CLINICAL STUDIES
Enhanced activity of sodium–lithium countertransport in patients with cardiac syndrome X
A potential link between cardiac and metabolic syndrome X
Achille Gaspardone, MD, MPhil, FACCa,
Claudio Ferri, MD*,
Filippo Crea, MD, FACCa,
Francesco Versaci, MD, FACCa,
Fabrizio Tomai, MD, FACCa,
Anna Santucci, MD ,
Luigi Chiariello, MD, FACCa and
Pier A. Gioffre, MDa
a Divisione di Cardiochirurgia, Università Tor Vergata, Rome, Italy
* Fondazione Andrea Cesalpino, Università La Sapienza, Rome, Italy
Dipartimento di Medicina Interna e Sanità Pubblica, Università de L’Aquila, L’Aquila, Italy
Manuscript received March 6, 1998;
revised manuscript received July 13, 1998,
accepted August 6, 1998.
Address for correspondence: Dr. Achille Gaspardone, Divisione di Cardiochirurgia, Università Tor Vergata, via Portuense 700, 00149 Rome, Italy
gaspardone{at}tin.it
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Abstract
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Objectives. This study was aimed at assessing both stimulated insulinemia and the sodium–lithium countertransport in a selected group of patients with cardiac syndrome X.
Background. Hyperinsulinemia, which is frequently present in patients with cardiac syndrome X, is often associated with an enhanced activity of the sodium–lithium countertransport, an in vitro marker of sodium–hydrogen exchange.
Methods. Fifteen patients with syndrome X and 14 matched controls were studied. After pharmacological washout, sodium–lithium countertransport was assessed from lithium-loaded red blood cells. Postload insulin levels were evaluated by a double-antibody radioimmunoassay.
Results. Maximal velocity of sodium–lithium countertransport was higher in patients with syndrome X compared to controls (635 ± 200 vs. 324 ± 49 µmol/liter/h, p = 0.001). Fourteen of the 15 patients with syndrome X (93%) presented sodium–lithium countertransport values higher than the mean +2 SD of the control group. At 120 min, 12 patients with syndrome X (80%) had plasma levels of insulin >420 pmol/liter, which corresponds to the mean value +2 SD of controls (p = 0.006).
Conclusions. Both enhanced activity of the sodium–lithium countertransport and stimulated hyperinsulinemia are present in the vast majority of patients with cardiac syndrome X. As enhanced activity of the sodium–lithium countertransport has the potential to cause both glucose intolerance and smooth muscle hyperreactivity, it might represent a common cause of the metabolic and vascular alterations frequently found in syndrome X.
Syndrome X describes patients with anginalike chest pain, noninvasive tests suggestive of myocardial ischemia, and angiographically normal coronary vessels with no evidence of inducible coronary artery spasm, in the absence of known associated cardiovascular disorders. Coronary prearteriolar dysfunction has been proposed as the cause of angina (1,2). Furthermore, hyperinsulinemia is frequently present in patients with syndrome X (3,4), thus suggesting that a metabolic disorder may play a role in the pathogenesis of this syndrome. However, the link between microvascular dysfunction and hyperinsulinemia is still elusive. Interestingly, in about one-third of patients with hypertension or non-insulin-dependent diabetes mellitus, hyperinsulinemia is associated with an enhanced activity of the red blood cell sodium–lithium countertransport (Na-Li CT) (5), which reflects the activity of the sodium–hydrogen exchange (6). The latter plays a major role in intracellular pH and calcium homeostasis (7). Stimulation of sodium–hydrogen exchange determines an increase in intracellular calcium concentration, which, in turn, causes an increase of vascular tone and of reactivity to vasoconstrictor stimuli (8). Early studies, carried out by ourselves (9,10) and others (11), have suggested the presence of an alteration of Na-Li CT and sodium–hydrogen exchange in patients with syndrome X.
In the attempt to understand the causes of syndrome X, red blood cell Na-Li CT activity and stimulated insulinemia were assessed in a well-selected group of consecutive patients with syndrome X.
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Methods
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Study populations.
Patients with syndrome X
This group consisted of 15 consecutive patients (14 women; mean age: 54 ± 6 years) referred to our institution for suspected coronary artery disease, and who met the following criteria: recurrent chest pain at rest and on effort; normal electrocardiogram (ECG) at rest; repeatedly positive exercise test for ischemiclike ECG changes (horizontal or downsloping ST-segment depression >1.5 mm at 60 ms from J-point in at least two contiguous leads lasting more than 1 min); normal left and right ventricular function at rest and no evidence of valvular heart disease nor of myocardial hypertrophy at echocardiography; rest systolic/diastolic blood pressure <140/90 mm Hg in the absence of any medications; no history nor heredity of diabetes; glucose intolerance or hypertension; a recent (<12 months) normal coronary angiogram without evidence of focal or diffuse coronary spasm after intracoronary administration of ergonovine maleate. Thallium-201 scintigraphy was positive for adenosine-induced regional uptake abnormalities in 12 patients. Menopause was present in seven women, five of which had had surgical hysterectomy.
Control group
This group consisted of 14 healthy subjects (13 women; mean age: 47 ± 15 years), without hypertension and/or diabetic heredity, matched to the patients with syndrome X for age, gender and body mass index (Table 1). All controls were recruited among hospital personnel and had normal physical examination, rest ECG, chest radiogram, echocardiogram and exercise stress test. Menopause was present in six women. None were taking medication.
Biochemical analysis.
All biochemical analyses were performed after 10 days of therapy discontinuation.
Sodium–lithium countertransport
The Na-Li CT was assessed from lithium-loaded red blood cells according to the well-accepted method of Canessa et al. (12). Briefly, red blood cells were separated within 3 h by centrifugation for 10 min at 300 g. After separation, red blood cells were then washed three times in a sodium-containing washing solution (in mmol/liter): magnesium chloride 75, sucrose 85, glucose 10, and Tris-MOPS 10, pH 7.4 at 4°C, and the maximum velocity (Vmax) of the Na-Li CT was assessed from the external sodium-stimulated lithium efflux after lithium loading.
Glucose tolerance test
Patients and control subjects followed their habitual diet until the morning of the study day. After an overnight fast, they were given a glucose solution to drink (75 mg in 200 ml water). Venous blood samples were taken during fasting and at 30, 60, 90, 120 and 180 min after the oral glucose load. Plasma glucose levels were assessed by an Analox microsat autoanalyzer using the glucose oxidase/peroxidase method. Immunoreactive insulin levels were determined using Pharmacia Insulin radioimmunoassay kit (Pharmacia Diagnostics AB, Uppsala, Sweden).
Statistical analysis.
Continuous normally distributed data are expressed as mean ± 1 SD and were analyzed by two-tailed unpaired Students’ t test. Data on insulin, which are not normally distributed, are expressed as median and interquartile range. Chi-square test with continuity correction was applied to compare proportions. Repeated measures analysis of variance was used to compare the two groups over time regarding plasma concentrations of glucose and insulin; for a p value <0.05 pairwise comparisons were performed by using Scheffe F test and Mann–Whitney rank-sum test as appropriate. Differences between groups were considered to be statistically significant at a p value <0.05.
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Results
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Sodium–lithium countertransport.
The Na-Li CT was significantly higher in patients with syndrome X compared to controls (635 ± 200 vs. 324 ± 49 µmol/liter/h, p = 0.001) (Fig. 1). Of note, 14 of the 15 patients with syndrome X (93%) presented Na-Li CT values higher than the mean +2 SD of the control group (which correspond to 97.5% of the normal population).
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Figure 1 Sodium–lithium countertransport activity in red blood cells of patients with syndrome X and controls.
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Glucose tolerance test.
Fasting plasma glucose was normal in all patients with syndrome X and controls, and there was no significant difference among the two groups at all sampling points during the tolerance test. Fasting plasma insulin was higher in patients with syndrome X than in controls, but the difference did not reach statistical significance. At 30, 60, 90, 120 and 180 min, plasma insulin levels were higher in patients with syndrome X than in controls (Table 2). At 120 min, 12 patients with syndrome X (80%) had plasma levels of insulin higher than 420 pmol/liter, which corresponds to the mean value +2 SD of our control population (p = 0.006).
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Discussion
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The results of our study indicate that the vast majority of patients with cardiac syndrome X exhibit an enhanced activity of the Na-Li CT, an in vitro marker of the sodium–hydrogen exchange activity (5,6). An influence of medications on Na-Li CT can be ruled out as patients discontinued therapy 10 days before the assay, which was performed on washed red blood cells (13).
The sodium–hydrogen exchange represents the most important cellular system in the control of intracellular pH and plays a major role in the regulation of cellular calcium homeostasis (7). The demonstration of an enhanced activity of the sodium–hydrogen exchange provides a clue to link together the many and apparently different dowels of this intriguing syndrome. Indeed, coronary prearteriolar dysfunction, hyperinsulinemia and the predominance of sympathetic activity commonly observed in patients with syndrome X may all be explained by an enhanced activity of the sodium–hydrogen exchange.
Stimulation of sodium–hydrogen exchange results in alkalinization of intracellular medium and in an increase of intracellular-free calcium concentration (7). These changes, in turn, may cause an increase of coronary microvascular tone and an enhanced susceptibility to vasoconstrictor agents (14). Furthermore, the frequent occurrence of myocardial hypercontractility (15), abnormal esophageal motility (16), airway hyperreactivity (17) and reduced forearm vasodilator reserve (18) in patients with syndrome X may be due to the ubiquity of this pump, which is expressed in cardiac and smooth muscle cells.
An elevated Vmax of red blood cell Na-Li CT, along with its effects on intracellular calcium concentration, has been indicated as a functional abnormality involved in the pathogenesis of insulin resistance and hyperinsulinemia (19). The latter, in turn, may enhance coronary microvascular dysfunction through an alteration of endothelial function (20).
Finally, a number of clinical studies have demonstrated a predominance of sympathetic activity in patients with syndrome X (21), which could enhance coronary prearteriolar dysfunction and sensitize small coronary arteries to vasoconstrictor stimuli (22). Of note, an increase of intracellular sodium concentration, mediated by an enhanced activity of the sodium–hydrogen pump, causes a reduction of type I cathecholamine reuptake with consequent increase of extracellular cathecholamine concentration (23). This observation accords with the recent demonstration of massive regional defects in [123I]metaiodobenzylguanidine myocardial uptake, a cathecholamine analogue, in the majority of patients with syndrome X (24). Furthermore, insulin promotes norepinephrine release within the forearm tissues and enhances vascular responsiveness by activating the sympathetic nervous system (25).
Study limitations.
A limitation of the present study is that quantitative relationship among Na-Li CT, hyperinsulinemia and coronary microvascular dysfunction was not specifically investigated; of note, in patients with cardiac syndrome X, coronary microvascular dysfunction appears to be limited to very small myocardial regions and difficult to investigate quantitatively by using conventional techniques (26,27). Another potential limitation is that the enhanced Na-Li CT may represent an epiphenomenon secondary to impaired physical activity in patients with syndrome X. However, exercise tolerance, a surrogate of physical capacity, was similar in patients with syndrome X and in controls.
Conclusions.
Both enhanced activity of the Na-Li CT and stimulated hyperinsulinemia are present in the vast majority of patients with cardiac syndrome X. As enhanced activity of the Na-Li CT has the potential to cause both glucose intolerance and smooth muscle hyperreactivity, it might represent a common link between metabolic and vascular alterations frequently found in patients with syndrome X.
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Footnotes
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This study was supported by a grant from the Consiglio Nazionale delle Ricerche (CNR 94.00555.PF41/97) and Fondazione Andrea Cesalpino, Rome, Italy.
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References
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Abstract
Methods