed by Chi-square test or Fisher’s exact test for sample sizes less than 5. A probability value <0.05 identified a statistically significant result. Linear regression analysis was used to study the degree of relation between diastolic dysfunction (as measured by E/A ratio) with degree of sympathetic nervous system dysfunction as measured by H/M ratio and plasma norepinephrine level. Correlation analysis was performed between plasma norepinephrine and H/M ratio and WOR. Absolute values of r, less than 0.4, 0.4 to 0.6 and more than 0.6 were considered as weak, moderate, and strong, respectively. Statistical analyses were performed using MedCalc, version 12.5 (MedCalc Software, Ostend, Belgium)
Patients were divided into two groups; group A (grade I diastolic dysfunction, 10 patients) and group B (normal diastolic function, 14 patients). There was no difference between both groups on the baseline characteristics (Table 1). Group A included 10 subjects with grade I diastolic dysfunction but no echocardiographic criteria for elevated left atrium filling pressure. None of the patients had a clinical diagnosis of heart failure or structural heart disease other than left ventricular hypertrophy. The prevalence of co-morbid conditions among study subjects was low and none of the subjects had an estimated glomerular filtration rate less than 60 ml/min. The blood pressure was controlled with ACE inhibitors in 22 subjects or ARBs in 2 subjects. There were no significant differences among groups in regard to serum angiotensin II level (Table 1). The degree of blood pressure control was equal as shown by ambulatory blood pressure monitoring, with no significant difference in the systolic or diastolic blood pressure or nocturnal dip in blood pressure (Table 1).
There were no significant differences between study groups with regard to early 123I-MIBG activity or WOR (Table 1). Patients with diastolic dysfunction had a higher level of plasma NE (0.46 vs 0.26 ng/ml, p=0.01) as compared to patients with normal diastolic function (Table 1). There was a statistically significant inverse correlation between E/A ratio and the log of plasma norepinephrine level (r= - 0.43, P=0.03) (Figure 1). There was no statistically significant correlation between E/A ratio and early H/M ratio (p=0.07) (Figure 2), late H/M ratio (p=0.12) or WOR (p=0.99). There was also no correlation between plasma NE and early or late H/M ratio or WOR (p=0.85, p=0.89, p=0.52).
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