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Role of Free Fatty Acids on Cardiac Autonomic Nervous System in Noninsulin-Dependent Diabetic Patients: Effects of Metabolic Control

Department of Geriatric Medicine and Metabolic Diseases, II University of Naples, Naples, Italy 1–80138

Address all correspondence and requests for reprints to: Giuseppe Paolisso, M.D., Department of Geriatric Medicine and Metabolic Diseases, IV Internal Medicine, Piazza Miraglia 2, I-80138 Napoli, Italy. E-mail: gpaoliss{at}tin.it

Abstract

Decreased heart rate variability (HRV) is a risk factor for cardiovascular mortality. Elevated plasma free fatty acid (FFA) levels decrease HRV in healthy subjects. Thus, we investigated the effect of changes in plasma FFA levels on HRV, in non–insulin-dependent diabetes (NIDDM) patients. Thirty NIDDM patients free from diabetic neuropathy volunteered for a study made by two phases. In study A, changes in HRV along a 10% lipid emulsion infusion + heparin (n = 15) or saline infusion (control study; n = 15) were investigated. In study B, all patients (n = 30) underwent further determination of HRV after 3 months of improved metabolic control achieved by intensified insulin treatment. In study A, lipid emulsion infusion increased plasma FFA (P < 0.001) and catecholamine concentrations (P < 0.005), mean arterial blood pressure (P < 0.005), low frequency/high frequency (LF/HF) ratio (P < 0.001). Delta plasma FFA levels correlated with delta LF/HF ratio (r = 0.57; P < 0.02). Along with saline infusion, metabolic and cardiovascular parameters remained unchanged throughout the test. In study B, improved metabolic control lowered fasting plasma glucose (P < 0.005), FFA (P < 0.001), norepinephrine (P < 0.02), epinephrine (P < 0.04), and glycosylated hemoglobin levels (P < 0.001), mean arterial blood pressure(P < 0.05), and LF/HF ratio (P < 0.001). Again percent decline in plasma FFA correlated with the percent change in LF/HF ratio (r = 0.72; P < 0.001). In a multivariate analysis, percent changes in LF/HF ratio were associated with percent changes in plasma FFA independently of gender and percent changes in body mass index, waist/hip ratio, plasma norepinephrine, epinephrine, glycosylated hemoglobin, and daily insulin therapy. Our study demonstrates that changes in plasma FFA levels may have a parallel effect on cardiac sympathetic/parasympathetic nervous system balance in NIDDM patients.

SUDDEN DEATH AND severe arrhythmias very frequently occur in non–insulin-dependent diabetes mellitus (NIDDM) (1, 2, 3, 4). Despite the fact that macroangiopathy might have a pivotal role, it is very likely that imbalanced cardiac sympathetic/parasympathetic nervous system balance might provide a further explication. Indeed, such imbalanced cardiac autonomic nervous system activity has been related to the degree of glucose tolerance and/or occurrence of diabetic neuropathy (5, 6, 7, 8, 9, 10). More recently, a role of plasma free fatty acids (FFA) has been stressed. In fact, elevated plasma FFA levels might disrupt cardiac plasma membrane structure and function and raise intracellular calcium concentration (11, 12), thus affecting cardiac activity. Very recent data have shown that FFA might exaggerate cardiac sympathetic nervous system activity in healthy subjects (13). Thus, one cannot rule out that elevated plasma FFA concentration might be responsible for cardiac sympathetic nervous system overactivity in NIDDM patients.

Heart rate variability (HRV) is a sensitive and reproducible test allowing to investigate cardiac autonomic tone over time (14, 15, 16, 17); furthermore, reduced HRV, expression of exaggerated cardiac sympathetic nervous system, is associated with increased cardiovascular mortality (18, 19, 20, 21, 22, 23, 24). To the best of our knowledge, no studies have still evaluated the possible relationship between plasma FFA concentration and cardiac autonomic tone in NIDDM patients unaffected by diabetic neuropathy.

In light of such evidence, we investigated the effect of an acute increase of FFA as well as of a decline in plasma FFA level because of improved metabolic control on cardiac autonomic tone in NIDDM patients free form diabetic neuropathy.

Experimental Subjects

Thirty NIDDM patients, in poor metabolic control with insulin, volunteered for study. All patients were studied after a 14-h overnight fast and were required to refrain from drinking alcohol in the previous 15 days. No smokers were recruited. Each patient was admitted to our department 2 days before each study and was fed an isocaloric diet with an energy distribution of 50% carbohydrate, 30% fat, and 20% protein. Sodium intake ranged from 4.5 to 6 g/day depending on the weight-maintenance energy requirement. In all patients the presence of diabetic neuropathy was excluded by clinical investigation and Ewing’s test (25). No patients had coronary heart diseases (as demonstrated by treadmill test) or arrhythmias. The mean duration of diabetes was of 4.1 ± 1.1 yr. All subjects gave an informed consent to participate in the study, which was approved by the Ethical Committee of our institution.

Materials and Methods

Anthropometric determinations

Weight and height were measured using a standard technique. Body mass index (BMI) was calculated as body weight (kg)/height (m²). Waist circumference was measured at the midpoint between the lower rib margin and the iliac crest (normally umbilical level) and hip circumference at the level of the trochanter. Both circumferences were measured to the nearest 0.5 cm with a plastic tape and the waist/hip ratio (WHR) was calculated.

Experimental design

The study was made in two phases. Study A was designed for investigating the changes in cardiac autonomic tone following a 10% lipid emulsion infusion + heparin (n = 15) or saline infusion (control study; n = 15). The order of the patients/tests was assigned randomly. At 0700 h a catheter was inserted into the right brachial vein for substance infusions. Respiratory frequency was also calculated over a period of 2 min before the test. Patients with a respiratory rate less than 10 breaths/min (i.e., < 0.15 Hz) were excluded from the study. After 30 min resting, baseline 60-min HRV recording was started. At 0830 h, patients randomized to the intervention group received an infusion of lipid emulsion (10% triglyceride, Intralipid, Pharmacia, Uppsala, Sweden) (infusion rate: 0.4 mL/min) plus heparin (a bolus of 200 U followed by 0.2 U/min x kg body weight) (n = 15). Such infusion lasted 3 h. Patients randomized to the control group received an infusion of 0.9% NaCl (n = 15). In the control study, the saline load was matched to the overall volume and duration of infusions received during the lipid emulsion + heparin tests. In study B, all patients underwent a further determination of HRV after 3 months of improved metabolic control achieved by intensified insulin treatment. Glycosylated hemoglobin (HbA_1c) levels were used as indicator of metabolic control.

Data acquisition and analysis

The software used for data acquisition and analysis has been previously described (26, 27). Briefly, the ambulatory electrocardiographic recording tapes were analyzed using the program Holter AD35 TOP (Remco Italy Cardioline, Milan, Italy). From the surface electrogram, the computer program first calculates the interval thacogram. From section of thacogram of 512 interval values, simple statistics (mean and variance) are calculated. The computer program automatically calculates the autoregressive coefficients necessary to define the power spectral density estimate and prints out the power and frequency of every spectral component. Two major oscillatory components are usually detectable: One synchronous with respiration is described as high frequency (HF) (about 0.25 Hz and varying with respiration), whereas the other, corresponding to the slow waves of arterial pressure, is described as low frequency (LF) (about 0.1 Hz). Each spectral component is presented in normalized form (normalized units), by dividing it by the total power minus the direct current component, if present. Only components >5% of total power were considered significant. LF/HF ratio is considered an index of cardiac sympathetic/parasympathetic tone balance (14, 15)

Analytical techniques

Plasma glucose concentration was determined by the glucose oxidative methods (glucose autoanalyzer, Beckman Coulter, Inc., Fullerton, CA). Plasma fasting high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol levels were determined by routine laboratory methods. Plasma FFA concentrations were determined according to Dole and Meinertz (28). For avoiding in vitro lypolysis, plasma FFA levels were determined in chilled plasma containing EDTA and 0.275 mg/ml paroxon, a lipoprotein lipase inhibitor. Plasma C-peptide levels were determined by RIA methods (Sorin Biomedical, Milan, Italy). Stable HbA1 levels were determined in triplicate according to Compagnucci et al. (29) by ion-exchange microcolumns at constant temperature (18 C). Blood samples for catecholamines were drawn with the patient at rest for at least 30 min and the samples immediately placed on ice, before determination by high performance liquid chromatography.

Statistical analyses

All results are mean ± SD. Delta LF/HF ratio was calculated as difference between pre- and postlipid emulsion. Percentage changes in plasma FFA, HbA_1c, norepinephrine and epinephrine levels, and LF/HF ratio were calculated, with baseline value equal to 100%. Because of the skewed distribution, total power, LF, and HF were logarithmically transformed for statistical testing and back-trans-formed for presentation in Table and in figures. Mean arterial blood pressure (MABP) was calculated as diastolic blood pressure plus one-third pulse pressure. Student’s t test for paired data was used to compare data within each group at baseline and at the end of study as well as between pre- and postmetabolic control. ANOVA allowed the calculating difference between placebo and lipid emulsion. In this latter test, with P < 0.05, a Scheffé’s test was also performed to determine which intervention most influenced the overall difference between groups. Pearson’s simple correlation allowed studying the association between two variables. Multivariate regression analysis tested the independent association and contribution of gender, percent changes in BMI, WHR, plasma FFA, catecholamines, HbA_1c levels, and daily insulin therapy with the dependent variable (LF/HF ratio). A P value of 0.05 was chosen as the level of significance. All calculations were made on an IBM PC computer (SPSS, Inc., Chicago, IL; version 9.0).

Clinical and laboratory characteristics of study patients are reported in Table 1. All patients were adults, slightly overweight and normotensive and in poor metabolic control by insulin therapy as demonstrated by HbA_1c levels. Categorizing the patients in those submitted to lipid infusion and control study, no differences at baseline between two groups in anthropometric, metabolic, and cardiovascular variables were found (Table 1). In baseline condition plasma FFA concentration correlated with LF/HF ratio either in lipid emulsion (r = 0.48, P < 0.01) and in the control group (r = 0.46; P < 0.01).

Lipid emulsion infusion (Table 2)

Lipid emulsion infusion was associated with a significant increase in plasma FFA, triglyceride and catecholamine concentrations, LF component, and LF/HF ratio and a decrease in RR interval, total power, and HF component. At the end of study, plasma triglyceride concentration correlated with LF component (r = 0.49; P < 0.05), LF/HF ratio (r = 0.51; P < 0.04), plasma norepinephrine (r = 0.55; P < 0.04) and epinephrine concentrations (r = 0.58 P < 0.02), and plasma FFA concentrations correlated with LF/HF ratio and plasma norepinephrine and epinephrine concentrations (Fig. 1). No correlation between plasma triglycerides and HF component (r = 0.38 P < 0.1) and MABP (r = 0.40 P < 0.1) was found.

View larger version (10K): [in this window] [in a new window]   Figure 1. Simple correlations between plasma FFA levels and LF/HF ratio and plasma norepinephrine and plasma epinephrine levels (n = 15).

Difference between pre- and postmetabolic control (Table 3)

All patients underwent study B. Improved metabolic control was achieved increasing the number of units of insulin/day from 26 ± 6.3 to 38 ± 6.1 (P < 0.001) and the number of injections/day from two to three. Anthropometric parameters, fasting plasma C-peptide, and LDL and HDL cholesterol levels were similar between pre- and postmetabolic control. In contrast, fasting plasma glucose, FFA, norepinephrine, epinephrine levels, MABP, and HbA_1c levels were significantly lower in postmetabolic control. With regard to cardiovascular parameters, postmetabolic control was associated with a significant increase in RR interval, total power, and HF component and a decrease in LF component and LF/HF ratio. Finally, in postmetabolic control the percent decline in plasma HbA_1c, norepinephrine and epinephrine levels, and LF/HF ratio were positively correlated with percent decline in plasma FFA (Fig. 2). For evaluating the independent association of percentage changes in the LF/HF ratio with percentage changes in FFA a multivariate analysis was made (Table 4). In such a test, the LF/HF ratio was the dependent variable, and gender, percent changes in BMI, WHR, plasma FFA, norepinephrine, epinephrine, HbA_1c levels, and daily insulin therapy were the independent variables. Such a model explained 68% of the variability in the percentage changes in the LF/HF ratio with percentage changes in plasma FFA and norepinephrine and epinephrine levels independently and significantly associated with percentage changes in the LF/HF ratio (Table 4). Furthermore, percentage changes in plasma FFA and norepinephrine and epinephrine levels explained 26%, 17%, and 13%, respectively, of the LF/HF ratio variability.

View larger version (24K): [in this window] [in a new window]   Figure 2. Simple correlations between percent decrease in plasma FFA levels and percent decrease in plasma HbA1c levels, percent decrease in LF/HF ratio, and percent decrease in plasma norepinephrine and epinephrine levels (n = 30).

Our study demonstrates that in raising plasma FFA concentrations, a cardiac sympathetic overactivity occurs in NIDDM patients; in contrast, the same group of patients submitted to an intensified insulin treatment for improving metabolic control had a secondary decline in plasma FFA levels and a decrease in cardiac sympathetic nervous system activity.

Previous studies demonstrated an impaired cardiovascular autonomic activity in NIDDM patients characterized by a reduction in parasympathetic tone with relative increase in sympathetic activity (8, 9). Such imbalanced sympathetic/parasympathetic tone can be responsible for the many cases of sudden death (18, 19, 20, 22) in diabetic patients despite the absence of documented preexisting heart disease (20). The mechanism of action by which diabetes mellitus might affect the autonomic nervous system remains an unsolved problem. Hyperglycemia seems to have a key role through different mechanisms (30). First, hyperglycemia may be a marker of more extensive cardiac damage especially in patients affected by acute myocardial infarction (31). Second, acute hyperglycemia may precipitate an osmotic diuresis (32, 33). Third, hyperglycemia is a reflection of relative insulin deficiency that, in turn, is associated with an increase in plasma FFA concentration secondary to increased lipolysis (34, 35). Thus, hyperglycemia might have a negative impact on cardiac activity through the changes in plasma FFA levels. The toxic effect of FFA on cardiac cell membranes has been recently pointed out (11). Indeed, high concentrations of FFA during myocardial ischemia increase myocardial oxygen demands and reduce myocardial contractility in dogs (12). Nevertheless, several (13, 36, 37, 38, 39), but not all (40), studies have also outlined that elevated plasma FFA levels have a stimulatory effect on sympathetic nervous system. Recently, it has been also demonstrated that elevated plasma FFA concentrations per se may stimulate cardiac sympathetic nervous activity in healthy subjects (13). Such latter effect, confirmed in the present study in NIDDM patients, provides a further pathophysiological mechanism for explicating the relationship between poor metabolic control and sudden death or severe arrhythmias. Our hypothesis is supported by the fact that multivariate analysis of the data of study B showed that changes in plasma FFA concentration were associated with change in LF/HF ratio independently of gender and the changes in BMI, WHR, plasma norepinephrine, epinephrine, HBA_1c levels, and daily insulin therapy. Furthermore, these results are in agreement with the fact that HRV parameters are indices of a heart response to the increased sympathetic nervous system activity rather than of the changes of plasma neurohormone concentrations.

A potential limitation of our study (mainly study B) might regard the results found after improved insulin therapy. In fact, one can argue that the effect observed at cardiac autonomic nervous level might be due to the rise in insulin levels rather than to a decline of plasma FFA levels. Indeed, such a possibility seems unlikely because: 1) elevated plasma insulin levels might stimulate sympathetic nervous system, and we observed a decline in LF/HF ratio following improved metabolic control; 2) previous studies have demonstrated a poor response of the cardiac autonomic nervous system in diabetics and in patients affected by other causes of insulin resistance (26, 41); c) in multivariate analysis the relationship between LF/HF was independent of the change in daily insulin therapy.

A further possible limitation of our study might consist in the fact that Intralipid, which is mainly made by mixing different lipids with a prevalence of FFAs, was delivered to raise plasma FFA concentrations. Indeed, it is widely accepted that a different proportion of saturated/unsaturated fatty acids may differently affect plasma membrane function in such a glucose transport (42, 43). Whether such a difference occurs for plasma cardiac membrane is still unknown, and it should be the object of future investigations.

In conclusion, our study demonstrates that an increase in plasma FFA levels may stimulate cardiac autonomic nervous system, and a decrease in plasma FFA levels has opposite effects. Our results seem especially interesting in light of the data showing that diabetic patients are at high risk for sudden death in the presence of cardiac sympathetic overactivity (44, 45). Further studies should demonstrate that pharmacological tools useful for lowering plasma FFA levels would have beneficial effects upon cardiac autonomic nervous system activity. Furthermore, we emphasize that epidemiological studies in diabetic patients should consider plasma FFA levels as an important variable affecting the cardiac mortality risk.

Received January 24, 2001.

Revised February 23, 2001.

Accepted March 1, 2001.

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